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Daniel LL, Nepal P, Zanussi J, Dickson AL, Straub P, Miller‐Fleming TW, Wei W, Hung AM, Cox NJ, Kawai VK, Mosley JD, Stein CM, Feng Q, Liu G, Tao R, Chung CP. PTPN2 and Leukopenia in Individuals With Normal TPMT and NUDT15 Metabolizer Status Taking Azathioprine. Clin Transl Sci 2025; 18:e70220. [PMID: 40442974 PMCID: PMC12122386 DOI: 10.1111/cts.70220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 02/25/2025] [Accepted: 03/03/2025] [Indexed: 06/02/2025] Open
Abstract
Leukopenia is a common dose-dependent side effect of azathioprine, often leading to drug discontinuation. Variants in TPMT and NUDT15 are associated with azathioprine-induced leukopenia but only explain 25% of cases. Thus, we aimed to identify novel genetic risk factors among TPMT and NUDT15 normal metabolizers through a genome-wide association study (GWAS). Using BioVU, Vanderbilt's electronic health record linked to genetic data, we assembled a discovery cohort of new users of azathioprine. The analysis was conducted in 1184 new users of azathioprine who had no history of prior thiopurine use or an organ transplant. A replication cohort of 521 patients was derived from All of Us, an NIH-funded project that links healthcare data and genetics. The GWAS was adjusted for sex, age, indication (inflammatory bowel disease, systemic lupus erythematosus, other autoimmune condition, or unknown), concurrent use of xanthine oxidase inhibitors (allopurinol or febuxostat) or immunosuppressants, prior TPMT or NUDT15 testing, and 10 principal components of ancestry. In BioVU, 65% of patients were female with a median age of 44 [IQR: 30, 57] and 125 patients developed leukopenia. In All of Us, 69% were female with a median age of 51 [36, 61], and 44 patients developed leukopenia. An intronic variant in PTPN2, rs11664064, reached genome-wide significance in BioVU (OR = 3.61; p = 1.96E-8) and replicated in All of Us (OR = 2.42, p = 0.039). Our finding suggests an association between rs11664064 in PTPN2 and azathioprine-induced leukopenia. PTPN2 plays a role in immune cell development and differentiation, providing a plausible mechanism for this association.
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Affiliation(s)
- Laura L. Daniel
- Department of MedicineUniversity of MiamiCoral GablesFloridaUSA
| | - Puran Nepal
- Department of MedicineUniversity of MiamiCoral GablesFloridaUSA
| | - Jacy Zanussi
- Department of MedicineUniversity of MiamiCoral GablesFloridaUSA
| | - Alyson L. Dickson
- Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Peter Straub
- Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | | | - Wei‐Qi Wei
- Department of Biomedical InformaticsVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Adriana M. Hung
- Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
- VA Tennessee Valley Healthcare SystemNashvilleTennesseeUSA
| | - Nancy J. Cox
- Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Vivian K. Kawai
- Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Jonathan D. Mosley
- Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
- Department of Biomedical InformaticsVanderbilt University Medical CenterNashvilleTennesseeUSA
| | | | - QiPing Feng
- Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
- VA Tennessee Valley Healthcare SystemNashvilleTennesseeUSA
| | - Ge Liu
- Department of Biomedical InformaticsVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Ran Tao
- Department of BiostatisticsVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Cecilia P. Chung
- Department of MedicineUniversity of MiamiCoral GablesFloridaUSA
- Miami VA Healthcare SystemMiamiFloridaUSA
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Rivada AR, de Oliveira JG, Martin-Vazquez Garcia ME, de Brachene AC, Yi X, Junior JC, Zimath P, Van Goethem F, Pattou F, Kerr-Conte J, Buemi A, Mourad N, Eizirik D. The type 1 diabetes candidate genes PTPN2 and BACH2 regulate novel IFN-α-induced crosstalk between the JAK/STAT and MAPKs pathways in human beta cells. RESEARCH SQUARE 2025:rs.3.rs-6079043. [PMID: 40162226 PMCID: PMC11952633 DOI: 10.21203/rs.3.rs-6079043/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease that leads to the progressive loss of pancreatic beta cells. Interferons (IFNs) contribute to the initiation and amplification of beta cell autoimmunity. STAT1 is the main mediator of IFN signalling but little is known on its complex activation processes and role in the progression of beta cell failure. We presently show that two T1D candidate genes (i.e. PTPN2 and BACH2) modulate STAT1 activation via two different pathways, namely the JAK/STAT, involved in the short-term phosphorylation of its tyrosine residue (Y701), and the MAPKs pathway, involved in the long-term phosphorylation of its serine residue (S727). Each STAT1 phosphorylation type can independently induce expression of the chemokine CXCL10, but both residues are necessary for the expression of MHC class I molecules. IFN-α-induced STAT1 activation is dynamic and residue-dependent, being STAT1-Y701 fast (detectable after 4h) but transitory (back to basal by 24h) while STAT1-S727 increases slowly (peak at 48h) and is associated with the long-term effects of IFN-α exposure. These pathways can be chemically dissociated in human beta cells by the use of JAK1/2, TYK2 or JNK1 inhibitors. The present findings provide a novel understanding of the dynamics of STAT1 activation and will be useful to develop novel and hopefully targeted (i.e. favouring individuals with particular polymorphisms) therapies for T1D and other autoimmune diseases.
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Affiliation(s)
- Arturo Roca Rivada
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles
| | | | | | | | | | - Jose Costa Junior
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles
| | - Priscila Zimath
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles
| | - Flore Van Goethem
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles
| | - François Pattou
- Recherche Translationnelle sur le diabète UMR 1190, Université de Lille, Inserm, Institut Pasteur Lille, CHU Lille
| | - Julie Kerr-Conte
- University of Lille, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Lille (CHU Lille), Institute Pasteur Lille
| | - Antoine Buemi
- Pôle de chirurgie expérimentale et transplantation, Institut de recherche expérimentale et clinique, Université catholique de Louvain
| | - Nizar Mourad
- Pôle de chirurgie expérimentale et transplantation, Institut de recherche expérimentale et clinique, Université catholique de Louvain
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Ou Y, Zhao YL, Su H. Pancreatic β-Cells, Diabetes and Autophagy. Endocr Res 2025; 50:12-27. [PMID: 39429147 DOI: 10.1080/07435800.2024.2413064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 07/23/2024] [Accepted: 08/18/2024] [Indexed: 10/22/2024]
Abstract
PURPOSE Pancreatic β-cells play a critical role in regulating plasma insulin levels and glucose metabolism balance, with their dysfunction being a key factor in the progression of diabetes. This review aims to explore the role of autophagy, a vital cellular self-maintenance process, in preserving pancreatic β-cell functionality and its implications in diabetes pathogenesis. METHODS We examine the current literature on the role of autophagy in β-cells, highlighting its function in maintaining cell structure, quantity, and function. The review also discusses the effects of both excessive and insufficient autophagy on β-cell dysfunction and glucose metabolism imbalance. Furthermore, we discuss potential therapeutic agents that modulate the autophagy pathway to influence β-cell function, providing insights into therapeutic strategies for diabetes management. RESULTS Autophagy acts as a self-protective mechanism within pancreatic β-cells, clearing damaged organelles and proteins to maintain cellular stability. Abnormal autophagy activity, either overactive or deficient, can disrupt β-cell function and glucose regulation, contributing to diabetes progression. CONCLUSION Autophagy plays a pivotal role in maintaining pancreatic β-cell function, and its dysregulation is implicated in the development of diabetes. Targeting the autophagy pathway offers potential therapeutic strategies for diabetes management, with agents that modulate autophagy showing promise in preserving β-cell function.
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Affiliation(s)
- Yang Ou
- School of Medicine, Kunming University of Science and Technology, Kunming, Yunnan Province, China
- Faculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming, P.R. China
- Department of Endocrinology and Metabolism, First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, P.R. China
| | - Yan-Li Zhao
- School of Medicine, Kunming University of Science and Technology, Kunming, Yunnan Province, China
| | - Heng Su
- Department of Endocrinology and Metabolism, First People's Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, P.R. China
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Yang Y, Chen Y, Liu C, Wang S, Zhao Y, Cao W, Wang K. Analysis of Exosomal miRNA and Hepatic mRNA Expression in the Dysregulation of Insulin Action in Perimenopausal Mice. J Diabetes Res 2025; 2025:6251747. [PMID: 39823117 PMCID: PMC11737908 DOI: 10.1155/jdr/6251747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 12/04/2024] [Accepted: 12/19/2024] [Indexed: 01/19/2025] Open
Abstract
Introduction: The aim of present study was to evaluate the impact of perimenopause on insulin resistance. Specifically, insulin sensitivity was assessed in a perimenopausal mouse model treated with 4-vinylcyclohexene diepoxide (VCD), together with the changes in exosomal miRNA and hepatic mRNA expression profiles. Methods: Homeostasis model assessment of insulin resistance (HOMA-IR) was utilized to assess the status of insulin resistance, and insulin action was evaluated during menopausal transition. RNA sequencing (RNA-seq) analysis was used to identify altered expression profiles of exosomal miRNAs and hepatic mRNAs. Differentially expressed miRNA (DEM)-differentially expressed gene (DEG) network analyses were also conducted. Furthermore, altered expression levels of these exosomal miRNAs and genes were validated in plasma exosomes and liver tissue of perimenopausal mice. Results: HOMA-IR in VCD-treated mice was significantly increased, and hepatic glycogen was significantly decreased. Key exosomal miRNAs (miR-17-3p, miR-134-5p, miR-700-5p, and miR-6899-3p) and hepatic genes (G6pdx, Ptpn2, Lepr, Kras, and Braf) may be associated with impaired insulin signaling during perimenopause. Conclusion: The perimenopausal period acts as a potential factor in introducing insulin resistance as evidenced by impaired insulin action and altered expression profiles of exosomal miRNAs and hepatic genes. The present study contributes to the understanding that abnormal cargos carried by plasma exosomes, such as miRNAs, may be related to altered expression of the corresponding genes in the liver and abnormal insulin response.
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Affiliation(s)
- Yu Yang
- Department of Endocrinology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yu Chen
- Department of Endocrinology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu Province, China
| | - Changju Liu
- Department of Endocrinology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Su Wang
- Department of Endocrinology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Yijing Zhao
- Department of Endocrinology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Wen Cao
- Department of Endocrinology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Kun Wang
- Department of Endocrinology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
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Saadh MJ, Allela OQB, Abdul Kareem R, Sanghvi G, PadmaPriya G, Thakur R, Kumari M, Gupta S, Khaitov K, Sameer HN, Yaseen A, Athab ZH, Adil M. Psoriasis: Immunological and genetic blueprints driving pathogenesis and potential for personalized therapies. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2025; 28:680-690. [PMID: 40343299 PMCID: PMC12057758 DOI: 10.22038/ijbms.2025.85335.18442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 02/26/2025] [Indexed: 05/11/2025]
Abstract
Psoriasis is a long-lasting inflammatory skin condition that impacts millions globally. The occurrence of this disorder differs significantly across various areas, resulting from a complex interplay of genetic and environmental influences. In psoriasis, the pathogenesis represents a complex interaction of innate and adaptive immunity that plays a significant role in the disease manifestation process. Many genetic factors predispose to psoriasis, which is considered a polygenic disease. Several genes concerning pathways like NF-κB and PI3K/Akt that modulate the amplification of inflammatory response and keratinocyte dysregulation have been elaborated in the light of their differential expression, susceptibility loci, and polymorphisms. Such genetic insights could open a whole new avenue for precision medicine in which biomarkers and gene-targeting therapies are promising options for personalized treatment. This review emphasizes the need for complex investigations into psoriasis, from molecular mechanisms to clinical manifestations, to bridge the gap between basic research and therapeutic development by furthering the understanding of psoriasis and paving the way for innovative treatments addressing skin lesions and systemic effects.
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Affiliation(s)
- Mohamed J. Saadh
- Faculty of Pharmacy, Middle East University, Amman, 11831, Jordan
| | | | | | - Gaurav Sanghvi
- Marwadi University Research Center, Department of Microbiology, Faculty of Science, Marwadi University, Rajkot-360003, Gujarat, India
| | - G. PadmaPriya
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
| | - Rishabh Thakur
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - Mukesh Kumari
- Department of Applied Sciences-Chemistry, NIMS Institute of Engineering & Technology, NIMS University Rajasthan, Jaipur, India
| | - Sofia Gupta
- Department of Chemistry, Chandigarh Engineering College, Chandigarh Group of Colleges-Jhanjeri, Mohali140307, Punjab, India
| | - Kakhramon Khaitov
- Department of Dermatovenerology, Pediatric Dermatovenerology and AIDS, Tashkent Pediatric Medical Institute, Bogishamol Street 223, Tashkent, 100140, Uzbekistan
| | - Hayder Naji Sameer
- College of Pharmacy, National University of Science and Technology, Dhi Qar, 64001, Iraq
| | | | - Zainab H. Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
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Tong KK, Yu YF, Yang XY, Wu JY, Yu R, Tan CC. Does type 1 diabetes serve as a protective factor against inflammatory bowel disease: A Mendelian randomization study. World J Diabetes 2024; 15:1551-1561. [PMID: 39099830 PMCID: PMC11292335 DOI: 10.4239/wjd.v15.i7.1551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 05/02/2024] [Accepted: 05/28/2024] [Indexed: 07/08/2024] Open
Abstract
BACKGROUND The impact of type 1 diabetes (T1D) on inflammatory bowel disease (IBD) remains unclear. AIM To analyze the causal relationship between T1D and IBD using Mendelian ran-domization (MR). METHODS Single nucleotide polymorphisms were sourced from FinnGen for T1D, IBD, ulcerative colitis (UC) and Crohn's disease (CD). Inverse variance-weighted, MR-Egger, and weighted median tests were used to assess exposure-outcome causality. The MR-Egger intercept was used to assess horizontal pleiotropy. Co-chran's Q and leave-one-out method were used to analyze heterogeneity and sensitivity, respectively. RESULTS Our MR analysis indicated that T1D was associated with a reduced risk of IBD [odds ratio (OR): 0.959; 95% confidence interval (CI): 0.938-0.980; P < 0.001] and UC (OR: 0.960; 95%CI: 0.929-0.992; P = 0.015), with no significant association observed in terms of CD risk (OR: 0.966; 95%CI: 0.913-1.022; P = 0.227). The MR-Egger intercept showed no horizontal pleiotropy (P > 0.05). Cochran's Q and leave-one-out sensitivity analyses showed that the results were not heterogeneous (P > 0.05) and were robust. CONCLUSION This MR analysis suggests that T1D serves as a potential protective factor against IBD and UC but is independent of CD.
