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Liang DF, Li X, Guo WL, Tang SH, Ye XY, Zhang S, Yang LY. The association analysis between Glucose-6-Phosphate dehydrogenase deficiency and susceptibility to common diseases in children. Pediatr Res 2025:10.1038/s41390-025-04148-0. [PMID: 40425847 DOI: 10.1038/s41390-025-04148-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 04/02/2025] [Accepted: 05/12/2025] [Indexed: 05/29/2025]
Abstract
BACKGROUND This study investigates the relationship between G6PD deficiency and susceptibility to common pediatric diseases. METHODS A retrospective analysis was conducted on hospitalized children who underwent G6PD screening at the Guangzhou Women and Children's Medical Center from January 2019 to March 2024. RESULTS Among 36,619 children, 20,662 were male. The prevalence of G6PD deficiency in males was significantly higher in conditions such as nephritis (OR 2.43,95%CI 1.45-4.21), allergic purpura (OR 2.24, 95%CI 1.24-4.09), patent ductus arteriosus (OR 2.04, 95%CI 1.32-3.33), atrial septal defect (OR 2.14, 95%CI 1.41-3.45), ventricular septal defect (OR 1.73, 95%CI 1.12-2.80), and type 1 diabetes (OR 2.04, 95%CI 1.16-3.66). Among 15,957 female patients, the prevalence of G6PD deficiency was significantly elevated in systemic lupus erythematosus (SLE) (OR 1.87, 95%CI 1.27-2.70), juvenile arthritis (OR 1.79, 95%CI 1.16-2.68), nephritis (OR 1.72, 95%CI 1.16-2.49), patent ductus arteriosus (OR 1.27, 95%CI 1.00-1.61), atrial septal defect (OR 1.33, 95%CI 1.10-1.61), and ventricular septal defect (OR 1.55, 95%CI 1.26-1.91). CONCLUSION G6PD deficiency may increase the risk of autoimmune diseases, congenital heart defects, and type 1 diabetes in children. Further studies are required to elucidate its role in pediatric disease susceptibility and inform clinical management. IMPACT 1. This study found that G6PD deficiency is significantly associated with increased susceptibility to several common pediatric diseases, including autoimmune diseases, congenital heart defects, and type 1 diabetes. Notably, in both male and female patients, G6PD deficiency was significantly linked to specific conditions, such as SLE, juvenile arthritis, and congenital heart disease. 2. Our findings indicate that G6PD deficiency is not merely an enzymatic defect but may also impact the immune and cardiovascular systems. Specifically, an increased incidence of congenital heart disease has been observed in children with G6PD deficiency for the first time.
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Affiliation(s)
- De-Feng Liang
- Department of Emergency, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, Guangdong, China
| | - Xue Li
- Department of Rheumatology and Immunology, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wen-Lin Guo
- Department of Hematology and Oncology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, Guangdong, China
| | - Shu-Han Tang
- Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Xiao-Ying Ye
- Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China
| | - Song Zhang
- Department of Allergy, Immunology and Rheumatology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, China.
| | - Li-Ye Yang
- Precision Medical Lab Center, People's Hospital of Yangjiang, Yangjiang, Guangdong Province, PR China.
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Yu Y, Ba X, Li T, Xu W, Zhao J, Zhang N, Zhao Y, Wang T, Zhang X, Wang X, Bai B, Wang B. PTPN22 and the pathogenesis of ulcerative colitis: Insights into T cell differentiation and the JAK/STAT signaling pathway. Cell Signal 2025; 127:111551. [PMID: 39643025 DOI: 10.1016/j.cellsig.2024.111551] [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: 04/30/2024] [Revised: 10/20/2024] [Accepted: 12/01/2024] [Indexed: 12/09/2024]
Abstract
70 % of the ulcerative colitis (UC) linked gene loci are associated with other autoimmune or immunodeficient diseases. The phosphatase activity of PTPN22 can regulate the development of T cells and contribute to regulate the level of inflammation in autoimmune diseases. We produced PTPN22-CS thymus-specific transgenic mice, which suppressed PTPN22 enzyme activity in the thymocytes. Overexpressed PTPN22-CS facilitated the development of the thymocytes towards CD4+T cells and resulted in an increased proportion of the Th1 and Treg cells in the UC mesenteric lymph nodes. PTPN22-CS promoted the activation of the JAK/STAT signaling pathway in the Th1 and Treg cells that localized in the colon, resulting in an excessive production of inflammatory mediators such as IL-2 and IFN-γ. Consequently, PTPN22-CS contributes to the inflammatory response of ulcerative colitis. In summary, the tyrosine phosphatase activity of PTPN22 plays a role in modulating UC by regulating T cell differentiation and modulating the JAK/STAT signaling pathway, thereby influencing the inflammatory response in colonic. These findings provide new insight into the association between PTPN22 and the pathogenesis of UC.
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Affiliation(s)
- Yang Yu
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Xinlei Ba
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Tong Li
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Wenying Xu
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Jiahui Zhao
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China
| | - Na Zhang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Yanjiao Zhao
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China
| | - Tao Wang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Xiaonan Zhang
- Department of Pathophysiology, Bengbu Medical University, Longzihu, Bengbu, 233030, Anhui, PR China..
| | - Xipeng Wang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China
| | - Bin Bai
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
| | - Bing Wang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China; College of Life and Health Sciences, Northeastern University, Shenyang, #195 Chuangxin Road, Hunnan Xinqu, Shenyang, Liaoning 110169, China.
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Mavridou M, Pearce SH. Exploring antigenic variation in autoimmune endocrinopathy. Front Immunol 2025; 16:1561455. [PMID: 40093006 PMCID: PMC11906412 DOI: 10.3389/fimmu.2025.1561455] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 02/07/2025] [Indexed: 03/19/2025] Open
Abstract
Autoimmune disorders develop owing to a misdirected immune response against self-antigen. Genetic studies have revealed that numerous variants in genes encoding immune system proteins are associated with the development of autoimmunity. Indeed, many of these genetic variants in key immune receptors or transcription factors are common in the pathogenesis of several different autoimmune conditions. In contrast, the proclivity to develop autoimmunity to any specific target organ or tissue is under-researched. This has particular relevance to autoimmune endocrine conditions, where organ-specific involvement is the rule. Genetic polymorphisms in the genes encoding the targets of autoimmune responses have been shown to be associated with predisposition to several autoimmune diseases, including type 1 diabetes, autoimmune thyroid disease and Addison's disease. Mechanistically, variations leading to decreased intrathymic expression, overexpression, different localisation, alternative splicing or post-translational modifications can interfere in the tolerance induction process. This review will summarise the different ways genetic variations in certain genes encoding endocrine-specific antigens (INS, TSHR, TPO, CYP21A2, PIT-1) may predispose to different autoimmune endocrine conditions.
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Affiliation(s)
- Maria Mavridou
- Translational and Clinical Research Institute, Newcastle University, BioMedicine
West, Newcastle-upon-Tyne, United Kingdom
| | - Simon H. Pearce
- Translational and Clinical Research Institute, Newcastle University, BioMedicine
West, Newcastle-upon-Tyne, United Kingdom
- Endocrine Unit, Royal Victoria Infirmary,
Newcastle-upon-Tyne, United Kingdom
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Brownlie RJ, Salmond RJ. Regulation of T Cell Signaling and Immune Responses by PTPN22. Mol Cell Biol 2024; 44:443-452. [PMID: 39039893 PMCID: PMC11486154 DOI: 10.1080/10985549.2024.2378810] [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: 06/06/2024] [Revised: 07/01/2024] [Accepted: 07/07/2024] [Indexed: 07/24/2024] Open
Abstract
Protein tyrosine phosphatases (PTPs) play central roles in the regulation of cell signaling, organismal development, cellular differentiation and proliferation, and cancer. In the immune system, PTPs regulate the activation, differentiation and effector function of lymphocytes and myeloid cells whilst single-nucleotide polymorphisms (SNPs) in PTP-encoding genes have been identified as risk factors for the development of autoimmunity. In this review we describe the roles for PTP nonreceptor type 22 (PTPN22) in the regulation of T lymphocyte signaling and activation in autoimmunity, infection and cancer. We summarize recent progress in our understanding of the regulation of PTPN22 activity, the impact of autoimmune disease-associated PTPN22 SNPs on T cell responses and describe approaches to harness PTPN22 as a target to improve T cell-based immunotherapies in cancer.