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Affiliation(s)
- Ke-Ke Tong
- The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, Hunan Province, China
| | - Yun-Feng Yu
- The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, Hunan Province, China
| | - Xin-Yu Yang
- School of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, Hunan Province, China
| | - Jing-Yi Wu
- The Third Hospital, Zhejiang Chinese Medical University, Hangzhou 310005, Zhejiang Province, China
| | - Rong Yu
- The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, Hunan Province, China
| | - Chuan-Chuan Tan
- The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, Hunan Province, China
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Pan Z, Zhang W. Causal relationship between primary sclerosing cholangitis and systemic lupus erythematosus: a bidirectional Mendelian randomization study. Eur J Med Res 2024; 29:351. [PMID: 38943194 PMCID: PMC11212221 DOI: 10.1186/s40001-024-01941-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 06/17/2024] [Indexed: 07/01/2024] Open
Abstract
BACKGROUND Observational studies have found a link between two autoimmune diseases, namely, primary sclerosing cholangitis (PSC) and systemic lupus erythematosus (SLE). However, the relationship remains unclear. METHODS Bidirectional Mendelian randomization (MR) analysis and statistical methods, including inverse variance weighting, weighted median, and MR-Egger tests, were performed using data from genome-wide association studies to detect a causal relationship between PSC and SLE. Sensitivity analyses were subsequently performed to assess the robustness of the results. Univariate MR methods were also investigated. RESULTS Results of MR analysis suggested that PSC was associated with an increased risk for SLE (odds ratio: 1.33, 95% confidence interval: 1.10-1.61, P=0.0039) However, SLE had no significant causal relationship with PSC. CONCLUSION Results of MR analysis revealed that patients with PSC were at an increased risk for SLE, which provides new insights into the relationship between these two autoimmune diseases.
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Affiliation(s)
- Ziwen Pan
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, 430030, China
| | - Weijie Zhang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, 430030, China.
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Zhang B, Sun C, Zhu Y, Qin H, Kong D, Zhang J, Shao B, Li X, Ren S, Wang H, Hao J, Wang H. Upregulation of TCPTP in Macrophages Is Involved in IL-35 Mediated Attenuation of Experimental Colitis. Mediators Inflamm 2024; 2024:3282679. [PMID: 38962170 PMCID: PMC11221972 DOI: 10.1155/2024/3282679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 04/11/2024] [Accepted: 06/01/2024] [Indexed: 07/05/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic intestinal inflammatory disease with complex etiology. Interleukin-35 (IL-35), as a cytokine with immunomodulatory function, has been shown to have therapeutic effects on UC, but its mechanism is not yet clear. Therefore, we constructed Pichia pastoris stably expressing IL-35 which enables the cytokines to reach the diseased mucosa, and explored whether upregulation of T-cell protein tyrosine phosphatase (TCPTP) in macrophages is involved in the mechanisms of IL-35-mediated attenuation of UC. After the successful construction of engineered bacteria expressing IL-35, a colitis model was successfully induced by giving BALB/c mice a solution containing 3% dextran sulfate sodium (DSS). Mice were treated with Pichia/IL-35, empty plasmid-transformed Pichia (Pichia/0), or PBS by gavage, respectively. The expression of TCPTP in macrophages (RAW264.7, BMDMs) and intestinal tissues after IL-35 treatment was detected. After administration of Pichia/IL-35, the mice showed significant improvement in weight loss, bloody stools, and shortened colon. Colon pathology also showed that the inflammatory condition of mice in the Pichia/IL-35 treatment group was alleviated. Notably, Pichia/IL-35 treatment not only increases local M2 macrophages but also decreases the expression of inflammatory cytokine IL-6 in the colon. With Pichia/IL-35 treatment, the proportion of M1 macrophages, Th17, and Th1 cells in mouse MLNs were markedly decreased, while Tregs were significantly increased. In vitro experiments, IL-35 significantly promoted the expression of TCPTP in macrophages stimulated with LPS. Similarly, the mice in the Pichia/IL-35 group also expressed more TCPTP than that of the untreated group and the Pichia/0 group.
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Affiliation(s)
- Baoren Zhang
- Department of General SurgeryTianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
| | - Chenglu Sun
- Department of General SurgeryTianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
| | - Yanglin Zhu
- Department of General SurgeryTianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
| | - Hong Qin
- Department of General SurgeryTianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
| | - Dejun Kong
- School of MedicineNankai University, Tianjin, China
| | - Jingyi Zhang
- Department of General SurgeryTianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
| | - Bo Shao
- Department of General SurgeryTianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
| | - Xiang Li
- Department of General SurgeryTianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
| | - Shaohua Ren
- Department of General SurgeryTianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
| | - Hongda Wang
- Department of General SurgeryTianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
| | - Jingpeng Hao
- Department of General SurgeryTianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
- Department of Anorectal SurgeryTianjin Medical University Second Hospital, Tianjin, China
| | - Hao Wang
- Department of General SurgeryTianjin Medical University General Hospital, Tianjin, China
- Tianjin General Surgery Institute, Tianjin, China
- Tianjin Key Laboratory of Precise Vascular Reconstruction and Organ Function Repair, Tianjin, China
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Xie X, Wu C, Hao Y, Wang T, Yang Y, Cai P, Zhang Y, Huang J, Deng K, Yan D, Lin H. Benefits and risks of drug combination therapy for diabetes mellitus and its complications: a comprehensive review. Front Endocrinol (Lausanne) 2023; 14:1301093. [PMID: 38179301 PMCID: PMC10766371 DOI: 10.3389/fendo.2023.1301093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 11/27/2023] [Indexed: 01/06/2024] Open
Abstract
Diabetes is a chronic metabolic disease, and its therapeutic goals focus on the effective management of blood glucose and various complications. Drug combination therapy has emerged as a comprehensive treatment approach for diabetes. An increasing number of studies have shown that, compared with monotherapy, combination therapy can bring significant clinical benefits while controlling blood glucose, weight, and blood pressure, as well as mitigating damage from certain complications and delaying their progression in diabetes, including both type 1 diabetes (T1D), type 2 diabetes (T2D) and related complications. This evidence provides strong support for the recommendation of combination therapy for diabetes and highlights the importance of combined treatment. In this review, we first provided a brief overview of the phenotype and pathogenesis of diabetes and discussed several conventional anti-diabetic medications currently used for the treatment of diabetes. We then reviewed several clinical trials and pre-clinical animal experiments on T1D, T2D, and their common complications to evaluate the efficacy and safety of different classes of drug combinations. In general, combination therapy plays a pivotal role in the management of diabetes. Integrating the effectiveness of multiple drugs enables more comprehensive and effective control of blood glucose without increasing the risk of hypoglycemia or other serious adverse events. However, specific treatment regimens should be tailored to individual patients and implemented under the guidance of healthcare professionals.
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Affiliation(s)
- Xueqin Xie
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Changchun Wu
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuduo Hao
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Tianyu Wang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Yuhe Yang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Peiling Cai
- School of Basic Medical Sciences, Chengdu University, Chengdu, China
| | - Yang Zhang
- Innovative Institute of Chinese Medicine and Pharmacy, Academy for Interdiscipline, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jian Huang
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Kejun Deng
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
| | - Dan Yan
- Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hao Lin
- Center for Informational Biology, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China
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Fidalgo M, Faria R, Carvalho C, Carvalheiras G, Mendonça D, Farinha F, da Silva BM, Vasconcelos C. Multiple autoimmune syndrome: Clinical, immunological and genotypic characterization. Eur J Intern Med 2023; 116:119-130. [PMID: 37385917 DOI: 10.1016/j.ejim.2023.06.020] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 06/17/2023] [Accepted: 06/20/2023] [Indexed: 07/01/2023]
Abstract
INTRODUCTION The existence of subphenotypes common to several autoimmune diseases (AIDs) suggests a shared physiopathology - autoimmune tautology. Multiple Autoimmune Syndrome (MAS) - the coexistence of three or more AIDs in one person-, best illustrates that polyautoimmunity is more than a coincidence. OBJECTIVES Characterize and compare the monoautoimmune and MAS patients. Understand if clustering of AIDs leads to differences in disease severity, autoantibodies expression or genetic polymorphisms that could be markers for polyautoimmunity. METHODS Currently adult patients were selected from unit cohort. MAS was assumed when ≥3 AIDs were present. 343 patients were included after exclusion criteria: having two AIDs or undetermined diagnosis. Clinical and immunological data were collected from medical files. HLA-DRB1 was genotyped by PCR-SSP methodology and PTPN22(rs2476601) polymorphisms by TaqMan Real Time PCR. Data were analysed using Chi-Square, Fisher's exact tests and logistic regression. Odds ratios (OR) and 95% confidence intervals were calculated. RESULTS In comparison with control population: ELEVATED FREQUENCIES: HLA-DRB1*03 in study cohort (OR=3.68,p<0.001) and in monoautoimmune SLE (OR=2.79,p<0.001) and SjS (OR=8.27,p<0.001); HLA-DRB1*15 in monoautoimmune SjS (OR=2.39,p = 0.011); HLA-DRB1*16 in MAS SLE (OR=2.67,p = 0.031); PTPN22_T in all groups except monoautoimmune SjS and triple positive systemic MAS. DIMINISHED FREQUENCIES HLA-DRB1*11 in study cohort (OR=0.57,p = 0.013), in MAS SLE (OR=0.39,p = 0.031) and monoautoimmune SjS (OR=0.10,p = 0.005); HLA-DRB1*13 in study cohort (OR=0.52,p = 0.001) and in monoautoimmune SLE (OR=0.53,p = 0.009) and SjS (OR=0.38,p = 0.031); HLA-DRB1*14 in study cohort (OR=0.32,p = 0.013) and monoautoimmune SLE (OR=0.21,p = 0.021); SLE group: HLA-DRB1*07 frequency was higher in monoautoimmune patients (OR=0.43,p = 0.023). MAS patients had significantly more NPSLE (OR=2.99,p<0.001), subacute cutaneous lesions (OR=2.30,p = 0.037), muscle&tendon (OR=2.00,p = 0.045), and haematological (OR=3.18,p = 0.006) involvement and Raynaud's (OR=2.94,p<0.001). SjS group: MAS patients had more frequently cryoglobulins (OR=2.96,p = 0.030), low complement (OR=2.43,p = 0.030) and Raynaud's (OR=4.38,p<0.001); monoautoimmune patients had more parotid enlargement (OR=0.12,p<0.001). APS group: MAS patients had more non-thrombotic manifestations (OR=4.69,p = 0.020) and Raynaud's (OR=9.12,p<0.001). Triple positive systemic MAS (SLE+SjS+APS) had more frequently severe kidney involvement (OR=11.67,p = 0.021) and CNS thrombosis (OR=4.44,p = 0.009). Anti-U1RNP increased frequency was transversally attributable to MAS. CONCLUSIONS The coexistence of AIDs contributes to a more severe disease course. We confirmed previously established genetic risk and protection factors and suggest a new protective one - HLA-DRB1*14. HLA-DRB1*07 and anti-U1RNP could be markers for mono and polyautoimmunity, respectively; HLA-DRB1*13 could be a predictor for vascular risk in patients with multiple AIDs. PTPN22(rs2476601) polymorphism could be associated with less severe disease.
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Affiliation(s)
- Mariana Fidalgo
- Internal Medicine Resident, Clinical Internship at Unidade de Imunologia Clínica (2), Portugal.
| | - Raquel Faria
- Unidade de Imunologia Clínica, Centro Hospitalar do Porto, Portugal; Unit for Multidisciplinary Research in Biomedicine, Portugal
| | - Cláudia Carvalho
- Unit for Multidisciplinary Research in Biomedicine, Portugal; Laboratório de Imunogenética, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Portugal
| | | | - Denisa Mendonça
- Departamento de Estudos de Populações, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Portugal; EpiUnit, Instituto de Saúde Pública, Universidade do Porto, Portugal
| | - Fátima Farinha
- Unidade de Imunologia Clínica, Centro Hospitalar do Porto, Portugal; Unit for Multidisciplinary Research in Biomedicine, Portugal
| | - Berta Martins da Silva
- Unit for Multidisciplinary Research in Biomedicine, Portugal; Laboratório de Imunogenética, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Portugal
| | - Carlos Vasconcelos
- Unidade de Imunologia Clínica, Centro Hospitalar do Porto, Portugal; Unit for Multidisciplinary Research in Biomedicine, Portugal
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Zhang L, Yu H, You Q, Rong J, Song C, Sun X. CARD9 gene rs4077515 polymorphism is associated with the susceptibility of Hashimoto's thyroiditis and the development of thyroid cancer. Cancer Epidemiol 2022; 81:102273. [PMID: 36265241 DOI: 10.1016/j.canep.2022.102273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 09/13/2022] [Accepted: 09/30/2022] [Indexed: 11/02/2022]
Abstract
AMIS: Hashimoto's thyroiditis (HT) is the most common type of autoimmune thyroiditis and is a risk factor for the occurrence of thyroid papillary carcinoma (PTC). The study aimed to explore the distribution of CARD9 rs4077515 polymorphism in HT and PTC patients, in order to evaluate its association with the occurrence and development of HT. METHODS 150 HT patients and 120 PTC cases were included. Genotypes of CARD9 rs40775155 polymorphism were sequenced and counted. RESULTS A remarkable increase trend of rs4077515 AA genotype was found in HT cases in comparison with the control group, while GG genotype frequency exhibited a down trend. An excess of A allele was also detected in HT group. HT cases carrying AG and AA genotypes had high risk to receive hormonotherapy and needed a much larger dose. In comparison with HT cases, both AG and AA appeared more frequently in PTC patients, and are associated with the tumor size, LN metastasis and surgical margin. The AG (OR = 2.566, 95 % CI = 1.376-4.786) and AA (OR = 3.040, 95 % CI = 1.525-6.060) genotype carriers had a greater risk of developing PTC. The A allele of rs4077515 polymorphism was a risk allele for the onset of PTC among HT cases (OR = 1.775, 95 % CI = 1.260-2.502). CONCLUSION CARD9 rs4077515 polymorphism is likely to be a risk factor for HT in the Chinese Han population, it also contributes to the development of PTC for HT patients.
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Affiliation(s)
- Limei Zhang
- Endocrine Department, Zibo Central Hospital, Zibo 255000, Shandong, China
| | - Hui Yu
- Endocrine Department, Zibo Central Hospital, Zibo 255000, Shandong, China
| | - Qiang You
- Endocrine Department, Zibo Central Hospital, Zibo 255000, Shandong, China
| | - Jiansheng Rong
- Department of Pathology, Zibo Central Hospital, Zibo 255000, Shandong, China
| | - Chao Song
- Department of Pathology, Zibo Central Hospital, Zibo 255000, Shandong, China
| | - Xiaoyu Sun
- Department of Pathology, Zibo Central Hospital, Zibo 255000, Shandong, China.
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12
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Goh XT, Fong SK, Chai HC, Kee BP, Chua KH. The first association study of Protein Tyrosine Phosphatase, Non-Receptor Type 2 (PTPN2) gene polymorphisms in Malaysian patients with Crohn's disease. Gene 2022; 836:146661. [PMID: 35680018 DOI: 10.1016/j.gene.2022.146661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 04/21/2022] [Accepted: 06/03/2022] [Indexed: 11/20/2022]
Abstract
Crohn's disease (CD) is one of the sub-entities of Inflammatory Bowel Disease which causes chronic inflammation in the gastrointestinal tract. The development of CD has shown to have a strong genetic association. Therefore, the present study aimed to investigate the association between genetic polymorphisms in a susceptible locus of CD, the protein tyrosine phosphatase, non-receptor type 2 (PTPN2) gene and the development of CD in Malaysian patients. A total of 137 CD patients and 274 matched healthy controls were recruited in the present study. Genomic DNA was extracted from the venous blood of participants and five targeted single nucleotide polymorphisms (SNPs) in the PTPN2 gene were genotyped using polymerase chain reaction. Associations between the SNPs and CD were determined using Fisher's exact test and odds ratio. Findings showed that all five selected SNPs were not significantly associated with the development of CD in Malaysian patients, which was in contrast to studies among the European populations. Malaysian Chinese with rs487273 heterozygous G/T genotype was found to have a lower occurrence of CD (P-value = 0.0253; OR = 0.4396). Patients with rs2542152 homozygous T genotype were associated with stricturing behaviour (P-value = 0.0302, OR = 2.9944). The rs16939895 A/G genotype was associated with inflammation at the ileum site (P-value = 0.0387, OR = 2.2105)while homozygous G genotype was associated with colonic CD (P-value = 0.0164, OR = 2.3917). Functional studies of these SNPs are needed to evaluate their potential use as a biomarker for disease phenotypes among Asian patients.
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Affiliation(s)
- Xiang Ting Goh
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
| | - Suh Kuan Fong
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
| | - Hwa Chia Chai
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
| | - Boon Pin Kee
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
| | - Kek Heng Chua
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
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Chatterjee K, Dutta AK, Goel A, Aaron R, Balakrishnan V, Thomas A, John A, Jaleel R, David D, Kurien RT, Chowdhury SD, Simon EG, Joseph AJ, Premkumar P, Pulimood AB. Common polymorphisms of protein tyrosine phosphate non-receptor type 2 gene are not associated with risk of Crohn’s disease in Indian. World J Gastrointest Pathophysiol 2022; 13:114-123. [PMID: 36161231 PMCID: PMC9350595 DOI: 10.4291/wjgp.v13.i4.114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/18/2022] [Accepted: 05/23/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Multiple genetic risk factors for Crohn’s disease (CD) have been identified. However, these observations are not consistent across different populations. The protein tyrosine phosphate non-receptor type 2 (PTPN2) gene plays a role in various aspects of host defense including epithelial barrier function, autophagy, and innate and adaptive immune response. Two common polymorphisms in the PTPN2 gene (rs2542151 and rs7234029) have been associated with risk of CD in Western countries.
AIM To evaluate the association of PTPN2 gene polymorphisms with risk of CD in Indian population.
METHODS We conducted a prospective case-control study. Patients with CD were recruited, and their clinical and investigation details were noted. Controls were patients without organic gastrointestinal disease or other comorbid illnesses. Two common polymorphisms in the PTPN2 gene (rs2542151 and rs7234029) were assessed. DNA was extracted from peripheral blood samples of cases and controls and target DNA was amplified using specific sets of primers. The amplified fragments were digested with restriction enzymes and the presence of polymorphism was detected by restriction fragment length polymorphism. The frequency of alleles was determined. The frequencies of genotypes and alleles were compared between cases and controls to look for significant differences.
RESULTS A total of 108 patients with CD (mean age 37.5 ± 12.7 years, females 42.6%) and 100 controls (mean age 39.9 ± 13.5 years, females 37%) were recruited. For the single nucleotide polymorphism (SNP) rs7234029, the overall frequency of G variant genotype (AG or GG) was noted to be significantly lower in the cases compared to controls (35.2% vs 50%, P = 0.05). For the SNP rs2542151, the overall frequency of G variant genotype (GT or GG) was noted to be similar in cases compared to controls (43.6% vs 47%, P = 0.73). There were no significant differences in minor allele (G) frequency for both polymorphisms between the cases and controls. Both the SNPs had no significant association with age of onset of illness, gender, disease location, disease behaviour, perianal disease, or extraintestinal manifestations of CD.
CONCLUSION Unlike observation form the West, polymorphisms in the PTPN2 gene (rs7234029 and rs2542151) are not associated with an increased risk of developing CD in Indian patients.
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Affiliation(s)
- Kaushik Chatterjee
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Amit Kumar Dutta
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Ashish Goel
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Rekha Aaron
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Vijayalekshmi Balakrishnan
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Ajith Thomas
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Anoop John
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Rajeeb Jaleel
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Deepu David
- Department of Gastroenterology, Christian Medical College, Vellore 632004, Tamil Nadu, India
| | - Reuben Thomas Kurien
- Department of Gastroenterology, Christian Medical College, Vellore 632004, Tamil Nadu, India
| | - SD Chowdhury
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
| | - Ebby George Simon
- Department of Gastroenterology, Christian Medical College, Vellore 632004, Tamil Nadu, India
| | - AJ Joseph
- Department of Gastroenterology, Christian Medical College, Vellore 632004, Tamil Nadu, India
| | - Prasanna Premkumar
- Departments of Biostatistics, Christian Medical College, Vellore 632004, Tamil Nadu, India
| | - Anna B Pulimood
- Department of Gastrointestinal Sciences, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
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Millrine D, Jenkins RH, Hughes STO, Jones SA. Making sense of IL-6 signalling cues in pathophysiology. FEBS Lett 2022; 596:567-588. [PMID: 34618359 PMCID: PMC9673051 DOI: 10.1002/1873-3468.14201] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/29/2021] [Accepted: 09/30/2021] [Indexed: 12/15/2022]
Abstract
Unravelling the molecular mechanisms that account for functional pleiotropy is a major challenge for researchers in cytokine biology. Cytokine-receptor cross-reactivity and shared signalling pathways are considered primary drivers of cytokine pleiotropy. However, reports epitomized by studies of Jak-STAT cytokine signalling identify interesting biochemical and epigenetic determinants of transcription factor regulation that affect the delivery of signal-dependent cytokine responses. Here, a regulatory interplay between STAT transcription factors and their convergence to specific genomic enhancers support the fine-tuning of cytokine responses controlling host immunity, functional identity, and tissue homeostasis and repair. In this review, we provide an overview of the signalling networks that shape the way cells sense and interpret cytokine cues. With an emphasis on the biology of interleukin-6, we highlight the importance of these mechanisms to both physiological processes and pathophysiological outcomes.
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Affiliation(s)
- David Millrine
- Division of Infection & ImmunitySchool of MedicineCardiff UniversityUK
- Systems Immunity University Research InstituteCardiff UniversityUK
- Present address:
Medical Research Council Protein Phosphorylation and Ubiquitylation UnitSir James Black CentreSchool of Life SciencesUniversity of Dundee3rd FloorDundeeUK
| | - Robert H. Jenkins
- Division of Infection & ImmunitySchool of MedicineCardiff UniversityUK
- Systems Immunity University Research InstituteCardiff UniversityUK
| | - Stuart T. O. Hughes
- Division of Infection & ImmunitySchool of MedicineCardiff UniversityUK
- Systems Immunity University Research InstituteCardiff UniversityUK
| | - Simon A. Jones
- Division of Infection & ImmunitySchool of MedicineCardiff UniversityUK
- Systems Immunity University Research InstituteCardiff UniversityUK
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15
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Getahun A. Role of inhibitory signaling in peripheral B cell tolerance*. Immunol Rev 2022; 307:27-42. [PMID: 35128676 PMCID: PMC8986582 DOI: 10.1111/imr.13070] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 01/17/2022] [Indexed: 12/16/2022]
Abstract
At least 20% of B cells in the periphery expresses an antigen receptor with a degree of self-reactivity. If activated, these autoreactive B cells pose a risk as they can contribute to the development of autoimmune diseases. To prevent their activation, both B cell-intrinsic and extrinsic tolerance mechanisms are in place in healthy individuals. In this review article, I will focus on B cell-intrinsic mechanisms that prevent the activation of autoreactive B cells in the periphery. I will discuss how inhibitory signaling circuits are established in autoreactive B cells, focusing on the Lyn-SHIP-1-SHP-1 axis, how they contribute to peripheral immune tolerance, and how disruptions of these circuits can contribute to the development of autoimmunity.
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Affiliation(s)
- Andrew Getahun
- Department of Immunology and Microbiology University of Colorado SOM Aurora Colorado USA
- Department of Immunology and Genomic Medicine National Jewish Health Denver Colorado USA
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16
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Takahashi K, Anno T, Matsuda A, Kimura Y, Kawasaki F, Kaku K, Tomoda K, Kawamoto H, Kaneto H. Case Report: Onset of Type 1 Diabetes Mellitus in a Patient With Ulcerative Colitis and Sjogren's Syndrome Under Euthyroid Hashimoto's Thyroiditis. Front Endocrinol (Lausanne) 2022; 13:836102. [PMID: 35370946 PMCID: PMC8967944 DOI: 10.3389/fendo.2022.836102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 02/08/2022] [Indexed: 12/22/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) is often complicated with some other autoimmune disorders. The complication of various autoimmune disorders is known as autoimmune polyglandular syndrome (APS). Once autoimmune thyroid disease develops, various autoimmune diseases can also occur. Such phenomena are classified as APS types 3A to 3D. In this report, we show the onset of T1DM in a patient with ulcerative colitis (UC) and Sjogren's syndrome. The most important and interesting point in this case is that, if we did not check her thyroid-associated antibodies, we could not have diagnosed her as APS. From the data of this case, we assumed that the patient suffered from APS type 3A, 3B, and 3D variants. This case pointed out very clearly the importance of testing for thyroid-associated antibodies under various autoimmune disease conditions even if the thyroid hormone levels are euthyroid. Moreover, based on the strong linkage between inflammatory bowel disease and T1DM and the compatibility with both T1DM and APS type 3, we think it is possible that Hashimoto's disease is present under complicated conditions together with UC and T1DM. It would be important to repeatedly check for thyroid-associated antibodies even in euthyroid patients, especially under various autoimmune disease conditions.