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Minniakhmetov I, Yalaev B, Khusainova R, Bondarenko E, Melnichenko G, Dedov I, Mokrysheva N. Genetic and Epigenetic Aspects of Type 1 Diabetes Mellitus: Modern View on the Problem. Biomedicines 2024; 12:399. [PMID: 38398001 PMCID: PMC10886892 DOI: 10.3390/biomedicines12020399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/06/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
Omics technologies accumulated an enormous amount of data that advanced knowledge about the molecular pathogenesis of type 1 diabetes mellitus and identified a number of fundamental problems focused on the transition to personalized diabetology in the future. Among them, the most significant are the following: (1) clinical and genetic heterogeneity of type 1 diabetes mellitus; (2) the prognostic significance of DNA markers beyond the HLA genes; (3) assessment of the contribution of a large number of DNA markers to the polygenic risk of disease progress; (4) the existence of ethnic population differences in the distribution of frequencies of risk alleles and genotypes; (5) the infancy of epigenetic research into type 1 diabetes mellitus. Disclosure of these issues is one of the priorities of fundamental diabetology and practical healthcare. The purpose of this review is the systemization of the results of modern molecular genetic, transcriptomic, and epigenetic investigations of type 1 diabetes mellitus in general, as well as its individual forms. The paper summarizes data on the role of risk HLA haplotypes and a number of other candidate genes and loci, identified through genome-wide association studies, in the development of this disease and in alterations in T cell signaling. In addition, this review assesses the contribution of differential DNA methylation and the role of microRNAs in the formation of the molecular pathogenesis of type 1 diabetes mellitus, as well as discusses the most currently central trends in the context of early diagnosis of type 1 diabetes mellitus.
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Affiliation(s)
- Ildar Minniakhmetov
- Endocrinology Research Centre, Dmitry Ulyanov Street, 11, 117292 Moscow, Russia; (R.K.); (E.B.); (G.M.); (I.D.); (N.M.)
| | - Bulat Yalaev
- Endocrinology Research Centre, Dmitry Ulyanov Street, 11, 117292 Moscow, Russia; (R.K.); (E.B.); (G.M.); (I.D.); (N.M.)
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Vidya AS, Khader A, Devi K, Anandkumar Archana G, Reeshma J, Reshma NJ. PLACK syndrome associated with alopecia areata and a novel homozygous base pair insertion in exon 18 of CAST gene. Indian J Dermatol Venereol Leprol 2024; 90:102-105. [PMID: 37317743 DOI: 10.25259/ijdvl_1138_2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 03/11/2023] [Indexed: 06/16/2023]
Affiliation(s)
- Aparna S Vidya
- Department of Dermatology, Government Medical College, Kozhikode, Kerala, India
| | - Anza Khader
- Department of Dermatology, Government Medical College, Kozhikode, Kerala, India
| | | | | | - Jose Reeshma
- Department of Dermatology, Government Medical College, Kozhikode, Kerala, India
| | - Neerackal J Reshma
- Department of Dermatology, Government Medical College, Kozhikode, Kerala, India
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Bai B, Li T, Zhao J, Zhao Y, Zhang X, Wang T, Zhang N, Wang X, Ba X, Xu J, Yu Y, Wang B. The Tyrosine Phosphatase Activity of PTPN22 Is Involved in T Cell Development via the Regulation of TCR Expression. Int J Mol Sci 2023; 24:14505. [PMID: 37833951 PMCID: PMC10572452 DOI: 10.3390/ijms241914505] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 09/15/2023] [Accepted: 09/21/2023] [Indexed: 10/15/2023] Open
Abstract
The protein tyrosine phosphatase PTPN22 inhibits T cell activation by dephosphorylating some essential proteins in the T cell receptor (TCR)-mediated signaling pathway, such as the lymphocyte-specific protein tyrosine kinase (Lck), Src family tyrosine kinases Fyn, and the phosphorylation levels of Zeta-chain-associated protein kinase-70 (ZAP70). For the first time, we have successfully produced PTPN22 CS transgenic mice in which the tyrosine phosphatase activity of PTPN22 is suppressed. Notably, the number of thymocytes in the PTPN22 CS mice was significantly reduced, and the expression of cytokines in the spleen and lymph nodes was changed significantly. Furthermore, PTPN22 CS facilitated the positive and negative selection of developing thymocytes, increased the expression of the TCRαβ-CD3 complex on the thymus cell surface, and regulated their internalization and recycling. ZAP70, Lck, Phospholipase C gamma1(PLCγ1), and other proteins were observed to be reduced in PTPN22 CS mouse thymocytes. In summary, PTPN22 regulates TCR internalization and recycling via the modulation of the TCR signaling pathway and affects TCR expression on the T cell surface to regulate negative and positive selection. PTPN22 affected the development of the thymus, spleen, lymph nodes, and other peripheral immune organs in mice. Our study demonstrated that PTPN22 plays a crucial role in T cell development and provides a theoretical basis for immune system construction.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Yang Yu
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang 110169, China; (B.B.); (T.L.); (J.Z.); (Y.Z.); (X.Z.); (T.W.); (N.Z.); (X.W.); (X.B.); (J.X.)
| | - Bing Wang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life Science and Health, Northeastern University, #195 Chuangxin Road, Hunnan Xinqu, Shenyang 110169, China; (B.B.); (T.L.); (J.Z.); (Y.Z.); (X.Z.); (T.W.); (N.Z.); (X.W.); (X.B.); (J.X.)
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Israel A, Schäffer AA, Berkovitch M, Ozeri DJ, Merzon E, Green I, Golan-Cohen A, Ruppin E, Vinker S, Magen E. Glucose-6-phosphate dehydrogenase deficiency and long-term risk of immune-related disorders. Front Immunol 2023; 14:1232560. [PMID: 37753082 PMCID: PMC10518697 DOI: 10.3389/fimmu.2023.1232560] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 08/29/2023] [Indexed: 09/28/2023] Open
Abstract
Introduction Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzymatic disorder that is particularly prevalent in Africa, Asia, and the Middle East. This study aimed to assess the long-term health risks associated with G6PD deficiency. Methods A retrospective cohort study was conducted using data from a national healthcare provider in Israel (Leumit Health Services). A total of 7,473 G6PD-deficient individuals were matched with 29,892 control subjects in a 1:4 ratio, based on age, gender, socioeconomic status, and ethnic groups. The exposure of interest was recorded G6PD diagnosis or positive G6PD diagnostic test. The main outcomes and measures included rates of infectious diseases, allergic conditions, and autoimmune disorders between 2002 and 2022. Results Significantly increased rates were observed for autoimmune disorders, infectious diseases, and allergic conditions in G6PD-deficient individuals compared to the control group. Specifically, notable increases were observed for rheumatoid arthritis (odds ratio [OR] 2.41, p<0.001), systemic lupus erythematosus (OR 4.56, p<0.001), scleroderma (OR 6.87, p<0.001), pernicious anemia (OR 18.70, p<0.001), fibromyalgia (OR 1.98, p<0.001), Graves' disease (OR 1.46, p=0.001), and Hashimoto's thyroiditis (OR 1.26, p=0.001). These findings were supported by elevated rates of positive autoimmune serology and higher utilization of medications commonly used to treat autoimmune conditions in the G6PD-deficient group. Discussion In conclusion, individuals with G6PD deficiency are at a higher risk of developing autoimmune disorders, infectious diseases, and allergic conditions. This large-scale observational study provides valuable insights into the comprehensive association between G6PD deficiency and infectious and immune-related diseases. The findings emphasize the importance of considering G6PD deficiency as a potential risk factor in clinical practice and further research is warranted to better understand the underlying mechanisms of these associations.
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Affiliation(s)
- Ariel Israel
- Leumit Research Institute, Leumit Health Services, Tel Aviv-Yafo, Israel
- School of Public Health and Family Medicine Department, Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
| | - Alejandro A. Schäffer
- Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD, United States
| | - Matitiahu Berkovitch
- School of Public Health and Family Medicine Department, Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
- Clinical Pharmacology and Toxicology Unit, Shamir Medical Center, Zerifin, Israel
| | - David J. Ozeri
- Leumit Research Institute, Leumit Health Services, Tel Aviv-Yafo, Israel
- Division of Rheumatology, Sheba Medical Center, Ramat Gan, Israel
| | - Eugene Merzon
- Leumit Research Institute, Leumit Health Services, Tel Aviv-Yafo, Israel
- Adelson School of Medicine, Ariel University, Ariel, Israel
| | - Ilan Green
- Leumit Research Institute, Leumit Health Services, Tel Aviv-Yafo, Israel
- School of Public Health and Family Medicine Department, Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
| | - Avivit Golan-Cohen
- Leumit Research Institute, Leumit Health Services, Tel Aviv-Yafo, Israel
- School of Public Health and Family Medicine Department, Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
| | - Eytan Ruppin
- Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD, United States
| | - Shlomo Vinker
- Leumit Research Institute, Leumit Health Services, Tel Aviv-Yafo, Israel
- School of Public Health and Family Medicine Department, Faculty of Medicine, Tel Aviv University, Tel Aviv-Yafo, Israel
| | - Eli Magen
- Leumit Research Institute, Leumit Health Services, Tel Aviv-Yafo, Israel
- Medicine A Department, Assuta Ashdod University Hospital Faculty of Health Sciences, Ben-Gurion University, Beer-Sheba, Israel
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Bai B, Wang T, Zhang X, Ba X, Zhang N, Zhao Y, Wang X, Yu Y, Wang B. PTPN22 activates the PI3K pathway via 14-3-3τ in T cells. FEBS J 2023; 290:4562-4576. [PMID: 37255287 DOI: 10.1111/febs.16878] [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: 11/08/2022] [Revised: 03/06/2023] [Accepted: 05/26/2023] [Indexed: 06/01/2023]
Abstract
The protein tyrosine phosphatase PTPN22 inhibits T cell activation by dephosphorylating some essential proteins in the T cell receptor-mediated signalling pathway, and its negative regulatory function protects organisms from autoimmune disease. 14-3-3τ is an adaptor protein that regulates target protein function through its intracellular localization. In the present study, we determined that PTPN22 binds to 14-3-3τ via the PTPN22-Ser640 phosphorylation side. PTPN22 binding to 14-3-3τ resulted in 14-3-3τ-Tyr179 dephosphorylation, and reduced the association between 14-3-3τ and Shc, which competitively increased 14-3-3ζ binding to Shc and activated phosphoinositide 3-kinase (PI3K) by bringing it to the membrane. In addition, PTPN22 decreased the tyrosine phosphorylation of p110 to activate PI3K. These two pathways cooperatively affect PI3K activity and the expression of PI3K downstream proteins, such as phosphorylated Akt, mammalian target of rapamycin and forkhead box O1, which inhibited the expression of some proinflammatory factors such as interleukin-1β, interleukin-2, interleukin-6, interferon-γ and tumour necrosis factor-α. Our research provides a preliminary theory for PTPN22 regulating T cell activation, development and immune response via the PI3K/Akt/mammalian target of rapamycin pathway and brings new information for clarifying the functions of PTPN22 in autoimmune diseases.
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Affiliation(s)
- Bin Bai
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang, China
| | - Tao Wang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang, China
| | - Xiaonan Zhang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang, China
| | - Xinlei Ba
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang, China
| | - Na Zhang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang, China
| | - Yanjiao Zhao
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang, China
| | - Xipeng Wang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang, China
| | - Yang Yu
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang, China
| | - Bing Wang
- Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang, China
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Israel A, Schäffer AA, Berkovitch M, Ozeri DJ, Merzon E, Green I, Golan-Cohen A, Ruppin E, Vinker S, Magen E. Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency and Long-Term Risk of Immune-Related diseases. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.03.23.23287616. [PMID: 37090544 PMCID: PMC10120794 DOI: 10.1101/2023.03.23.23287616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
BACKGROUND Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive enzymatic disorder, particularly prevalent in Africa, Asia and the Middle East. In the US, about 14% of black men are affected. Individuals with G6PD deficiency are often asymptomatic but may develop hemolysis following an infection or upon consumption of specific medications. Despite some evidence that G6PD deficiency affects the immune system, the long- term health risks associated with G6PD deficiency had not been studied in a large population. METHODS In this retrospective cohort study, health records from G6PD deficient individuals were compared to matched controls in a national healthcare provider in Israel (Leumit Health Services). Rates of infectious diseases, allergic conditions and autoimmune disorders were compared between groups. RESULTS The cohort included 7,473 G6PD deficient subjects (68.7% men) matched with 29,892 control subjects (4:1 ratio) of the same age, gender, socioeconomic status and ethnic group, followed during 14.3±6.2 years.Significantly increased rates for autoimmune disorders, infectious diseases and allergic conditions were observed throughout this period. Notable increases were observed for rheumatoid arthritis (OR 2.41, p<0.001), systemic lupus erythematosus (OR 4.56, p<0.001), scleroderma (OR 6.87, p<0.001), pernicious anemia (OR=18.70, P<0.001), fibromyalgia (OR 1.98, p<0.001), Graves' disease (OR 1.46, P=0.001), and Hashimoto's thyroiditis (OR 1.26, P=0.001). These findings were corroborated with elevated rates of positive autoimmune serology and higher rates of treatment with medications commonly used to treat autoimmune conditions in the G6PD deficient group. CONCLUSION G6PD deficient individuals suffer from higher rates of autoimmune disorders, infectious diseases, and allergic conditions.
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Affiliation(s)
- Ariel Israel
- Leumit Research Institute, Leumit Health Services, Tel Aviv-Yafo 6473817, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo 6997801 Israel
| | - Alejandro A Schäffer
- Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD 20892, USA
| | | | - David J. Ozeri
- Leumit Research Institute, Leumit Health Services, Tel Aviv-Yafo 6473817, Israel
- Division of Rheumatology, Sheba Medical Center
| | - Eugene Merzon
- Leumit Research Institute, Leumit Health Services, Tel Aviv-Yafo 6473817, Israel
- Adelson School of Medicine, Ariel University, Ariel 4070000, Israel
| | - Ilan Green
- Leumit Research Institute, Leumit Health Services, Tel Aviv-Yafo 6473817, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo 6997801 Israel
| | - Avivit Golan-Cohen
- Leumit Research Institute, Leumit Health Services, Tel Aviv-Yafo 6473817, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo 6997801 Israel
| | - Eytan Ruppin
- Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD 20892, USA
| | - Shlomo Vinker
- Leumit Research Institute, Leumit Health Services, Tel Aviv-Yafo 6473817, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv-Yafo 6997801 Israel
| | - Eli Magen
- Leumit Research Institute, Leumit Health Services, Tel Aviv-Yafo 6473817, Israel
- Medicine A Department, Assuta Ashdod University Hospital Faculty of Health Sciences, Ben-Gurion University, Beer-Sheba 8410501, Israel
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11
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Anderson W, Barahmand-pour-Whitman F, Linsley PS, Cerosaletti K, Buckner JH, Rawlings DJ. PTPN22 R620W gene editing in T cells enhances low-avidity TCR responses. eLife 2023; 12:e81577. [PMID: 36961507 PMCID: PMC10065793 DOI: 10.7554/elife.81577] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 03/21/2023] [Indexed: 03/25/2023] Open
Abstract
A genetic variant in the gene PTPN22 (R620W, rs2476601) is strongly associated with increased risk for multiple autoimmune diseases and linked to altered TCR regulation and T cell activation. Here, we utilize Crispr/Cas9 gene editing with donor DNA repair templates in human cord blood-derived, naive T cells to generate PTPN22 risk edited (620W), non-risk edited (620R), or knockout T cells from the same donor. PTPN22 risk edited cells exhibited increased activation marker expression following non-specific TCR engagement, findings that mimicked PTPN22 KO cells. Next, using lentiviral delivery of T1D patient-derived TCRs against the pancreatic autoantigen, islet-specific glucose-6 phosphatase catalytic subunit-related protein (IGRP), we demonstrate that loss of PTPN22 function led to enhanced signaling in T cells expressing a lower avidity self-reactive TCR, but not a high-avidity TCR. In this setting, loss of PTPN22 mediated enhanced proliferation and Th1 skewing. Importantly, expression of the risk variant in association with a lower avidity TCR also increased proliferation relative to PTPN22 non-risk T cells. Together, these findings suggest that, in primary human T cells, PTPN22 rs2476601 contributes to autoimmunity risk by permitting increased TCR signaling and activation in mildly self-reactive T cells, thereby potentially expanding the self-reactive T cell pool and skewing this population toward an inflammatory phenotype.