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Affiliation(s)
- Kaio Takahashi
- Department of General Internal Medicine 1, Kawasaki Medical School, Okayama, Japan
| | - Takatoshi Anno
- Department of General Internal Medicine 1, Kawasaki Medical School, Okayama, Japan
- *Correspondence: Takatoshi Anno,
| | - Akio Matsuda
- Department of General Internal Medicine 1, Kawasaki Medical School, Okayama, Japan
| | - Yukiko Kimura
- Department of General Internal Medicine 1, Kawasaki Medical School, Okayama, Japan
| | - Fumiko Kawasaki
- Department of General Internal Medicine 1, Kawasaki Medical School, Okayama, Japan
| | - Kohei Kaku
- Department of General Internal Medicine 1, Kawasaki Medical School, Okayama, Japan
| | - Koichi Tomoda
- Department of General Internal Medicine 1, Kawasaki Medical School, Okayama, Japan
| | - Hirofumi Kawamoto
- Department of General Internal Medicine 2, Kawasaki Medical School, Okayama, Japan
| | - Hideaki Kaneto
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, Kurashiki, Japan
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17
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Understanding the genetic basis for cholangiocarcinoma. Adv Cancer Res 2022; 156:137-165. [DOI: 10.1016/bs.acr.2022.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Khanbarari F, Ghasemi N, Vakili M, Samadi M. Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with unexplained recurrent pregnancy loss: A case-control study. Int J Reprod Biomed 2021; 19:873-880. [PMID: 34805727 PMCID: PMC8595908 DOI: 10.18502/ijrm.v19i10.9819] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 11/12/2020] [Accepted: 05/25/2021] [Indexed: 11/29/2022] Open
Abstract
Background Lymphoid-tyrosine-phosphatase which is encoded by the protein tyrosine phosphatase non-receptor 22 (PTPN22) gene plays a pivotal role in the regulation of immune responses by dephosphorylating several signaling intermediates of immune cells. Objective Since a balanced immune response has been shown to be important during pregnancy, the purpose of this research was to compare the frequency of the PTPN22 C1858T polymorphism in women with unexplained recurrent pregnancy loss (URPL) vs. in a control group for the first time. Materials and Methods Genomic DNA from 200 individuals with URPL and 200 individuals without URPL (the control group) at the infertility center in Yazd, Iran was isolated using the salting-out method. The PTPN22 C1858T polymorphism of the two groups was analyzed using polymerase chain reaction-restriction fragment length polymorphism. Genotype frequencies in the women with URPL and the fertile control group were compared using the Chi-square test. Results There were significant differences in the frequency of the PTPN22 1858T polymorphism in the URPL individuals vs. the healthy controls, i.e. 32.0% and 21.5%, respectively (p = 0.01). Conclusion Our findings suggest that the PTPN22 1858T polymorphism could play a role in recurrent pregnancy loss. Therefore, genotyping of the mentioned polymorphism can help clinicians to predict the probable risk of URPL.
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Affiliation(s)
- Fateme Khanbarari
- Immunology Department, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Nasrin Ghasemi
- Abortion Research Center, Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Mahmood Vakili
- Health Monitoring Research Center, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Morteza Samadi
- Abortion Research Center, Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Reproductive Immunology Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.,Research Center for Food Hygiene and Safety, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Sharp RC, Brown ME, Shapiro MR, Posgai AL, Brusko TM. The Immunoregulatory Role of the Signal Regulatory Protein Family and CD47 Signaling Pathway in Type 1 Diabetes. Front Immunol 2021; 12:739048. [PMID: 34603322 PMCID: PMC8481641 DOI: 10.3389/fimmu.2021.739048] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 08/31/2021] [Indexed: 12/11/2022] Open
Abstract
Background The pathogenesis of type 1 diabetes (T1D) involves complex genetic susceptibility that impacts pathways regulating host immunity and the target of autoimmune attack, insulin-producing pancreatic β-cells. Interactions between risk variants and environmental factors result in significant heterogeneity in clinical presentation among those who develop T1D. Although genetic risk is dominated by the human leukocyte antigen (HLA) class II and insulin (INS) gene loci, nearly 150 additional risk variants are significantly associated with the disease, including polymorphisms in immune checkpoint molecules, such as SIRPG. Scope of Review In this review, we summarize the literature related to the T1D-associated risk variants in SIRPG, which include a protein-coding variant (rs6043409, G>A; A263V) and an intronic polymorphism (rs2281808, C>T), and their potential impacts on the immunoregulatory signal regulatory protein (SIRP) family:CD47 signaling axis. We discuss how dysregulated expression or function of SIRPs and CD47 in antigen-presenting cells (APCs), T cells, natural killer (NK) cells, and pancreatic β-cells could potentially promote T1D development. Major Conclusions We propose a hypothesis, supported by emerging genetic and functional immune studies, which states a loss of proper SIRP:CD47 signaling may result in increased lymphocyte activation and cytotoxicity and enhanced β-cell destruction. Thus, we present several novel therapeutic strategies for modulation of SIRPs and CD47 to intervene in T1D.
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MESH Headings
- Animals
- Antigen-Presenting Cells/immunology
- Antigen-Presenting Cells/metabolism
- Antigens, Differentiation/genetics
- Antigens, Differentiation/metabolism
- CD47 Antigen/metabolism
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 1/immunology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/therapy
- Genetic Association Studies
- Humans
- Immunotherapy
- Insulin-Secreting Cells/immunology
- Insulin-Secreting Cells/metabolism
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Polymorphism, Genetic
- Receptors, Cell Surface/metabolism
- Receptors, Immunologic/genetics
- Receptors, Immunologic/metabolism
- Signal Transduction
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
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Affiliation(s)
- Robert C. Sharp
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Matthew E. Brown
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Melanie R. Shapiro
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Amanda L. Posgai
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
| | - Todd M. Brusko
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States
- Department of Pediatrics, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, United States
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Muralidharan C, Linnemann AK. β-Cell autophagy in the pathogenesis of type 1 diabetes. Am J Physiol Endocrinol Metab 2021; 321:E410-E416. [PMID: 34338043 PMCID: PMC8461796 DOI: 10.1152/ajpendo.00151.2021] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 07/26/2021] [Accepted: 07/26/2021] [Indexed: 11/22/2022]
Abstract
Type 1 diabetes is an insulin-dependent, autoimmune disease where the pancreatic β cells are destroyed resulting in hyperglycemia. This multifactorial disease involves multiple environmental and genetic factors, and has no clear etiology. Accumulating evidence suggests that early signaling defects within the β cells may promote a change in the local immune milieu leading to autoimmunity. Therefore, many studies have been focused on intrinsic β-cell mechanisms that aid in the restoration of cellular homeostasis under environmental conditions that cause dysfunction. One of these intrinsic mechanisms to promote homeostasis is autophagy, defects which are clearly linked with β-cell dysfunction in the context of type 2 diabetes. Recent studies have now also pointed towards β-cell autophagy defects in the context of type 1 diabetes. In this perspectives review, we will discuss the evidence supporting a role for β-cell autophagy in the pathogenesis of type 1 diabetes, including a potential role for unconventional secretion of autophagosomes/lysosomes in the changing dialogue between the β cell and immune cells.
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Affiliation(s)
- Charanya Muralidharan
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana
| | - Amelia K Linnemann
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana
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21
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Shaw AM, Qasem A, Naser SA. Modulation of PTPN2/22 Function by Spermidine in CRISPR-Cas9-Edited T-Cells Associated with Crohn's Disease and Rheumatoid Arthritis. Int J Mol Sci 2021; 22:8883. [PMID: 34445589 PMCID: PMC8396355 DOI: 10.3390/ijms22168883] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/12/2021] [Accepted: 08/17/2021] [Indexed: 12/02/2022] Open
Abstract
Crohn's Disease (CD) and Rheumatoid Arthritis (RA) share some single nucleotide polymorphisms (SNPs) in protein tyrosine phosphatase non-receptor types 2 and 22 (PTPN2/22). Recently, we reported that clinical samples from CD and RA patients associated with PTPN2:rs478582 or PTPN22:rs2476601 genotypes were linked to overactive immune response and exacerbation of inflammation. Here, we investigated in vitro the effects of these SNPs in Jurkat T-cells using CRISPR-Cas9. All cells were evaluated for PTPN22/22 loss of function and effects on cell response. We measured gene expression via RT-qPCR and cytokines by ELISA. We also measured cell proliferation using a BrdU labeling proliferation ELISA, and T-cell activation using CD-25 fluorescent immunostaining. In PTPN2 SNP-edited cells, PTPN2 expression decreased by 3.2-fold, and proliferation increased by 10.2-fold compared to control. Likewise, expression of PTPN22 decreased by 2.4-fold and proliferation increased by 8.4-fold in PTPN22 SNP-edited cells. IFN-γ and TNF-α secretions increased in both edited cell lines. CD25 expression (cell activation) was 80.32% in PTPN2 SNP-edited cells and 85.82% in PTPN22 SNP-edited cells compared to 70.48% in unedited Jurkat T-cells. Treatment of PTPN2 and PTPN22-edited cells with a maximum 20 μM spermidine restored PTPN2/22 expression and cell response including cell proliferation, activation, and cytokines secretion. Most importantly, the effect of spermidine on edited cells restored normal expression and secretion of IFN-γ and TNF-α. The data clearly demonstrated that edited SNPs in PTPN2 or PTPN22 were associated with reduced gene expression, which resulted in an increase in cell proliferation and activation and overactive immune response. The data validated our earlier observations in CD and RA clinical samples. Surprisingly, spermidine restored PTPN2/22 expression in edited Jurkat T-cells and the consequent beneficial effect on cell response and inflammation. The study supports the use of polyamines dietary supplements for management of CD and in RA patients.
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MESH Headings
- Arthritis, Rheumatoid/genetics
- CRISPR-Cas Systems
- Crohn Disease/genetics
- Gene Expression Regulation, Leukemic/drug effects
- Genetic Predisposition to Disease
- Humans
- Jurkat Cells
- Leukemia, T-Cell/drug therapy
- Leukemia, T-Cell/genetics
- Leukemia, T-Cell/pathology
- Lymphocyte Activation
- Polymorphism, Single Nucleotide
- Protein Tyrosine Phosphatase, Non-Receptor Type 2/antagonists & inhibitors
- Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics
- Protein Tyrosine Phosphatase, Non-Receptor Type 2/metabolism
- Protein Tyrosine Phosphatase, Non-Receptor Type 22/antagonists & inhibitors
- Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics
- Protein Tyrosine Phosphatase, Non-Receptor Type 22/metabolism
- Spermidine/pharmacology
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Affiliation(s)
| | | | - Saleh A. Naser
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 4110 Libra Drive, Orlando, FL 32816, USA; (A.M.S.); (A.Q.)
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22
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Wang YN, Liu S, Jia T, Feng Y, Xu X, Zhang D. T Cell Protein Tyrosine Phosphatase in Glucose Metabolism. Front Cell Dev Biol 2021; 9:682947. [PMID: 34268308 PMCID: PMC8276021 DOI: 10.3389/fcell.2021.682947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 06/09/2021] [Indexed: 11/17/2022] Open
Abstract
T cell protein tyrosine phosphatase (TCPTP), a vital regulator in glucose metabolism, inflammatory responses, and tumor processes, is increasingly considered a promising target for disease treatments and illness control. This review discusses the structure, substrates and main biological functions of TCPTP, as well as its regulatory effect in glucose metabolism, as an attempt to be referenced for formulating treatment strategies of metabolic disorders. Given the complicated regulation functions in different tissues and organs of TCPTP, the development of drugs inhibiting TCPTP with a higher specificity and a better biocompatibility is recognized as a promising therapeutic strategy for diabetes or obesity. Besides, treatments targeting TCPTP in a specific tissue or organ are suggested to be considerably promising.
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Affiliation(s)
- Ya-Nan Wang
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Shiyue Liu
- Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China.,Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tingting Jia
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Yao Feng
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Xin Xu
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Dongjiao Zhang
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
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23
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Shapiro MR, Thirawatananond P, Peters L, Sharp RC, Ogundare S, Posgai AL, Perry DJ, Brusko TM. De-coding genetic risk variants in type 1 diabetes. Immunol Cell Biol 2021; 99:496-508. [PMID: 33483996 PMCID: PMC8119379 DOI: 10.1111/imcb.12438] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 01/08/2021] [Accepted: 01/20/2021] [Indexed: 12/13/2022]
Abstract
The conceptual basis for a genetic predisposition underlying the risk for developing type 1 diabetes (T1D) predates modern human molecular genetics. Over half of the genetic risk has been attributed to the human leukocyte antigen (HLA) class II gene region and to the insulin (INS) gene locus - both thought to confer direction of autoreactivity and tissue specificity. Notwithstanding, questions still remain regarding the functional contributions of a vast array of minor polygenic risk variants scattered throughout the genome that likely influence disease heterogeneity and clinical outcomes. Herein, we summarize the available literature related to the T1D-associated coding variants defined at the time of this review, for the genes PTPN22, IFIH1, SH2B3, CD226, TYK2, FUT2, SIRPG, CTLA4, CTSH and UBASH3A. Data from genotype-selected human cohorts are summarized, and studies from the non-obese diabetic (NOD) mouse are presented to describe the functional impact of these variants in relation to innate and adaptive immunity as well as to β-cell fragility, with expression profiles in tissues and peripheral blood highlighted. The contribution of each variant to progression through T1D staging, including environmental interactions, are discussed with consideration of how their respective protein products may serve as attractive targets for precision medicine-based therapeutics to prevent or suspend the development of T1D.
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Affiliation(s)
- Melanie R Shapiro
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA
| | - Puchong Thirawatananond
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA
| | - Leeana Peters
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA
| | - Robert C Sharp
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA
| | - Similoluwa Ogundare
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA
| | - Amanda L Posgai
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA
| | - Daniel J Perry
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA
| | - Todd M Brusko
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA
- Department of Pediatrics, College of Medicine, Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA
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24
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Armitage LH, Wallet MA, Mathews CE. Influence of PTPN22 Allotypes on Innate and Adaptive Immune Function in Health and Disease. Front Immunol 2021; 12:636618. [PMID: 33717184 PMCID: PMC7946861 DOI: 10.3389/fimmu.2021.636618] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 01/18/2021] [Indexed: 01/18/2023] Open
Abstract
Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) regulates a panoply of leukocyte signaling pathways. A single nucleotide polymorphism (SNP) in PTPN22, rs2476601, is associated with increased risk of Type 1 Diabetes (T1D) and other autoimmune diseases. Over the past decade PTPN22 has been studied intensely in T cell receptor (TCR) and B cell receptor (BCR) signaling. However, the effect of the minor allele on PTPN22 function in TCR signaling is controversial with some reports concluding it has enhanced function and blunts TCR signaling and others reporting it has reduced function and increases TCR signaling. More recently, the core function of PTPN22 as well as functional derangements imparted by the autoimmunity-associated variant allele of PTPN22 have been examined in monocytes, macrophages, dendritic cells, and neutrophils. In this review we will discuss the known functions of PTPN22 in human cells, and we will elaborate on how autoimmunity-associated variants influence these functions across the panoply of immune cells that express PTPN22. Further, we consider currently unresolved questions that require clarification on the role of PTPN22 in immune cell function.