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Affiliation(s)
- Warren Anderson
- Center for Immunity and Immunotherapies, Seattle Children's Research InstituteSeattleUnited States
| | | | - Peter S Linsley
- Benaroya Research Institute at Virginia MasonSeattleUnited States
| | | | - Jane H Buckner
- Benaroya Research Institute at Virginia MasonSeattleUnited States
| | - David J Rawlings
- Department of Pediatrics and Immunology, University of WashingtonSeattleUnited States
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12
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Harley ITW, Allison K, Scofield RH. Polygenic autoimmune disease risk alleles impacting B cell tolerance act in concert across shared molecular networks in mouse and in humans. Front Immunol 2022; 13:953439. [PMID: 36090990 PMCID: PMC9450536 DOI: 10.3389/fimmu.2022.953439] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 07/19/2022] [Indexed: 11/23/2022] Open
Abstract
Most B cells produced in the bone marrow have some level of autoreactivity. Despite efforts of central tolerance to eliminate these cells, many escape to periphery, where in healthy individuals, they are rendered functionally non-responsive to restimulation through their antigen receptor via a process termed anergy. Broad repertoire autoreactivity may reflect the chances of generating autoreactivity by stochastic use of germline immunoglobulin gene segments or active mechanisms may select autoreactive cells during egress to the naïve peripheral B cell pool. Likewise, it is unclear why in some individuals autoreactive B cell clones become activated and drive pathophysiologic changes in autoimmune diseases. Both of these remain central questions in the study of the immune system(s). In most individuals, autoimmune diseases arise from complex interplay of genetic risk factors and environmental influences. Advances in genome sequencing and increased statistical power from large autoimmune disease cohorts has led to identification of more than 200 autoimmune disease risk loci. It has been observed that autoantibodies are detectable in the serum years to decades prior to the diagnosis of autoimmune disease. Thus, current models hold that genetic defects in the pathways that control autoreactive B cell tolerance set genetic liability thresholds across multiple autoimmune diseases. Despite the fact these seminal concepts were developed in animal (especially murine) models of autoimmune disease, some perceive a disconnect between human risk alleles and those identified in murine models of autoimmune disease. Here, we synthesize the current state of the art in our understanding of human risk alleles in two prototypical autoimmune diseases - systemic lupus erythematosus (SLE) and type 1 diabetes (T1D) along with spontaneous murine disease models. We compare these risk networks to those reported in murine models of these diseases, focusing on pathways relevant to anergy and central tolerance. We highlight some differences between murine and human environmental and genetic factors that may impact autoimmune disease development and expression and may, in turn, explain some of this discrepancy. Finally, we show that there is substantial overlap between the molecular networks that define these disease states across species. Our synthesis and analysis of the current state of the field are consistent with the idea that the same molecular networks are perturbed in murine and human autoimmune disease. Based on these analyses, we anticipate that murine autoimmune disease models will continue to yield novel insights into how best to diagnose, prognose, prevent and treat human autoimmune diseases.
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Affiliation(s)
- Isaac T. W. Harley
- Division of Rheumatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
- Human Immunology and Immunotherapy Initiative (HI3), Department of Immunology, University of Colorado School of Medicine, Aurora, CO, United States
- Rheumatology Section, Medicine Service, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, United States
| | - Kristen Allison
- Division of Rheumatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
- Human Immunology and Immunotherapy Initiative (HI3), Department of Immunology, University of Colorado School of Medicine, Aurora, CO, United States
| | - R. Hal Scofield
- Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
- Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
- Medical/Research Service, US Department of Veterans Affairs Medical Center, Oklahoma City, OK, United States
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13
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Hu M, Chen Z, Liao Y, Wu J, Zheng D, Zhang H. Clinical value of the expression levels of protein tyrosine phosphatase non-receptor type 22.6 mRNA in peripheral blood mononuclear cells in Crohn's disease. Clin Exp Immunol 2022; 209:311-315. [PMID: 35751647 PMCID: PMC9521657 DOI: 10.1093/cei/uxac061] [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: 04/27/2022] [Revised: 06/16/2022] [Accepted: 06/24/2022] [Indexed: 01/23/2023] Open
Abstract
OBJECTIVE To explore the relationship between the expression levels of protein tyrosine phosphatase non-receptor type (PTPN) 22.6 mRNA in peripheral blood mononuclear cells (PBMCs) and the disease activity as well as clinical characteristics in Crohn's disease (CD) patients. METHODS A total of 480 subjects were enrolled. Data were collected including baseline information, expression levels of PTPN22.6 mRNA in PBMCs for all subjects, C-reactive protein (CRP) levels in serum, clinical characteristics, and disease activity for all patients. Expression levels of PTPN22.6 mRNA in PBMCs, CRP levels in serum, clinical characteristics according to Montreal Classification [8], and Crohn's disease activity index (CDAI) were the primary observation outcomes. RESULTS The expression levels of PTPN22.6 mRNA (P = 0.032) in PBMCs and serum CRP levels (P < 0.001) were significantly higher in active CD patients than in inactive CD patients (P = 0.032). Correlation analysis showed that there was a positive correlation between expression levels of PTPN22.6 mRNA and CDAI value (r = 0.512, P = 0.003), as well as expression levels of PTPN22.6 mRNA and CRP levels in the CD group (r = 0.456, P = 0.006). There were significantly higher expression levels of PTPN22.6 mRNA in PBMCs in patients with structuring behavior than that in patients with non-stricturing and non-penetrating (NSNP) behaviors (P = 0.018) and penetrating behaviors (P = 0.024). CONCLUSIONS The expression levels of PTPN22.6 mRNA can be used as an indicator to help predict CD diagnosis, disease activity, serum CRP level, and behavior type of CD disease.
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Affiliation(s)
| | | | - Yusheng Liao
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory for Molecular Diagnosis of Hubei Province, Wuhan, People’s Republic of China
| | - Jie Wu
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory for Molecular Diagnosis of Hubei Province, Wuhan, People’s Republic of China
| | - Dan Zheng
- Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory for Molecular Diagnosis of Hubei Province, Wuhan, People’s Republic of China
| | - Heng Zhang
- Correspondence: Heng Zhang, Department of Gastroenterology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology Sheng Li Street 26, Wuhan 430014, Hubei Province, People’s Republic of China.
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14
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Jassim BA, Lin J, Zhang ZY. PTPN22: Structure, Function, and Developments in Inhibitor Discovery with Applications for Immunotherapy. Expert Opin Drug Discov 2022; 17:825-837. [PMID: 35637605 PMCID: PMC9378720 DOI: 10.1080/17460441.2022.2084607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION While immunotherapy strategies such as immune checkpoint inhibition and adoptive T cell therapy have become commonplace in cancer therapy, they suffer from limitations, including lack of patient response and toxicity. To wield the maximum potential of the immune system, cancer immunotherapy must integrate novel targets and therapeutic strategies with potential to augment clinical efficacy of currently utilized immunotherapies. PTPN22, a member of the protein tyrosine phosphatase (PTP) superfamily that downregulates T cell signaling and proliferation, has recently emerged as a systemically druggable and novel immunotherapy target. AREAS COVERED This review describes the basics of PTPN22 structure and function and provides comprehensive insight into recent advances in small molecule PTPN22 inhibitor development and the immense potential of PTPN22 inhibition to synergize with current immunotherapies. EXPERT OPINION It is apparent that small molecule PTPN22 inhibitors have enormous potential to augment efficacy of current immunotherapy strategies such as checkpoint inhibition and adoptive cell transfer. Nevertheless, several constraints must be overcome before these inhibitors can be applied as useful therapeutics, namely selectivity, potency, and in vivo efficacy.