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Affiliation(s)
- Lucas H. Armitage
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, United States
| | - Mark A. Wallet
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, United States
- Immuno-Oncology at Century Therapeutics, LLC, Philadelphia, PA, United States
| | - Clayton E. Mathews
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, United States
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25
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Wang YN, Liu S, Jia T, Feng Y, Zhang W, Xu X, Zhang D. T Cell Protein Tyrosine Phosphatase in Osteoimmunology. Front Immunol 2021; 12:620333. [PMID: 33692794 PMCID: PMC7938726 DOI: 10.3389/fimmu.2021.620333] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 01/04/2021] [Indexed: 12/23/2022] Open
Abstract
Osteoimmunology highlights the two-way communication between bone and immune cells. T cell protein tyrosine phosphatase (TCPTP), also known as protein-tyrosine phosphatase non-receptor 2 (PTPN2), is an intracellular protein tyrosine phosphatase (PTP) essential in regulating immune responses and bone metabolism via dephosphorylating target proteins. Tcptp knockout in systemic or specific immune cells can seriously damage the immune function, resulting in bone metabolism disorders. This review provided fresh insights into the potential role of TCPTP in osteoimmunology. Overall, the regulation of osteoimmunology by TCPTP is extremely complicated. TCPTP negatively regulates macrophages activation and inflammatory factors secretion to inhibit bone resorption. TCPTP regulates T lymphocytes differentiation and T lymphocytes-related cytokines signaling to maintain bone homeostasis. TCPTP is also expected to regulate bone metabolism by targeting B lymphocytes under certain time and conditions. This review offers a comprehensive update on the roles of TCPTP in osteoimmunology, which can be a promising target for the prevention and treatment of inflammatory bone loss.
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Affiliation(s)
- Ya-Nan Wang
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Shiyue Liu
- Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China.,Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Tingting Jia
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Yao Feng
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Wenjing Zhang
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Xin Xu
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Dongjiao Zhang
- Department of Implantology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China.,Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
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26
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Type 1 diabetes: genes associated with disease development. Cent Eur J Immunol 2021; 45:439-453. [PMID: 33658892 PMCID: PMC7882399 DOI: 10.5114/ceji.2020.103386] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 01/02/2020] [Indexed: 11/17/2022] Open
Abstract
Type 1 diabetes (T1D) is the third most common autoimmune disease which develops due to genetic and environmental risk factors. Based on the World Health Organization (WHO) report from 2014 the number of people suffering from all types of diabetes ascended to 422 million, compared to 108 million in 1980. It was calculated that this number will double by the end of 2030. In 2015 American Diabetes Association (ADA) announced that 30.3 million Americans (that is 9.4% of the overall population) had diabetes of which only approximately 1.25 million had T1D. Nowadays, T1D represents roughly 10% of adult diabetes cases total. Multiple genetic abnormalities at different loci have been found to contribute to type 1 diabetes development. The analysis of genome-wide association studies (GWAS) of T1D has identified over 50 susceptible regions (and genes within these regions). Many of these regions are defined by single nucleotide polymorphisms (SNPs) but molecular mechanisms through which they increase or lower the risk of diabetes remain unknown. Genetic factors (in existence since birth) can be detected long before the emergence of immunological or clinical markers. Therefore, a comprehensive understanding of the multiple genetic factors underlying T1D is extremely important for further clinical trials and development of personalized medicine for diabetic patients. We present an overview of current studies and information about regions in the human genome associated with T1D. Moreover, we also put forward information about epigenetic modifications, non-coding RNAs and environmental factors involved in T1D development and onset.
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27
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Clark M, Kroger CJ, Ke Q, Tisch RM. The Role of T Cell Receptor Signaling in the Development of Type 1 Diabetes. Front Immunol 2021; 11:615371. [PMID: 33603744 PMCID: PMC7884625 DOI: 10.3389/fimmu.2020.615371] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 12/15/2020] [Indexed: 12/15/2022] Open
Abstract
T cell receptor (TCR) signaling influences multiple aspects of CD4+ and CD8+ T cell immunobiology including thymic development, peripheral homeostasis, effector subset differentiation/function, and memory formation. Additional T cell signaling cues triggered by co-stimulatory molecules and cytokines also affect TCR signaling duration, as well as accessory pathways that further shape a T cell response. Type 1 diabetes (T1D) is a T cell-driven autoimmune disease targeting the insulin producing β cells in the pancreas. Evidence indicates that dysregulated TCR signaling events in T1D impact the efficacy of central and peripheral tolerance-inducing mechanisms. In this review, we will discuss how the strength and nature of TCR signaling events influence the development of self-reactive T cells and drive the progression of T1D through effects on T cell gene expression, lineage commitment, and maintenance of pathogenic anti-self T cell effector function.
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Affiliation(s)
- Matthew Clark
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Charles J Kroger
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Qi Ke
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Roland M Tisch
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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28
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Sayed S, Nabi AHMN. Diabetes and Genetics: A Relationship Between Genetic Risk Alleles, Clinical Phenotypes and Therapeutic Approaches. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1307:457-498. [PMID: 32314317 DOI: 10.1007/5584_2020_518] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Unveiling human genome through successful completion of Human Genome Project and International HapMap Projects with the advent of state of art technologies has shed light on diseases associated genetic determinants. Identification of mutational landscapes such as copy number variation, single nucleotide polymorphisms or variants in different genes and loci have revealed not only genetic risk factors responsible for diseases but also region(s) playing protective roles. Diabetes is a global health concern with two major types - type 1 diabetes (T1D) and type 2 diabetes (T2D). Great progress in understanding the underlying genetic predisposition to T1D and T2D have been made by candidate gene studies, genetic linkage studies, genome wide association studies with substantial number of samples. Genetic information has importance in predicting clinical outcomes. In this review, we focus on recent advancement regarding candidate gene(s) associated with these two traits along with their clinical parameters as well as therapeutic approaches perceived. Understanding genetic architecture of these disease traits relating clinical phenotypes would certainly facilitate population stratification in diagnosing and treating T1D/T2D considering the doses and toxicity of specific drugs.
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Affiliation(s)
- Shomoita Sayed
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh
| | - A H M Nurun Nabi
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh.
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29
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Elhag DA, Kumar M, Al Khodor S. Exploring the Triple Interaction between the Host Genome, the Epigenome, and the Gut Microbiome in Type 1 Diabetes. Int J Mol Sci 2020; 22:ijms22010125. [PMID: 33374418 PMCID: PMC7795494 DOI: 10.3390/ijms22010125] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 12/13/2020] [Accepted: 12/15/2020] [Indexed: 12/11/2022] Open
Abstract
Type 1 diabetes (T1D) is an auto-immune disorder characterized by a complex interaction between the host immune system and various environmental factors in genetically susceptible individuals. Genome-wide association studies (GWAS) identified different T1D risk and protection alleles, however, little is known about the environmental factors that can be linked to these alleles. Recent evidence indicated that, among those environmental factors, dysbiosis (imbalance) in the gut microbiota may play a role in the pathogenesis of T1D, affecting the integrity of the gut and leading to systemic inflammation and auto-destruction of the pancreatic β cells. Several studies have identified changes in the gut microbiome composition in humans and animal models comparing T1D subjects with controls. Those changes were characterized by a higher abundance of Bacteroides and a lower abundance of the butyrate-producing bacteria such as Clostridium clusters IV and XIVa. The mechanisms by which the dysbiotic bacteria and/or their metabolites interact with the genome and/or the epigenome of the host leading to destructive autoimmunity is still not clear. As T1D is a multifactorial disease, understanding the interaction between different environmental factors such as the gut microbiome, the genetic and the epigenetic determinants that are linked with the early appearance of autoantibodies can expand our knowledge about the disease pathogenesis. This review aims to provide insights into the interaction between the gut microbiome, susceptibility genes, epigenetic factors, and the immune system in the pathogenesis of T1D.
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30
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Sur S. In silico analysis reveals interrelation of enriched pathways and genes in type 1 diabetes. Immunogenetics 2020; 72:399-412. [PMID: 32860078 DOI: 10.1007/s00251-020-01177-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 08/25/2020] [Indexed: 02/07/2023]
Abstract
Type 1 diabetes (T1D) is a multifactorial, polygenic complex autoimmune disease damaging pancreatic islet β cells. Numerous genes linked to T1D have been discovered through genetical studies, GWAS and polymorphisms. Most genetical studies focused on independent genes while others overemphasized on SNPs. Here, a collective analysis of documented T1D-associated genes was performed using bioinformatics tools. Enriched biological pathways, functions, enrichment clustering, networks and interactomes were analysed. Besides, meta-analyses of T1D-associated genes and T1D-related genes from SNPs were investigated to find common genes, pathways, enrichment and interrelationships. Notable enriched pathways comprised of cytokine-mediated signalling, cytokine production, interferon gamma production, myeloid leukocyte activation, activation of immune response, lymphocyte activation, adaptive immune response, Th17 cell differentiation etc. Enrichment analysis of T1D-associated genes emphasized the role of immune-linked machineries in metabolism, disease progression and aetiology of type 1 diabetes. Interactome analysis revealed overrepresentation of T1D-associated genes compared with T1D-related genes from SNPs. MCODE components highlighted the significance of pathways linked to vitamin D metabolism, signalling by interleukins, toll-like receptors, chemokines, PD-1, NOTCH, antigen processes etc. About 153 genes from MCODE complexes representing enriched pathways of T1D-associated genes and T1D-related genes from SNPs play a crucial role and may be important for further investigations. The information may be valuable for designing precision medicine-based therapeutics.
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Affiliation(s)
- Saubashya Sur
- Postgraduate Department of Botany, Life Sciences Block, Ramananda College, Bishnupur, West Bengal, 722122, India.
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31
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Abstract
PURPOSE OF REVIEW Diabetes is a spectrum of clinical manifestations, including latent autoimmune diabetes in adults (LADA). However, it has been questioned whether LADA exists or simply is a group of misclassified type 1 diabetes (T1D) and type 2 diabetes (T2D) patients. This review will provide an updated overview of the genetics of LADA, highlight what genetics tell us about LADA as a diabetes subtype, and point to future directions in the study of LADA. RECENT FINDINGS Recent studies have verified the genetic overlap between LADA and both T1D and T2D and have contributed identification of a novel LADA-specific locus, namely, PFKFB3, and subtype-specific signatures in the HLA region. Genetic risk scores comprising T1D-risk variants have been shown to be a promising tool for discriminating diabetes subtypes and identifying patients rapidly progressing to insulin dependence. Genetic data support the existence of LADA, but further studies are needed to fully determine the place of LADA in the diabetes spectrum.
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Affiliation(s)
- Mette K Andersen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen N, Denmark.
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32
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Patel AD, Pasha TY, Lunagariya P, Shah U, Bhambharoliya T, Tripathi RKP. A Library of Thiazolidin-4-one Derivatives as Protein Tyrosine Phosphatase 1B (PTP1B) Inhibitors: An Attempt To Discover Novel Antidiabetic Agents. ChemMedChem 2020; 15:1229-1242. [PMID: 32390300 DOI: 10.1002/cmdc.202000055] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 04/28/2020] [Indexed: 01/18/2023]
Abstract
Protein tyrosine phosphatase 1B (PTP1B) is an important target for the treatment of diabetes. A series of thiazolidin-4-one derivatives 8-22 was designed, synthesized and investigated as PTP1B inhibitors. The new molecules inhibited PTP1B with IC50 values in the micromolar range. 5-(Furan-2-ylmethylene)-2-(4-nitrophenylimino)thiazolidin-4-one (17) exhibited potency with a competitive type of enzyme inhibition. structure-activity relationship studies revealed various structural facets important for the potency of these analogues. The findings revealed a requirement for a nitro group-including hydrophobic heteroaryl ring for PTP1B inhibition. Molecular docking studies afforded good correlation with experimental results. H-bonding and π-π interactions were responsible for optimal binding and effective stabilization of virtual protein-ligand complexes. Furthermore, in-silico pharmacokinetic properties of test compounds predicted their drug-like characteristics for potential oral use as antidiabetic agents.Additionally, a binding site model demonstrating crucial pharmacophoric characteristics influencing potency and binding affinity of inhibitors has been proposed, which can be employed in the design of future potential PTP1B inhibitors.
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Affiliation(s)
- Ashish D Patel
- Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, Changa, Anand, 388421, India.,Department of Pharmaceutical Chemistry Parul Institute of Pharmacy, Parul University, Vadodara, Gujarat, 391760, India
| | - Thopallada Y Pasha
- Shri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, B G Nagara, Karnataka, 571448, India
| | - Paras Lunagariya
- Smt. R. D. Gardi B. Pharmacy College, Rajkot, Gujarat, 360110, India
| | - Umang Shah
- Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, Changa, Anand, 388421, India
| | - Tushar Bhambharoliya
- Wilson College of Textiles, North Carolina State University, North Carolina, 27606, USA
| | - Rati K P Tripathi
- Department of Pharmaceutical Science Sushruta School of Medical and Paramedical Sciences, Assam University (A Central University), Silchar, Assam, 788011, India.,Department of Pharmaceutical Chemistry Parul Institute of Pharmacy, Parul University, Vadodara, Gujarat, 391760, India
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Yahaya T, Salisu T. Genes predisposing to type 1 diabetes mellitus and pathophysiology: a narrative review. MEDICAL JOURNAL OF INDONESIA 2020; 29:100-9. [DOI: 10.13181/mji.rev.203732] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 01/23/2020] [Indexed: 02/08/2023] Open
Abstract
The possibility of targeting the causal genes along with the mechanisms of pathogenically complex diseases has led to numerous studies on the genetic etiology of some diseases. In particular, studies have added more genes to the list of type 1 diabetes mellitus (T1DM) suspect genes, necessitating an update for the interest of all stakeholders. Therefore this review articulates T1DM suspect genes and their pathophysiology. Notable electronic databases, including Medline, Scopus, PubMed, and Google-Scholar were searched for relevant information. The search identified over 73 genes suspected in the pathogenesis of T1DM, with human leukocyte antigen, insulin gene, and cytotoxic T lymphocyte-associated antigen 4 accounting for most of the cases. Mutations in these genes, along with environmental factors, may produce a defective immune response in the pancreas, resulting in β-cell autoimmunity, insulin deficiency, and hyperglycemia. The mechanisms leading to these cellular reactions are gene-specific and, if targeted in diabetic individuals, may lead to improved treatment. Medical practitioners are advised to formulate treatment procedures that target these genes in patients with T1DM.
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Takeuchi Y, Hirota K, Sakaguchi S. Impaired T cell receptor signaling and development of T cell-mediated autoimmune arthritis. Immunol Rev 2020; 294:164-176. [PMID: 31944330 DOI: 10.1111/imr.12841] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 12/31/2019] [Indexed: 12/22/2022]
Abstract
Mutations of the genes encoding T-cell receptor (TCR)-proximal signaling molecules, such as ZAP-70, can be causative of immunological diseases ranging from T-cell immunodeficiency to T-cell-mediated autoimmune disease. For example, SKG mice, which carry a hypomorphic point mutation of the Zap-70 gene, spontaneously develop T-cell-mediated autoimmune arthritis immunopathologically similar to human rheumatoid arthritis (RA). The Zap-70 mutation alters the sensitivity of developing T cells to thymic positive/negative selection by self-peptides/MHC complexes, shifting self-reactive TCR repertoire to include a dominant arthritogenic specificity and also affecting thymic development and function of autoimmune suppressive regulatory T (Treg) cells. Polyclonal self-reactive T cells, including potentially arthritogenic T cells, thus produced by the thymus recognize self-peptide/MHC complexes on antigen-presenting cells (APCs) in the periphery and stimulate them to produce cytokines including IL-6 to drive the arthritogenic T cells to differentiate into arthritogenic T-helper 17 (Th17) cells. Insufficient Treg suppression or activation of APCs via microbial and other environmental stimuli evokes arthritis by activating granulocyte-macrophage colony-stimulating factor-secreting effector Th17 cells, mediating chronic bone-destructive joint inflammation by activating myeloid cells, innate lymphoid cells, and synoviocytes in the joint. These findings obtained from the study of SKG mouse arthritis are instrumental in understanding how arthritogenic T cells are produced, become activated, and differentiate into effector T cells mediating arthritis, and may help devising therapeutic measures targeting autoimmune pathogenic Th17 cells or autoimmune-suppressing Treg cells to treat and prevent RA.
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Affiliation(s)
- Yusuke Takeuchi
- Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.,Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Keiji Hirota
- Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.,Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Shimon Sakaguchi
- Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan.,Laboratory of Experimental Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
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35
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Ramu D, Perumal V, Paul SFD. Association of common type 1 and type 2 diabetes gene variants with latent autoimmune diabetes in adults: A meta-analysis. J Diabetes 2019; 11:484-496. [PMID: 30456822 DOI: 10.1111/1753-0407.12879] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 11/09/2018] [Accepted: 11/13/2018] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND The aim of this meta-analysis was to determine the association of common type 1 diabetes (T1D) and type 2 diabetes (T2D) gene variants (protein tyrosine phosphatase non-receptor 22 [PTPN22] rs2476601C/T, insulin [INS] rs689A/T and transcription factor 7-like 2 [TCF7L2] rs7903146C/T) with latent autoimmune diabetes in adults (LADA). METHODS A systematic search of electronic databases was conducted up to 2017 and data from 16 independent case-control studies for three gene variants were pooled. The pooled allele and genotype frequencies for each T1D and T2D gene variant were used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Heterogeneity tests and evaluation of publication bias were performed for all studies. RESULTS In all, 8869 cases and 20 829 controls pooled from 16 case-control studies were included in the analysis. For rs2476601, a significant association was found for homozygote TT (OR 2.67; 95% CI 1.92-3.70; P < 0.0001), heterozygote CT (OR 1.61; 95% CI 1.44-1.79; P < 0.0001), and the T allele (OR 1.62; 95% CI 1.48-1.78; P < 0.0001). Overall, a significant inverse association was observed for rs689 in the TT genotype (OR 0.43; 95% CI 0.30-0.64; P < 0.0001), AT genotype (OR 0.53; 95% CI 0.45-0.62; P < 0.0001), and T allele (OR 0.61; 95% CI 0.52-0.71; P < 0.0001). For the rs7903146 polymorphism, the T allele (OR 1.19; 95% CI 1.00-1.40; P = 0.04) may be associated with the risk of LADA. CONCLUSION The rs2476601C/T, rs689A/T, and rs7903146C/T polymorphisms were found to be associated with the risk of LADA, thereby indicating that, genetically, LADA could be an admixture of both T1D and T2D.
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Affiliation(s)
- Deepika Ramu
- Department of Human Genetics, Sri Ramachandra Institute of Higher Education and Research, Chennai, India
| | | | - Solomon F D Paul
- Department of Human Genetics, Sri Ramachandra Institute of Higher Education and Research, Chennai, India
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Activation of naïve CD4 + T cells re-tunes STAT1 signaling to deliver unique cytokine responses in memory CD4 + T cells. Nat Immunol 2019; 20:458-470. [PMID: 30890796 PMCID: PMC7610646 DOI: 10.1038/s41590-019-0350-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 02/14/2019] [Indexed: 12/31/2022]
Abstract
The cytokine IL-6 controls the survival, proliferation and effector characteristics of lymphocytes through activation of the transcription factors STAT1 and STAT3. While STAT3 activity is an ever-present feature of IL-6 signaling in CD4+ T cells, prior T-cell receptor activation limits the IL-6 control of STAT1 in effector and memory populations. Here we show that STAT1 phosphorylation in response to IL-6 was regulated by protein tyrosine phosphatases (PTPN2, PTPN22) expressed in response to the activation of naïve CD4+ T cells. Transcriptomic and chromatin immunoprecipitation-sequencing of IL-6 responses in naïve and effector memory CD4+ T cells showed how the suppression of STAT1 activation shaped the functional identity and effector characteristics of memory CD4+ T cells. Thus, protein tyrosine phosphatases induced by activation of naïve T cells determined the way activated or memory CD4+ T cells sensed and interpreted cytokine signals.
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Increased Risk of Diabetes in Inflammatory Bowel Disease Patients: A Nationwide Population-based Study in Korea. J Clin Med 2019; 8:jcm8030343. [PMID: 30862129 PMCID: PMC6463263 DOI: 10.3390/jcm8030343] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 03/01/2019] [Accepted: 03/07/2019] [Indexed: 12/26/2022] Open
Abstract
The association of diabetes with inflammatory bowel disease (IBD) remains unclear. The risk of diabetes in patients with IBD compared with non-IBD controls was investigated. Using the National Health Insurance database of South Korea, 8070 patients with IBD based on the International Classification of Disease 10th revision (ICD-10) codes and rare intractable disease codes for Crohn’s disease (CD) and ulcerative colitis (UC) were compared with 40,350 non-IBD individuals (2010–2014). Newly diagnosed diabetes identified using ICD-10 codes and the prescription of anti-diabetic medication by the end of the follow-up period (2016) was investigated. During a mean follow-up of 5.1 years, the incidence of diabetes in patients with IBD was significantly higher compared with controls after adjusting for serum glucose levels and steroid use (23.19 vs. 22.02 per 1000 person-years; hazard ratio (HR), 1.135; 95% confidence interval (CI), 1.048–1.228). The risk of diabetes was significantly higher in patients with CD (HR, 1.677; 95% CI, 1.408–1.997), but not in UC (HR, 1.061; 95% CI, 0.973–1.156). The effect of IBD on the development of diabetes was significantly more prominent in younger patients (p < 0.001). Patients with CD are at a higher risk of diabetes. Regular monitoring for diabetes is recommended, even in younger CD patients who do not use steroid medication.
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38
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Mei Q, Liu C, Zhang X, Li Q, Jia X, Wu J, Sun W, Qiao Y, Wu J, Li Y, Yu J, Fu S, Xu L. Associations between PTPN2 gene polymorphisms and psoriasis in Northeastern China. Gene 2019; 681:73-79. [PMID: 30266502 DOI: 10.1016/j.gene.2018.09.047] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 09/25/2018] [Indexed: 02/06/2023]
Abstract
Psoriasis is a chronic immune-mediated disease with a complex etiology involving various genetic and immunological factors as well as environmental factors. Psoriasis is thought to be mediated by T-cells polarized to a Th17 fate. PTPN2 encodes the T-cell protein tyrosine phosphatase, which acts as a negative regulator of the JAK/STAT signaling pathways downstream of cytokines and plays a prominent role in T-cell activation, signaling and/or effector function. To evaluate the association between PTPN2 gene polymorphisms and psoriasis in the Northeastern Chinese population. A case-control study was conducted, and 398 patients with psoriasis and 397 healthy controls were genotyped for thirteen genetic polymorphisms in PTPN2. Allele analysis revealed that rs2847297, rs657555 and rs482160 polymorphisms were significantly associated with psoriasis (p = 0.0018, p = 0.0017 and p = 0.0086, respectively). Genotype analysis also revealed that these polymorphisms were significantly associated with psoriasis under different models (codominant, dominant and recessive models) (p < 0.05). In this study, three haplotypes (H1, H7 and H11) were also found to be associated with psoriasis (p = 0.0015, p = 0.0094, and p = 0.0124, respectively). These results indicate that PTPN2 genetic polymorphisms are associated with psoriasis in the Northeastern Chinese population.
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Affiliation(s)
- Qingbu Mei
- Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China; Department of Genetics, Qiqihar Medical University, Qiqihar 161000, China
| | - Chang Liu
- Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China
| | - Xuelong Zhang
- Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China
| | - Qiuyan Li
- Editorial Department of International Journal of Genetics, Harbin Medical University, Harbin 150081, China
| | - Xueyuan Jia
- Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China
| | - Jie Wu
- Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China
| | - Wenjing Sun
- Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China
| | - Yuandong Qiao
- Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China
| | - Jiawei Wu
- Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China
| | - Yuzhen Li
- Department of dermatology, the Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Jingcui Yu
- Scientific Research Centre, the Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China
| | - Songbin Fu
- Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China; Key Laboratory of Medical Genetics, (Harbin Medical University), Heilongjiang Higher Education Institutions, Harbin 150081, China.
| | - Lidan Xu
- Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China.
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The diabetes pandemic and associated infections: suggestions for clinical microbiology. ACTA ACUST UNITED AC 2018; 30:1-17. [PMID: 30662163 PMCID: PMC6319590 DOI: 10.1097/mrm.0000000000000155] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 10/08/2017] [Indexed: 12/15/2022]
Abstract
There are 425 million people with diabetes mellitus in the world. By 2045, this figure will grow to over 600 million. Diabetes mellitus is classified among noncommunicable diseases. Evidence points to a key role of microbes in diabetes mellitus, both as infectious agents associated with the diabetic status and as possible causative factors of diabetes mellitus. This review takes into account the different forms of diabetes mellitus, the genetic determinants that predispose to type 1 and type 2 diabetes mellitus (especially those with possible immunologic impact), the immune dysfunctions that have been documented in diabetes mellitus. Common infections occurring more frequently in diabetic vs. nondiabetic individuals are reviewed. Infectious agents that are suspected of playing an etiologic/triggering role in diabetes mellitus are presented, with emphasis on enteroviruses, the hygiene hypothesis, and the environment. Among biological agents possibly linked to diabetes mellitus, the gut microbiome, hepatitis C virus, and prion-like protein aggregates are discussed. Finally, preventive vaccines recommended in the management of diabetic patients are considered, including the bacillus calmette-Guerin vaccine that is being tested for type 1 diabetes mellitus. Evidence supports the notion that attenuation of immune defenses (both congenital and secondary to metabolic disturbances as well as to microangiopathy and neuropathy) makes diabetic people more prone to certain infections. Attentive microbiologic monitoring of diabetic patients is thus recommendable. As genetic predisposition cannot be changed, research needs to identify the biological agents that may have an etiologic role in diabetes mellitus, and to envisage curative and preventive ways to limit the diabetes pandemic.
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Pike KA, Tremblay ML. Protein Tyrosine Phosphatases: Regulators of CD4 T Cells in Inflammatory Bowel Disease. Front Immunol 2018; 9:2504. [PMID: 30429852 PMCID: PMC6220082 DOI: 10.3389/fimmu.2018.02504] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 10/10/2018] [Indexed: 12/12/2022] Open
Abstract
Protein tyrosine phosphatases (PTPs) play a critical role in co-ordinating the signaling networks that maintain lymphocyte homeostasis and direct lymphocyte activation. By dephosphorylating tyrosine residues, PTPs have been shown to modulate enzyme activity and both mediate and disrupt protein-protein interactions. Through these molecular mechanisms, PTPs ultimately impact lymphocyte responses to environmental cues such as inflammatory cytokines and chemokines, as well as antigenic stimulation. Mouse models of acute and chronic intestinal inflammation have been shown to be exacerbated in the absence of PTPs such as PTPN2 and PTPN22. This increase in disease severity is due in part to hyper-activation of lymphocytes in the absence of PTP activity. In accordance, human PTPs have been linked to intestinal inflammation. Genome wide association studies (GWAS) identified several PTPs within risk loci for inflammatory bowel disease (IBD). Therapeutically targeting PTP substrates and their associated signaling pathways, such as those implicated in CD4+ T cell responses, has demonstrated clinical efficacy. The current review focuses on the role of PTPs in controlling CD4+ T cell activity in the intestinal mucosa and how disruption of PTP activity in CD4+ T cells can contribute to intestinal inflammation.