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Affiliation(s)
- Brenson A Jassim
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Institute for Drug Discovery, West Lafayette
| | - Jianping Lin
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Institute for Drug Discovery, West Lafayette
| | - Zhong-Yin Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Institute for Drug Discovery, West Lafayette
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15
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Gootjes C, Zwaginga JJ, Roep BO, Nikolic T. Functional Impact of Risk Gene Variants on the Autoimmune Responses in Type 1 Diabetes. Front Immunol 2022; 13:886736. [PMID: 35603161 PMCID: PMC9114814 DOI: 10.3389/fimmu.2022.886736] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/08/2022] [Indexed: 11/17/2022] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease that develops in the interplay between genetic and environmental factors. A majority of individuals who develop T1D have a HLA make up, that accounts for 50% of the genetic risk of disease. Besides these HLA haplotypes and the insulin region that importantly contribute to the heritable component, genome-wide association studies have identified many polymorphisms in over 60 non-HLA gene regions that also contribute to T1D susceptibility. Combining the risk genes in a score (T1D-GRS), significantly improved the prediction of disease progression in autoantibody positive individuals. Many of these minor-risk SNPs are associated with immune genes but how they influence the gene and protein expression and whether they cause functional changes on a cellular level remains a subject of investigation. A positive correlation between the genetic risk and the intensity of the peripheral autoimmune response was demonstrated both for HLA and non-HLA genetic risk variants. We also observed epigenetic and genetic modulation of several of these T1D susceptibility genes in dendritic cells (DCs) treated with vitamin D3 and dexamethasone to acquire tolerogenic properties as compared to immune activating DCs (mDC) illustrating the interaction between genes and environment that collectively determines risk for T1D. A notion that targeting such genes for therapeutic modulation could be compatible with correction of the impaired immune response, inspired us to review the current knowledge on the immune-related minor risk genes, their expression and function in immune cells, and how they may contribute to activation of autoreactive T cells, Treg function or β-cell apoptosis, thus contributing to development of the autoimmune disease.
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Affiliation(s)
- Chelsea Gootjes
- Laboratory of Immunomodulation and Regenerative Cell Therapy, Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Jaap Jan Zwaginga
- Laboratory of Immunomodulation and Regenerative Cell Therapy, Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Bart O Roep
- Laboratory of Immunomodulation and Regenerative Cell Therapy, Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
| | - Tatjana Nikolic
- Laboratory of Immunomodulation and Regenerative Cell Therapy, Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
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16
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He YQ, Qiao YL, Xu S, Jiao WE, Yang R, Kong YG, Tao ZZ, Chen SM. Allergen induces CD11c+ dendritic cell autophagy to aggravate allergic rhinitis through promoting immune imbalance. Int Immunopharmacol 2022; 106:108611. [DOI: 10.1016/j.intimp.2022.108611] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 01/27/2022] [Accepted: 02/04/2022] [Indexed: 12/14/2022]
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17
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Kissler S. Genetic Modifiers of Thymic Selection and Central Tolerance in Type 1 Diabetes. Front Immunol 2022; 13:889856. [PMID: 35464420 PMCID: PMC9021641 DOI: 10.3389/fimmu.2022.889856] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 03/21/2022] [Indexed: 02/02/2023] Open
Abstract
Type 1 diabetes (T1D) is caused by the T cell-driven autoimmune destruction of insulin-producing cells in the pancreas. T1D served as the prototypical autoimmune disease for genome wide association studies (GWAS) after having already been the subject of many linkage and association studies prior to the development of GWAS technology. Of the many T1D-associated gene variants, a minority appear disease-specific, while most are shared with one or more other autoimmune condition. Shared disease variants suggest defects in fundamental aspects of immune tolerance. The first layer of protective tolerance induction is known as central tolerance and takes place during the thymic selection of T cells. In this article, we will review candidate genes for type 1 diabetes whose function implicates them in central tolerance. We will describe examples of gene variants that modify the function of T cells intrinsically and others that indirectly affect thymic selection. Overall, these insights will show that a significant component of the genetic risk for T1D - and autoimmunity in general - pertains to the earliest stages of tolerance induction, at a time when protective intervention may not be feasible.
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Affiliation(s)
- Stephan Kissler
- Section for Immunobiology, Joslin Diabetes Center, Boston, MA, United States,Department of Medicine, Harvard Medical School, Boston, MA, United States,*Correspondence: Stephan Kissler,
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18
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The Immunogenetics of Vasculitis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1367:299-334. [DOI: 10.1007/978-3-030-92616-8_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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19
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Yap BJM, Lai-Foenander AS, Goh BH, Ong YS, Duangjai A, Saokaew S, Chua CLL, Phisalprapa P, Yap WH. Unraveling the Immunopathogenesis and Genetic Variants in Vasculitis Toward Development of Personalized Medicine. Front Cardiovasc Med 2021; 8:732369. [PMID: 34621800 PMCID: PMC8491767 DOI: 10.3389/fcvm.2021.732369] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 08/26/2021] [Indexed: 12/23/2022] Open
Abstract
Leukocytoclastic vasculitis (LCV) is a systemic autoimmune disease characterized by the inflammation of the vascular endothelium. Cutaneous small vessel vasculitis (CSVV) and anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) are two examples of LCV. Advancements in genomic technologies have identified risk haplotypes, genetic variants, susceptibility loci and pathways that are associated with vasculitis immunopathogenesis. The discovery of these genetic factors and their corresponding cellular signaling aberrations have enabled the development and use of novel therapeutic strategies for vasculitis. Personalized medicine aims to provide targeted therapies to individuals who show poor response to conventional interventions. For example, monoclonal antibody therapies have shown remarkable efficacy in achieving disease remission. Here, we discuss pathways involved in disease pathogenesis and the underlying genetic associations in different populations worldwide. Understanding the immunopathogenic pathways in vasculitis and identifying associated genetic variations will facilitate the development of novel and targeted personalized therapies for patients.
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Affiliation(s)
- Bryan Ju Min Yap
- School of Biosciences, Taylor's University, Subang Jaya, Malaysia
| | | | - Bey Hing Goh
- Biofunctional Molecule Exploratory Research Group (BMEX), School of Pharmacy, Monash University Malaysia, Bandar Sunway, Malaysia.,College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yong Sze Ong
- Biofunctional Molecule Exploratory Research Group (BMEX), School of Pharmacy, Monash University Malaysia, Bandar Sunway, Malaysia
| | - Acharaporn Duangjai
- Unit of Excellence in Research and Product Development of Coffee, Division of Physiology, School of Medical Sciences, University of Phayao, Phayao, Thailand.,Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.,Unit of Excellence on Clinical Outcomes Research and IntegratioN (UNICORN), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
| | - Surasak Saokaew
- Unit of Excellence in Research and Product Development of Coffee, Division of Physiology, School of Medical Sciences, University of Phayao, Phayao, Thailand.,Center of Health Outcomes Research and Therapeutic Safety (Cohorts), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.,Unit of Excellence on Clinical Outcomes Research and IntegratioN (UNICORN), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.,Unit of Excellence on Herbal Medicine, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand.,Division of Pharmacy Practice, Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand
| | | | - Pochamana Phisalprapa
- Division of Ambulatory Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Wei Hsum Yap
- School of Biosciences, Taylor's University, Subang Jaya, Malaysia.,Centre for Drug Discovery and Molecular Pharmacology (CDDMP), Faculty of Health and Medical Sciences (FHMS), Taylor's University, Subang Jaya, Malaysia
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20
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Orozco RC, Marquardt K, Mowen K, Sherman LA. Proautoimmune Allele of Tyrosine Phosphatase, PTPN22, Enhances Tumor Immunity. THE JOURNAL OF IMMUNOLOGY 2021; 207:1662-1671. [PMID: 34417261 DOI: 10.4049/jimmunol.2100304] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 07/07/2021] [Indexed: 12/13/2022]
Abstract
The 1858C>T allele of the tyrosine phosphatase PTPN22 (causing amino acid substitution R620W in encoded protein lymphoid tyrosine phosphatase) is present in 5-10% of the North American population and is strongly associated with numerous autoimmune diseases. Although much research has been done to define how this allele potentiates autoimmunity, the influence PTPN22 and its proautoimmune allele have in tumor immunity is poorly defined. To interrogate the role this allele may have in the antitumor immune response, we used CRISPR/Cas9 to generate mice in which the ortholog of lymphoid tyrosine phosphatase, PEST domain-enriched protein (PEP), is mutated at position 619 to produce the relevant proautoimmune mutation (R619W). Results of this study show that mice homozygous for this alteration (PEP-619WW) resist tumor growth as compared with wild-type mice. Consistent with these results, tumors from PEP-619WW mice have more CD45 infiltrates containing more activated CD8 T cells and CD4 T cells. In addition, there are more conventional dendritic cell type 1 (cDC1) cells and fewer myeloid-derived suppressor cells in tumors from PEP-619WW mice. Interestingly, the tumor-infiltrating PEP-619WW cDC1 cells have decreased PD-L1 expression compared with cDC1 cells from PEP-wild-type mice. Taken together, our data show that the proautoimmune allele of Ptpn22 drives a strong antitumor response in innate and adaptive immune cells resulting in superior control of tumors.
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Affiliation(s)
- Robin C Orozco
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Kristi Marquardt
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Kerri Mowen
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
| | - Linda A Sherman
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
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21
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Ho WJ, Croessmann S, Lin J, Phyo ZH, Charmsaz S, Danilova L, Mohan AA, Gross NE, Chen F, Dong J, Aggarwal D, Bai Y, Wang J, He J, Leatherman JM, Yarchoan M, Armstrong TD, Zaidi N, Fertig EJ, Denny JC, Park BH, Zhang ZY, Jaffee EM. Systemic inhibition of PTPN22 augments anticancer immunity. J Clin Invest 2021; 131:146950. [PMID: 34283806 PMCID: PMC8409589 DOI: 10.1172/jci146950] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 07/16/2021] [Indexed: 12/19/2022] Open
Abstract
Both epidemiologic and cellular studies in the context of autoimmune diseases have established that protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a key regulator of T cell receptor (TCR) signaling. However, its mechanism of action in tumors and its translatability as a target for cancer immunotherapy have not been established. Here we show that a germline variant of PTPN22, rs2476601, portended a lower likelihood of cancer in patients. PTPN22 expression was also associated with markers of immune regulation in multiple cancer types. In mice, lack of PTPN22 augmented antitumor activity with greater infiltration and activation of macrophages, natural killer (NK) cells, and T cells. Notably, we generated a novel small molecule inhibitor of PTPN22, named L-1, that phenocopied the antitumor effects seen in genotypic PTPN22 knockout. PTPN22 inhibition promoted activation of CD8+ T cells and macrophage subpopulations toward MHC-II expressing M1-like phenotypes, both of which were necessary for successful antitumor efficacy. Increased PD1-PDL1 axis in the setting of PTPN22 inhibition could be further leveraged with PD1 inhibition to augment antitumor effects. Similarly, cancer patients with the rs2476601 variant responded significantly better to checkpoint inhibitor immunotherapy. Our findings suggest that PTPN22 is a druggable systemic target for cancer immunotherapy.
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Affiliation(s)
- Won Jin Ho
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Sarah Croessmann
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jianping Lin
- Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, USA
| | - Zaw H. Phyo
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Soren Charmsaz
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Ludmila Danilova
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Aditya A. Mohan
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Nicole E. Gross
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Fangluo Chen
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Jiajun Dong
- Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, USA
| | - Devesh Aggarwal
- Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, USA
| | - Yunpeng Bai
- Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, USA
| | - Janey Wang
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Jing He
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - James M. Leatherman
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Mark Yarchoan
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Todd D. Armstrong
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Neeha Zaidi
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Elana J. Fertig
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
| | - Joshua C. Denny
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- All of Us Research Program and National Human Genome Research Institute, NIH, Bethesda, Maryland, USA
| | - Ben H. Park
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Zhong-Yin Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology, Department of Chemistry, Center for Cancer Research and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana, USA
| | - Elizabeth M. Jaffee
- Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA
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22
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Tizaoui K, Terrazzino S, Cargnin S, Lee KH, Gauckler P, Li H, Shin JI, Kronbichler A. The role of PTPN22 in the pathogenesis of autoimmune diseases: A comprehensive review. Semin Arthritis Rheum 2021; 51:513-522. [PMID: 33866147 DOI: 10.1016/j.semarthrit.2021.03.004] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 01/16/2021] [Accepted: 03/03/2021] [Indexed: 02/07/2023]
Abstract
The incidence of autoimmune diseases is increasing worldwide, thus stimulating studies on their etiopathogenesis, derived from a complex interaction between genetic and environmental factors. Genetic association studies have shown the PTPN22 gene as a shared genetic risk factor with implications in multiple autoimmune disorders. By encoding a protein tyrosine phosphatase expressed by the majority of cells belonging to the innate and adaptive immune systems, the PTPN22 gene may have a fundamental role in the development of immune dysfunction. PTPN22 polymorphisms are associated with rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, and many other autoimmune conditions. In this review, we discuss the progress in our understanding of how PTPN22 impacts autoimmunity in both humans and animal models. In addition, we highlight the pathogenic significance of the PTPN22 gene, with particular emphasis on its role in T and B cells, and its function in innate immune cells, such as monocytes, dendritic and natural killer cells. We focus particularly on the complexity of PTPN22 interplay with biological processes of the immune system. Findings highlight the importance of studying the function of disease-associated PTPN22 variants in different cell types and open new avenues of investigation with the potential to drive further insights into mechanisms of PTPN22. These new insights will reveal important clues to the molecular mechanisms of prevalent autoimmune diseases and propose new potential therapeutic targets.
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Affiliation(s)
- Kalthoum Tizaoui
- Department of Basic Sciences, Division of Histology and Immunology, Faculty of Medicine Tunis, Tunis El Manar University, Tunis 1068, Tunisia
| | - Salvatore Terrazzino
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Novara, Italy
| | - Sarah Cargnin
- Department of Pharmaceutical Sciences and Interdepartmental Research Center of Pharmacogenetics and Pharmacogenomics (CRIFF), University of Piemonte Orientale, Novara, Italy
| | - Keum Hwa Lee
- Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Philipp Gauckler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
| | - Han Li
- University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
| | - Andreas Kronbichler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
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23
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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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24
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Multi-color Molecular Visualization of Signaling Proteins Reveals How C-Terminal Src Kinase Nanoclusters Regulate T Cell Receptor Activation. Cell Rep 2020; 33:108523. [PMID: 33357425 DOI: 10.1016/j.celrep.2020.108523] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 07/07/2020] [Accepted: 11/24/2020] [Indexed: 11/22/2022] Open
Abstract
Elucidating the mechanisms that controlled T cell activation requires visualization of the spatial organization of multiple proteins on the submicron scale. Here, we use stoichiometrically accurate, multiplexed, single-molecule super-resolution microscopy (DNA-PAINT) to image the nanoscale spatial architecture of the primary inhibitor of the T cell signaling pathway, Csk, and two binding partners implicated in its membrane association, PAG and TRAF3. Combined with a newly developed co-clustering analysis framework, we find that Csk forms nanoscale clusters proximal to the plasma membrane that are lost post-stimulation and are re-recruited at later time points. Unexpectedly, these clusters do not co-localize with PAG at the membrane but instead provide a ready pool of monomers to downregulate signaling. By generating CRISPR-Cas9 knockout T cells, our data also identify that a major risk factor for autoimmune diseases, the protein tyrosine phosphatase non-receptor type 22 (PTPN22) locus, is essential for Csk nanocluster re-recruitment and for maintenance of the synaptic PAG population.
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25
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Cubas R, Khan Z, Gong Q, Moskalenko M, Xiong H, Ou Q, Pai C, Rodriguez R, Cheung J, Chan AC. Autoimmunity linked protein phosphatase PTPN22 as a target for cancer immunotherapy. J Immunother Cancer 2020; 8:jitc-2020-001439. [PMID: 33127657 PMCID: PMC7604869 DOI: 10.1136/jitc-2020-001439] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/09/2020] [Indexed: 12/21/2022] Open
Abstract
Background Cancer immunotherapy has evolved from interferon-alpha (IFNα) and interleukin-2 in the 1980s to CTLA-4 and PD-1/PD-L1 checkpoint inhibitors (CPIs), the latter highlighting the importance of enhancing T-cell functions. While the search for novel immunomodulatory pathways continues, combination therapies augmenting multiple pathways can also increase efficacy. The association of autoimmune-related adverse events with clinical efficacy following CPI treatment has been inferred and suggests that breaking tolerance thresholds associated with autoimmunity may affect host immune responses for effective cancer immunotherapy. Results Here, we show that loss of autoimmune associated PTPN22, a key desensitization node for multiple signaling pathways, including IFNα receptor (IFNAR) and T-cell receptor, can augment tumor responses. Implantation of syngeneic tumors in Ptpn22-/- mice led to expansion and activation of peripheral and intratumoral T cells and, in turn, spontaneous tumor regression as well as enhanced responses in combination with anti-PD-L1 treatment. Using genetically modified mice expressing a catalytically inactive PTPN22 or the autoimmunity-associated human single-nucleotide polymorphism variant, augmentation of antitumor immunity was dependent on PTPN22 phosphatase activity and partially on its adaptor functions. Further, antitumor responses were dependent on both CD4+ and CD8+T cells and, in part, IFNAR function. Finally, we demonstrate that the autoimmune susceptibility Ptpn22(C1858T) variant is associated with lower risk of developing non-melanoma skin cancers, improved overall survival and increased risk for development of hyperthyroidism or hypothyroidism following atezolizumab (anti-PD-L1) treatment. Conclusions Together, these data suggest that inhibition of PTPN22 phosphatase activity may provide an effective therapeutic option for cancer immunotherapy and that exploring genetic variants that shift immune tolerance thresholds may serve as a paradigm for finding new cancer immunotherapy targets.