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Affiliation(s)
- Kelly A Pike
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada.,Inception Sciences Canada, Montréal, QC, Canada
| | - Michel L Tremblay
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada.,Rosalind and Morris Goodman Cancer Centre, McGill University, Montréal, QC, Canada.,Division of Experimental Medicine, Department of Medicine, McGill University, Montréal, QC, Canada.,Department of Biochemistry, McGill University, Montréal, QC, Canada
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41
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Capucilli P, Cianferoni A, Grundmeier RW, Spergel JM. Comparison of comorbid diagnoses in children with and without eosinophilic esophagitis in a large population. Ann Allergy Asthma Immunol 2018; 121:711-716. [PMID: 30194971 DOI: 10.1016/j.anai.2018.08.022] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 08/04/2018] [Accepted: 08/31/2018] [Indexed: 01/16/2023]
Abstract
BACKGROUND Previous reports suggest a higher prevalence of comorbid diseases in patients with eosinophilic esophagitis (EoE), although few have systematically quantified comorbidities in pediatric patients. OBJECTIVE To define the rate of comorbid diagnoses in pediatric EoE patients compared with rates in those without EoE. METHODS Retrospective cross-sectional review of electronic medical records for patients seen in a single large pediatric primary care network between January 2007 and December 2016 (n = 456,148). International Classification of Diseases, Ninth and Tenth Revision codes were used to determine prevalence rates for coexisting diagnoses. RESULTS A total of 428 patients held a diagnosis for EoE. Significant differences in rate of comorbid diseases included allergic rhinoconjunctivitis (60.0% of EoE cohort vs 17.4% of non-EoE cohort, P < .0001); asthma (59.8% of EoE, 21.4% of non-EoE, P < .0001); atopic dermatitis (17.8% of EoE, 6.6% of non-EoE, P < .0001); adrenal insufficiency (2.6% of EoE, 0.4% of non-EoE, P < .0001); autism spectrum disorder (7.5% of EoE, 1.9% of non-EoE, P < .0001); celiac disease (5.6% of EoE, 0.9% of non-EoE, P < .0001); connective tissue diseases (1.4% of EoE, 0.1% of non-EoE, P < .0001); cystic fibrosis (0.9% of EoE, 0.05% of non-EoE, P < .0001); inflammatory bowel disease (0.7% of EoE, 0.2% of non-EoE, P = .03); type 1 diabetes mellitus (1.2% of EoE, 0.3% of non-EoE, P = .0069). CONCLUSION Children with EoE have markedly higher rates of both atopic and non-atopic diseases compared with children without EoE. These associations have important implications for comprehensive EoE care and future research regarding associated disease mechanisms.
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Affiliation(s)
- Peter Capucilli
- Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Division of Allergy & Immunology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania.
| | - Antonella Cianferoni
- Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Division of Allergy & Immunology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania
| | - Robert W Grundmeier
- Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania; Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Jonathan M Spergel
- Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Division of Allergy & Immunology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania
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Xie F, Chan JCN, Ma RCW. Precision medicine in diabetes prevention, classification and management. J Diabetes Investig 2018; 9:998-1015. [PMID: 29499103 PMCID: PMC6123056 DOI: 10.1111/jdi.12830] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 02/12/2018] [Indexed: 12/18/2022] Open
Abstract
Diabetes has become a major burden of healthcare expenditure. Diabetes management following a uniform treatment algorithm is often associated with progressive treatment failure and development of diabetic complications. Recent advances in our understanding of the genomic architecture of diabetes and its complications have provided the framework for development of precision medicine to personalize diabetes prevention and management. In the present review, we summarized recent advances in the understanding of the genetic basis of diabetes and its complications. From a clinician's perspective, we attempted to provide a balanced perspective on the utility of genomic medicine in the field of diabetes. Using genetic information to guide management of monogenic forms of diabetes represents the best-known examples of genomic medicine for diabetes. Although major strides have been made in genetic research for diabetes, its complications and pharmacogenetics, ongoing efforts are required to translate these findings into practice by incorporating genetic information into a risk prediction model for prioritization of treatment strategies, as well as using multi-omic analyses to discover novel drug targets with companion diagnostics. Further research is also required to ensure the appropriate use of this information to empower individuals and healthcare professionals to make personalized decisions for achieving the optimal outcome.
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Affiliation(s)
- Fangying Xie
- Department of Medicine and TherapeuticsPrince of Wales HospitalThe Chinese University of Hong KongShatinHong Kong
| | - Juliana CN Chan
- Department of Medicine and TherapeuticsPrince of Wales HospitalThe Chinese University of Hong KongShatinHong Kong
- Hong Kong Institute of Diabetes and ObesityPrince of Wales HospitalThe Chinese University of Hong KongShatinHong Kong
- Li Ka Shing Institute of Health SciencesPrince of Wales HospitalThe Chinese University of Hong KongShatinHong Kong
- CUHK‐SJTU Joint Research Centre in Diabetes Genomics and Precision MedicinePrince of Wales HospitalThe Chinese University of Hong KongShatinHong Kong
| | - Ronald CW Ma
- Department of Medicine and TherapeuticsPrince of Wales HospitalThe Chinese University of Hong KongShatinHong Kong
- Hong Kong Institute of Diabetes and ObesityPrince of Wales HospitalThe Chinese University of Hong KongShatinHong Kong
- Li Ka Shing Institute of Health SciencesPrince of Wales HospitalThe Chinese University of Hong KongShatinHong Kong
- CUHK‐SJTU Joint Research Centre in Diabetes Genomics and Precision MedicinePrince of Wales HospitalThe Chinese University of Hong KongShatinHong Kong
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Cao BL, Qasem A, Sharp RC, Abdelli LS, Naser SA. Systematic review and meta-analysis on the association of tuberculosis in Crohn’s disease patients treated with tumor necrosis factor-α inhibitors (Anti-TNFα). World J Gastroenterol 2018; 24:2764-2775. [PMID: 29991880 PMCID: PMC6034143 DOI: 10.3748/wjg.v24.i25.2764] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 04/30/2018] [Accepted: 06/01/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To perform a meta-analysis on the risk of developing Mycobacterium tuberculosis (TB) infection in Crohn’s disease (CD) patients treated with tumor necrosis factor-alpha (TNFα) inhibitors.
METHODS A meta-analysis of randomized, double-blind, placebo-controlled trials of TNFα inhibitors for treatment of CD in adults was conducted. Arcsine transformation of TB incidence was performed to estimate risk difference. A novel epidemiologically-based correction (EBC) enabling inclusions of studies reporting no TB infection cases in placebo and treatment groups was developed to estimate relative odds.
RESULTS Twenty-three clinical trial studies were identified, including 5669 patients. Six TB infection cases were reported across 5 studies, all from patients receiving TNFα inhibitors. Eighteen studies reported no TB infection cases in placebo and TNFα inhibitor treatment arms. TB infection risk was significantly increased among patients receiving TNFα inhibitors, with a risk difference of 0.028 (95%CI: 0.0011-0.055). The odds ratio was 4.85 (95%CI: 1.02-22.99) with EBC and 5.85 (95%CI: 1.13-30.38) without EBC.
CONCLUSION The risk of TB infection is higher among CD patients receiving TNFα inhibitors. Understanding the immunopathogenesis of CD is crucial, since using TNFα inhibitors in these patients could favor mycobacterial infections, particularly Mycobacterium avium subspecies paratuberculosis, which ultimately could worsen their clinical condition.
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Affiliation(s)
- Brent L Cao
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, United States
| | - Ahmad Qasem
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, United States
| | - Robert C Sharp
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, United States
| | - Latifa S Abdelli
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, United States
| | - Saleh A Naser
- Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, United States
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44
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Zhang P, Lu Q. Genetic and epigenetic influences on the loss of tolerance in autoimmunity. Cell Mol Immunol 2018; 15:575-585. [PMID: 29503444 PMCID: PMC6079019 DOI: 10.1038/cmi.2017.137] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 10/21/2017] [Indexed: 12/23/2022] Open
Abstract
Immunological tolerance loss is fundamental to the development of autoimmunity; however, the underlying mechanisms remain elusive. Immune tolerance consists of central and peripheral tolerance. Central tolerance, which occurs in the thymus for T cells and bone marrow for B cells, is the primary way that the immune system discriminates self from non-self. Peripheral tolerance, which occurs in tissues and lymph nodes after lymphocyte maturation, controls self-reactive immune cells and prevents over-reactive immune responses to various environment factors. Loss of tolerance results in autoimmune disorders, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes (T1D) and primary biliary cirrhosis (PBC). The etiology and pathogenesis of autoimmune diseases are highly complicated. Both genetic predisposition and epigenetic modifications are implicated in the loss of tolerance and autoimmunity. In this review, we will discuss the genetic and epigenetic influences on tolerance breakdown in autoimmunity. Genetic and epigenetic influences on autoimmune diseases, such as SLE, RA, T1D and PBC, will also be briefly discussed.
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Affiliation(s)
- Peng Zhang
- Department of Dermatology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, 410011, Changsha, Hunan, China
| | - Qianjin Lu
- Department of Dermatology, The Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, 410011, Changsha, Hunan, China.
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Wang PF, Cai HQ, Zhang CB, Li YM, Liu X, Wan JH, Jiang T, Li SW, Yan CX. Molecular and clinical characterization of PTPN2 expression from RNA-seq data of 996 brain gliomas. J Neuroinflammation 2018; 15:145. [PMID: 29764444 PMCID: PMC5953404 DOI: 10.1186/s12974-018-1187-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 05/03/2018] [Indexed: 12/14/2022] Open
Abstract
Background Immune checkpoint inhibitors have been shown to promote antitumor immunity and achieve durable tumor remissions. However, certain tumors are refractory to current immunotherapy. These negative results encouraged us to uncover other therapeutic targets and strategies. PTPN2 (protein tyrosine phosphatase, non-receptor type 2) has been newly identified as an immunotherapy target. Loss of PTPN2 sensitizes the tumor to immunotherapy via IFNγ signaling. Methods Here, we investigated the relationship between PTPN2 mRNA levels and clinical characteristics in gliomas. RNA-seq data of a cohort of 325 patients with glioma were available from the Chinese Glioma Genome Atlas and 671 from The Cancer Genome Atlas. R language, GraphPad Prism 5, and SPSS 22.0 were used to analyze data and draw figures. Results PTPN2 transcript levels increased significantly with higher grades of glioma and in isocitrate dehydrogenase (IDH) wild-type and mesenchymal subtype gliomas. A comprehensive biological analysis was conducted, which indicated a crucial role of PTPN2 in the immune and inflammation responses in gliomas. Specifically, PTPN2 was positively associated with HCK, LCK, MHC II, and STAT1 but negatively related to IgG and interferon. Moreover, canonical correlation analysis showed a positive correlation of PTPN2 with infiltrating immune cells, such as macrophages, neutrophils, and CD8+ T cells. Clinically, higher levels of PTPN2 were associated with a worse overall survival both in patients with gliomas and glioblastomas. Conclusion PTPN2 expression level was increased in glioblastomas and associated with gliomas of the IDH wild-type and mesenchymal subtype. There was a close correlation between PTPN2 and the immune response and inflammatory activity in gliomas. Our results show that PTPN2 is a promising immunotherapy target and may provide additional treatment strategies. Electronic supplementary material The online version of this article (10.1186/s12974-018-1187-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Peng-Fei Wang
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Building 1, Ward 6, Xiang Shan Yi Ke Song Road 50, Haidian, Beijing, China
| | - Hong-Qing Cai
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Building 1, Ward 6, Xiang Shan Yi Ke Song Road 50, Haidian, Beijing, China.,Department of Neurosurgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chuan-Bao Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,Beijing Neurosurgical Institute, Beijing, China.,Chinese Glioma Genome Atlas Network (CGGA), Beijing, China
| | - Yan-Michael Li
- Department of Neurosurgery and Oncology, University of Rochester Medical Center, Rochester, NY, USA
| | - Xiang Liu
- Department of Imaging Sciences, University of Rochester Medical Center, Rochester, NY, USA
| | - Jing-Hai Wan
- Department of Neurosurgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tao Jiang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,Beijing Neurosurgical Institute, Beijing, China.,Chinese Glioma Genome Atlas Network (CGGA), Beijing, China
| | - Shou-Wei Li
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Building 1, Ward 6, Xiang Shan Yi Ke Song Road 50, Haidian, Beijing, China.
| | - Chang-Xiang Yan
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Building 1, Ward 6, Xiang Shan Yi Ke Song Road 50, Haidian, Beijing, China.