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Affiliation(s)
- Rafael Cubas
- Department of Translational Oncology, Genentech Inc, South San Francisco, California, USA
| | - Zia Khan
- Department of Human Genetics, Genentech, Inc, South San Francisco, California, USA
| | - Qian Gong
- Department of Research- Biology, Genentech, Inc, South San Francisco, California, USA
| | - Marina Moskalenko
- Department of Translational Oncology, Genentech Inc, South San Francisco, California, USA
| | - Huizhong Xiong
- Department of Translational Oncology, Genentech Inc, South San Francisco, California, USA
| | - Qinglin Ou
- Department of Research- Biology, Genentech, Inc, South San Francisco, California, USA
| | - Christine Pai
- Department of Research- Biology, Genentech, Inc, South San Francisco, California, USA
| | - Ryan Rodriguez
- Department of Translational Oncology, Genentech Inc, South San Francisco, California, USA
| | - Jeanne Cheung
- Department of Cancer Immunology, Genentech, Inc, South San Francisco, California, USA
| | - Andrew C Chan
- Department of Research- Biology, Genentech, Inc, South San Francisco, California, USA
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26
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Abbasifard M, Imani D, Bagheri-Hosseinabadi Z. PTPN22 gene polymorphism and susceptibility to rheumatoid arthritis (RA): Updated systematic review and meta-analysis. J Gene Med 2020; 22:e3204. [PMID: 32333475 DOI: 10.1002/jgm.3204] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 02/13/2020] [Accepted: 04/12/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Several genome-wide association studies have revealed a genetic background with respect to susceptibility to rheumatoid arthritis (RA). Although several individual case-control studies have evaluated the role of protein tyrosine phosphatase non-receptor 22 (PTPN22) gene rs2476601 single nucleotide polymorphism (SNP) in conferring a risk for RA, the results have been conflicting. Hence, this meta-analysis was aimed to provide a solution for this issue. METHODS To search for studies assessing the association between the PTPN22 gene rs2476601 SNP and the risk of RA, a systematic search was conducted in the main databases, including PubMed, Scopus and Web of Science, prior to December 2019. The odds ratio (OR) and corresponding 95% confidence interval (CI) was calculated to assess the possibility of association risk. RESULTS The literature search identified 52 case-control studies. The pooled analysis detected significant positive association of rs2476601 in all genetic models, including dominant model (OR = 1.69, 95% CI = 1.55-1.84, P < 0.001), recessive model (OR = 2.50, 95% CI = 2.06-3.05, P < 0.001), allelic model (OR = 1.80, 95% CI = 1.60-2.2, P < 0.001), TT versus CC model (OR = 2.79, 95% CI = 2.28-3.41, P < 0.001) and CT versus CC model (OR = 1.59, 95% CI = 1.50-1.67, P < 0.001). Analyses based on population stratification indicated that rs2476601 SNP strongly increased the risk of RA in Caucasians and Africans under all genotype models. CONCLUSIONS This meta-analysis reports that the PTPN22 gene rs2476601 SNP increases RA risk, especially in Caucasians and Africans.
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Affiliation(s)
- Mitra Abbasifard
- Department of internal Medicine, Ali-Ibn Abi-Talib hospital, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
- Rheumatology Research Center, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Danyal Imani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Zahra Bagheri-Hosseinabadi
- Department of Clinical Biochemistry, Faculty of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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27
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Zhang X, Yu Y, Bai B, Wang T, Zhao J, Zhang N, Zhao Y, Wang X, Wang B. PTPN22 interacts with EB1 to regulate T-cell receptor signaling. FASEB J 2020; 34:8959-8974. [PMID: 32469452 DOI: 10.1096/fj.201902811rr] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 02/14/2020] [Accepted: 03/18/2020] [Indexed: 12/21/2022]
Abstract
The PTPN22 gene encoding the Lyp/Pep protein tyrosine phosphatase is a negative regulator of T-cell receptor (TCR) signaling. Recent studies have shown that phosphorylation of end-binding protein 1 (EB1) is associated with the TCR activation. In this study, using 2-hybrid and mass spectrometry analyses, we identified EB1 as a protein associated with PTPN22. Furthermore, we discovered that EB1 specifically bound to the P1 domain of PTPN22 by competing with CSK, and the variant PTPN22-R620W does not affect the association with EB1, which is instrumental with respect to the regulation of TCR signaling. In addition, PTPN22 dephosphorylates EB1 at tyrosine-247 (Y247), which decreases the expression of the T-cell activation markers CD25 and CD69 and the phosphorylation levels of the TCR molecules ZAP-70, LAT, and Erk, leading to the eventual downregulation of the transcription factor NFAT and reduced the levels of secreted IL-2. The findings of this study provide new insights into the TCR signaling and the T-cell immune response, which are important for clarifying the mechanism of PTPN22-related autoimmune diseases.
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Affiliation(s)
- Xiaonan Zhang
- Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang, P.R. China
| | - Yang Yu
- Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang, P.R. China
| | - Bin Bai
- Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang, P.R. China
| | - Tao Wang
- Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang, P.R. China
| | - Jiahui Zhao
- Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang, P.R. China
| | - Na Zhang
- Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang, P.R. China
| | - Yanjiao Zhao
- Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang, P.R. China
| | - Xipeng Wang
- Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang, P.R. China
| | - Bing Wang
- Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang, P.R. China
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28
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Yang S, Svensson MND, Harder NHO, Hsieh WC, Santelli E, Kiosses WB, Moresco JJ, Yates JR, King CC, Liu L, Stanford SM, Bottini N. PTPN22 phosphorylation acts as a molecular rheostat for the inhibition of TCR signaling. Sci Signal 2020; 13:13/623/eaaw8130. [PMID: 32184287 DOI: 10.1126/scisignal.aaw8130] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The hematopoietic-specific protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is encoded by a major autoimmunity risk gene. PTPN22 inhibits T cell activation by dephosphorylating substrates involved in proximal T cell receptor (TCR) signaling. Here, we found by mass spectrometry that PTPN22 was phosphorylated at Ser751 by PKCα in Jurkat and primary human T cells activated with phorbol ester/ionomycin or antibodies against CD3/CD28. The phosphorylation of PTPN22 at Ser751 prolonged its half-life by inhibiting K48-linked ubiquitination and impairing recruitment of the phosphatase to the plasma membrane, which is necessary to inhibit proximal TCR signaling. Additionally, the phosphorylation of PTPN22 at Ser751 enhanced the interaction of PTPN22 with the carboxyl-terminal Src kinase (CSK), an interaction that is impaired by the PTPN22 R620W variant associated with autoimmune disease. The phosphorylation of Ser751 did not affect the recruitment of PTPN22 R620W to the plasma membrane but protected this mutant from degradation. Together, out data indicate that phosphorylation at Ser751 mediates a reciprocal regulation of PTPN22 stability versus translocation to TCR signaling complexes by CSK-dependent and CSK-independent mechanisms.