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Zhang P, Zhang W, Zhang D, Wang M, Aprecio R, Ji N, Mohamed O, Li Y, Ding Y, Wang Q. 25-Hydroxyvitamin D 3 -enhanced PTPN2 positively regulates periodontal inflammation through the JAK/STAT pathway in human oral keratinocytes and a mouse model of type 2 diabetes mellitus. J Periodontal Res 2018. [PMID: 29516520 DOI: 10.1111/jre.12535] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND OBJECTIVE Periodontitis is an increasingly prevalent complication of diabetes mellitus (known as diabetes mellitus-associated periodontitis), and 25-hydroxyvitamin D3 (25VD3 ) was recently found to be a critical regulator of innate immunity in this disease, but the underlying mechanisms remain poorly understood. T-cell protein tyrosine phosphatase non-receptor type 2 (PTPN2) is a potential downstream protein of the 25VD3 /vitamin D receptor pathway. The aim of this study was to investigate the regulation of PTPN2 in periodontal inflammation in diabetes mellitus-associated periodontitis. MATERIAL AND METHODS Porphyromonas gingivalis-infected db/db mice were treated with 25VD3 . Their fasting blood glucose and body weight were monitored every other week, and the levels of alveolar bone loss and serum inflammatory cytokines (tumor necrosis factor-α, interferon-γ and interleukin-6) were determined at the time of killing. The effect of PTPN2 on human OKF6-TERT2 oral keratinocytes was examined through the knockout of PTPN2 using the CRISPR/Cas9 knockout plasmid. The expression levels of the PTPN2, vitamin D receptor and JAK1/STAT3 signaling proteins in the gingival epithelium and OKF6-TERT2 cells were determined through western blot and immunohistochemical analyses. RESULTS After 25VD3 treatment, db/db mice exhibited alleviated serum inflammatory cytokines and alveolar bone loss, and 25VD3 -enhanced PTPN2 expression decreased the expression of the JAK1/STAT3 signaling proteins in the gingival epithelium. Analyses of human oral keratinocytes showed that 25VD3 increased the expression of PTPN2, which dephosphorylates protein substrates in the JAK1/STAT3 signaling pathway. CONCLUSION PTPN2 contributed to a decrease in periodontal inflammation in type 2 diabetes mellitus via dephosphorylate protein substrates in the JAK1/STAT3 signaling pathway after 25VD3 treatment in human oral keratinocytes and a mouse model of type 2 diabetes mellitus. A thorough understanding of PTPN2 and its involvement in inhibiting inflammation might provide alternative therapeutic approaches for the pathogenesis and treatment of diabetes mellitus-associated periodontitis.
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Affiliation(s)
- P Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - W Zhang
- Center for Dental Research, School of Dentistry, Loma Linda University, Loma Linda, CA, USA
| | - D Zhang
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, School of Stomatology, Shandong University, Jinan, China
| | - M Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - R Aprecio
- Center for Dental Research, School of Dentistry, Loma Linda University, Loma Linda, CA, USA
| | - N Ji
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - O Mohamed
- Center for Dental Research, School of Dentistry, Loma Linda University, Loma Linda, CA, USA
| | - Y Li
- Center for Dental Research, School of Dentistry, Loma Linda University, Loma Linda, CA, USA
| | - Y Ding
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.,Department of Periodontology, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Q Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Zhang Q, Li H, Hou S, Yu H, Su G, Deng B, Qi J, Zhou C, Kijlstra A, Yang P. Association of genetic variations in PTPN2 and CD122 with ocular Behcet's disease. Br J Ophthalmol 2018; 102:996-1002. [PMID: 29502070 DOI: 10.1136/bjophthalmol-2017-310820] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 12/29/2017] [Accepted: 02/15/2018] [Indexed: 11/04/2022]
Abstract
BACKGROUND Protein tyrosine phosphatases (PTPs) play critical roles in human autoimmunity. Previous studies found that PTPN2 may be the key regulatory factor in the T-cell-mediated immune response. PTPN2 regulates the Janus kinase/signal transducers and activators of transcription pathway by inhibiting signalling via the interleukin (IL)-2 receptor (CD122). An association between genetic variations in PTPN2 and CD122 with ocular Behcet's disease (BD) has not yet been addressed and was therefore the purpose of this study. METHODS A two-stage case-control study was performed in 906 patients with ocular BD and 2178 healthy controls. Genotyping analysis of 11 single nucleotide polymorphisms was carried out. The expression of PTPN2 in peripheral blood mononuclear cells (PBMCs) was quantified by real-time PCR and cytokine production was measured by ELISA. RESULTS The frequency of the GG genotype of PTPN2-rs7234029 was significantly lower in patients with ocular BD (p=1.94×10-5, pc=8.34×10-4, OR=0.466). Stratification according to gender showed that rs7234029 was significantly associated with BD in men. A stratified analysis according to the main clinical features showed that rs7234029 was significantly associated with genital ulcers, skin lesions and a positive pathergy test. No association could be detected between BD and CD122 gene polymorphisms. Functional studies showed that rs7234029 GG genotype carriers had a higher PNPT2 mRNA expression level than those which carrying the AA or AG genotype, and a decreased secretion of IL-17 and tumour necrosis factor-alpha was seen by PBMCs from GG carriers. No significant difference could be detected concerning IL-1β or IL-6 production by stimulated PBMCs between the different genotype groups. CONCLUSIONS This study shows that a PTPN2-rs7234029 polymorphism is associated with ocular BD and is strongly influenced by gender. In addition, our results suggest that the genetic association with PTPN2 may involve the regulation of PTPN2 mRNA expression and cytokine secretion.
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Affiliation(s)
- Qi Zhang
- Ophthalmology Department, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, People's Republic of China
| | - Hua Li
- Ophthalmology Department, Yongchuan Hospital, Chongqing Medical University, Chongqing, People's Republic of China
| | - Shengping Hou
- Ophthalmology Department, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, People's Republic of China
| | - Hongsong Yu
- Ophthalmology Department, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, People's Republic of China
| | - Guannan Su
- Ophthalmology Department, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, People's Republic of China
| | - Bolin Deng
- Ophthalmology Department, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, People's Republic of China
| | - Jian Qi
- Ophthalmology Department, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, People's Republic of China
| | - Chunjiang Zhou
- Ophthalmology Department, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, People's Republic of China
| | - Aize Kijlstra
- University Eye Clinic Maastricht, Maastricht, The Netherlands
| | - Peizeng Yang
- Ophthalmology Department, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, People's Republic of China
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Sharp RC, Beg SA, Naser SA. Role of PTPN2/22 polymorphisms in pathophysiology of Crohn's disease. World J Gastroenterol 2018; 24:657-670. [PMID: 29456405 PMCID: PMC5807669 DOI: 10.3748/wjg.v24.i6.657] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 01/03/2018] [Accepted: 01/18/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To establish the relationship of protein tyrosine phosphatase non-receptor type 2 and 22 (PTPN2/22) polymorphisms and mycobacterial infections in Crohn's disease (CD). METHODS All 133 subjects' blood samples were genotyped for nine single nucleotide polymorphisms (SNPs) in PTPN2/22 using TaqMan™ genotyping, while the effect of the SNPs on PTPN2/22 and IFN-γ gene expression was determined using RT-PCR. Detection of Mycobacterium avium subspecies paratuberculosis (MAP) IS900 gene was done by nPCR after DNA extraction from the isolated leukocytes of each subjects' blood samples. T-cells isolated from the patient samples were tested for response to phytohematoagglutonin (PHA) mitogen or mycobacterial antigens by BrdU proliferation assays for T-cell activity. RESULTS Out of the nine SNPs examined, subjects with either heterozygous (TC)/minor (CC) alleles in PTPN2:rs478582 occurred in 83% of CD subjects compared to 61% healthy controls (P-values < 0.05; OR = 3.03). Subjects with either heterozygous (GA)/minor (AA) alleles in PTPN22:rs2476601 occurred in 16% of CD compared to 6% healthy controls (OR = 2.7). Gene expression in PTPN2/22 in CD subjects was significantly decreased by 2 folds compared to healthy controls (P-values < 0.05). IFN-γ expression levels were found to be significantly increased by approxiately 2 folds in subjects when either heterozygous or minor alleles in PTPN2:rs478582 and/or PTPN22:rs2476601 were found (P-values < 0.05). MAP DNA was detected in 61% of CD compared to only 8% of healthy controls (P-values < 0.05, OR = 17.52), where subjects with either heterozygous or minor alleles in PTPN2:rs478582 and/or PTPN22:rs2476601 had more MAPbacteremia presence than subjects without SNPs did. The average T-cell proliferation in CD treated with PHA or mycobacteria antigens was, respectively, 1.3 folds and 1.5 folds higher than healthy controls without any significant SNP. CONCLUSION The data suggests that SNPs in PTPN2/22 affect the negative regulation of the immune response in CD patients, thus leading to an increase in inflammation/apoptosis and susceptibility of mycobacteria.
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Affiliation(s)
- Robert C Sharp
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, United States
| | - Shazia A Beg
- University of Central College of Medicine, Health Center, Orlando, FL 32816, United States
| | - Saleh A Naser
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, United States
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Sharp RC, Beg SA, Naser SA. Polymorphisms in Protein Tyrosine Phosphatase Non-receptor Type 2 and 22 (PTPN2/22) Are Linked to Hyper-Proliferative T-Cells and Susceptibility to Mycobacteria in Rheumatoid Arthritis. Front Cell Infect Microbiol 2018; 8:11. [PMID: 29423382 PMCID: PMC5788942 DOI: 10.3389/fcimb.2018.00011] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 01/09/2018] [Indexed: 12/19/2022] Open
Abstract
A shared genetic pre-disposition, chronic inflammation, and treatment with similar biologics between Rheumatoid arthritis (RA) and Crohn's disease (CD) have intrigued us to investigate whether the two disorders share trigger association or possible causation. We hypothesized earlier that Single Nucleotide Polymorphisms (SNPs) in the negative regulators Protein Tyrosine Phosphatase Non-receptor type 2 and 22 (PTPN2/22) lead to a dysregulated immune response, susceptibility to environmental triggers, and continued apoptosis as seen in chronic inflammation in RA and CD. To test the hypothesis, peripheral leukocytes samples from 132 consented subjects were genotyped for 9 SNPs in PTPN2/22 using TaqMan™ genotyping. The effect of the SNPs on PTPN2/22 and IFN-γ expression was determined using real time PCR. T-cell proliferation and response to phytohematoagglutonin (PHA) mitogen and mycobacterial antigens were determined by BrdU proliferation assay. Blood samples were also analyzed for the Mycobacterium avium subspecies paratuberculosis (MAP) IS900 gene by nPCR. Out of 9 SNPs examined, heterozygous (TC) or minor (CC) alleles of PTPN2:rs478582 occurred in 79% RA compared to 60% healthy controls (p-values ≤ 0.05; OR = 2.28). Similarly, heterozygous (GA) or minor (AA) alleles of PTPN22:rs2476601 occurred in 29% RA compared to 6% healthy controls (p-values ≤ 0.05; OR = 5.90). PTPN2/22 expression in RA was decreased by 1.2-fold compared to healthy controls. PTPN2:rs478582 upregulated IFN-γ in RA by 1.5-fold. Combined PTPN2:rs478582 and PTPN22:rs2476601 increased T-cell proliferation by 2.7-fold when treated with PHA. Surprisingly, MAP DNA was detected in 34% of RA samples compared to 8% healthy controls, (p-values ≤ 0.05, OR = 5.74). RA samples with PTPN2:rs478582 and/or PTPN22:rs2476601 were more positive for MAP than samples without polymorphisms. Combined occurrence of PTPN2:rs478582 and PTPN22:rs2476601 in association with the presence of MAP has significantly increased T-cell response and elevated IFN-γ expression in RA samples. The data suggest that genetic polymorphisms may play vital role in T-cell regulation, susceptibility to mycobacteria and ultimately response to treatment. This is the first study to report the detection of MAP DNA in the blood of RA patients; further studies are needed using larger number of samples.
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Affiliation(s)
- Robert C. Sharp
- Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, United States
| | - Shazia A. Beg
- Health Center, Universtiy of Central Florida College of Medicine, Orlando, FL, United States
| | - Saleh A. Naser
- Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, United States
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50
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Hao X, Zeng P, Zhang S, Zhou X. Identifying and exploiting trait-relevant tissues with multiple functional annotations in genome-wide association studies. PLoS Genet 2018; 14:e1007186. [PMID: 29377896 PMCID: PMC5805369 DOI: 10.1371/journal.pgen.1007186] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 02/08/2018] [Accepted: 01/04/2018] [Indexed: 12/18/2022] Open
Abstract
Genome-wide association studies (GWASs) have identified many disease associated loci, the majority of which have unknown biological functions. Understanding the mechanism underlying trait associations requires identifying trait-relevant tissues and investigating associations in a trait-specific fashion. Here, we extend the widely used linear mixed model to incorporate multiple SNP functional annotations from omics studies with GWAS summary statistics to facilitate the identification of trait-relevant tissues, with which to further construct powerful association tests. Specifically, we rely on a generalized estimating equation based algorithm for parameter inference, a mixture modeling framework for trait-tissue relevance classification, and a weighted sequence kernel association test constructed based on the identified trait-relevant tissues for powerful association analysis. We refer to our analytic procedure as the Scalable Multiple Annotation integration for trait-Relevant Tissue identification and usage (SMART). With extensive simulations, we show how our method can make use of multiple complementary annotations to improve the accuracy for identifying trait-relevant tissues. In addition, our procedure allows us to make use of the inferred trait-relevant tissues, for the first time, to construct more powerful SNP set tests. We apply our method for an in-depth analysis of 43 traits from 28 GWASs using tissue-specific annotations in 105 tissues derived from ENCODE and Roadmap. Our results reveal new trait-tissue relevance, pinpoint important annotations that are informative of trait-tissue relationship, and illustrate how we can use the inferred trait-relevant tissues to construct more powerful association tests in the Wellcome trust case control consortium study.
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Affiliation(s)
- Xingjie Hao
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, Hubei, China
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, United States of America
- Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, United States of America
| | - Ping Zeng
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, United States of America
- Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, United States of America
| | - Shujun Zhang
- Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Xiang Zhou
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, United States of America
- Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, United States of America
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