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Affiliation(s)
- Shen Yang
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Mattias N D Svensson
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Nathaniel H O Harder
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.,Division of Cellular Biology, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Wan-Chen Hsieh
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Eugenio Santelli
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - William B Kiosses
- Core Microscopy, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - James J Moresco
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - John R Yates
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Charles C King
- Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA
| | - Lin Liu
- Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, 92037, USA.,Veterans Affairs San Diego Healthcare System, San Diego, CA 90026, USA
| | - Stephanie M Stanford
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.,Division of Cellular Biology, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
| | - Nunzio Bottini
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. .,Division of Cellular Biology, La Jolla Institute for Immunology, La Jolla, CA 92037, USA
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29
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Knipper JA, Wright D, Cope AP, Malissen B, Zamoyska R. PTPN22 Acts in a Cell Intrinsic Manner to Restrict the Proliferation and Differentiation of T Cells Following Antibody Lymphodepletion. Front Immunol 2020; 11:52. [PMID: 32047502 PMCID: PMC6997546 DOI: 10.3389/fimmu.2020.00052] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 01/09/2020] [Indexed: 11/25/2022] Open
Abstract
Lymphopenic insult has been shown to precipitate the initiation of autoimmune disease in murine models such as the Non-obese diabetic mouse. Similarly, in man lymphopenia induced by mAb therapy, for instance Alemtuzumab as treatment for Multiple Sclerosis, can precipitate development of secondary autoimmune disease in up to 30 % of patients. We asked whether an identified autoimmune susceptibility locus might increase the risk of developing autoimmunity in the context of mAb-induced lymphopenia in a mouse model. A single nucleotide polymorphism (SNP) in the gene encoding the tyrosine phosphatase PTPN22 (R620W) is associated with multiple human autoimmune diseases, and PTPN22 has been shown to modulate T cell responses, particularly to weak antigens. In keeping with this, PTPN22-deficient or PTPN22 R619W mutant murine T cells adoptively transferred into immunodeficient lymphopenic hosts showed a higher lymphopenia-induced proliferation rate than WT cells. We induced lymphopenia by treating wild-type or PTPN22 knock-out mice with T cell depleting antibodies and monitored reconstitution of the T cell pool. We found that PTPN22 deficient T cells acquired a more activated effector phenotype, with significantly more IFNγ producing cells. This resulted from expansion driven by self-peptide MHC, as it was evident when the contribution of IL-7 to lymphopenic expansion was blocked with IL-7R Ab. Interestingly, Foxp3+ Tregs were also considerably expanded in PTPN22-deficient and PTPN22 R619W mice, as was the frequency of both CD25+ and CD25- CD4 T cells that produce IL-10. Using bone marrow chimeric mice, we showed that PTPN22 influenced development of both regulatory and effector T cell functions in a cell-intrinsic manner. Overall the expansion of Tregs is likely to keep the expanded T effector populations in check and sparing Treg during therapeutic mAb depletion may be a useful strategy to prevent occurrence of secondary autoimmunity.
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Affiliation(s)
- Johanna A Knipper
- Ashworth Laboratories, Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom
| | - David Wright
- Ashworth Laboratories, Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Andrew P Cope
- Faculty of Life Sciences and Medicine, Centre for Inflammation Biology and Cancer Immunology, School of Immunology and Microbial Sciences, King's College London, London, United Kingdom
| | - Bernard Malissen
- Centre d'Immunologie de Marseille-Luminy, INSERM, CNRS, Aix Marseille Université, Marseille, France.,Centre d'Immunophénomique, Aix Marseille Université, INSERM, CNRS UMR, Marseille, France
| | - Rose Zamoyska
- Ashworth Laboratories, Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom
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30
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Valta M, Gazali AM, Viisanen T, Ihantola EL, Ekman I, Toppari J, Knip M, Veijola R, Ilonen J, Lempainen J, Kinnunen T. Type 1 diabetes linked PTPN22 gene polymorphism is associated with the frequency of circulating regulatory T cells. Eur J Immunol 2019; 50:581-588. [PMID: 31808541 DOI: 10.1002/eji.201948378] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 10/23/2019] [Indexed: 12/19/2022]
Abstract
Dysfunction of FOXP3-positive regulatory T cells (Tregs) likely plays a major role in the pathogenesis of multiple autoimmune diseases including type 1 diabetes (T1D). Whether genetic polymorphisms associated with the risk of autoimmune diseases affect Treg frequency or function is currently unclear. Here, we analysed the effect of T1D-associated major HLA class II haplotypes and seven single nucleotide polymorphisms in six non-HLA genes [INS (rs689), PTPN22 (rs2476601), IL2RA (rs12722495 and rs2104286), PTPN2 (rs45450798), CTLA4 (rs3087243), and ERBB3 (rs2292239)] on peripheral blood Treg frequencies. These were determined by flow cytometry in 65 subjects who had progressed to T1D, 86 islet autoantibody-positive at-risk subjects, and 215 islet autoantibody-negative healthy controls. The PTPN22 rs2476601 risk allele A was associated with an increase in total (p = 6 × 10-6 ) and naïve (p = 4 × 10-5 ) CD4+CD25+CD127lowFOXP3+ Treg frequencies. These findings were validated in a separate cohort comprising ten trios of healthy islet autoantibody-negative children carrying each of the three PTPN22 rs2476601 genotypes AA, AG, and GG (p = 0.005 for total and p = 0.03 for naïve Tregs, respectively). In conclusion, our analysis implicates the autoimmune PTPN22 rs2476601 risk allele A in controlling the frequency of Tregs in human peripheral blood.
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Affiliation(s)
- Milla Valta
- Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland
| | - Ahmad Mahfuz Gazali
- Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | - Tyyne Viisanen
- Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | - Emmi-Leena Ihantola
- Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | - Ilse Ekman
- Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | - Jorma Toppari
- Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland.,Department of Pediatrics, Turku University Hospital, Turku, Finland
| | - Mikael Knip
- Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Finland.,Folkhälsan Research Center, Helsinki, Finland.,Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland
| | - Riitta Veijola
- Department of Pediatrics, PEDEGO Research Unit, Medical Research Center, University of Oulu, Oulu, Finland and Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
| | - Jorma Ilonen
- Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.,Clinical Microbiology, Turku University Hospital, Turku, Finland
| | - Johanna Lempainen
- Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.,Department of Pediatrics, Turku University Hospital, Turku, Finland.,Clinical Microbiology, Turku University Hospital, Turku, Finland
| | - Tuure Kinnunen
- Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.,Eastern Finland Laboratory Centre (ISLAB), Kuopio, Finland
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31
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Anderson W, Thorpe J, Long SA, Rawlings DJ. Efficient CRISPR/Cas9 Disruption of Autoimmune-Associated Genes Reveals Key Signaling Programs in Primary Human T Cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2019; 203:3166-3178. [PMID: 31722988 PMCID: PMC6904544 DOI: 10.4049/jimmunol.1900848] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 10/10/2019] [Indexed: 12/18/2022]
Abstract
Risk of autoimmunity is associated with multiple genetic variants. Genome-wide association studies have linked single-nucleotide polymorphisms in the phosphatases PTPN22 (rs2476601) and PTPN2 (rs1893217) to increased risk for multiple autoimmune diseases. Previous mouse studies of loss of function or risk variants in these genes revealed hyperactive T cell responses, whereas studies of human lymphocytes revealed contrasting phenotypes. To better understand this dichotomy, we established a robust gene editing platform to rapidly address the consequences of loss of function of candidate genes in primary human CD4+ T cells. Using CRISPR/Cas9, we obtained efficient gene disruption (>80%) of target genes encoding proteins involved in Ag and cytokine receptor signaling pathways including PTPN22 and PTPN2 Loss-of-function data in all genes studied correlated with previous data from mouse models. Further analyses of PTPN2 gene-disrupted T cells demonstrated dynamic effects, by which hyperactive IL-2R signaling promoted compensatory transcriptional events, eventually resulting in T cells that were hyporesponsive to IL-2. These results imply that altered phosphatase activity promotes evolving phenotypes based on Ag experience and/or other programming signals. This approach enables the discovery of molecular mechanisms modulating risk of autoimmunity that have been difficult to parse in traditional mouse models or cross-sectional human studies.
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Affiliation(s)
- Warren Anderson
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101
- Department of Pathology, University of Washington, Seattle, WA 98195
| | - Jerill Thorpe
- Benaroya Research Institute at Virginia Mason, Seattle, WA 98101
| | - S Alice Long
- Benaroya Research Institute at Virginia Mason, Seattle, WA 98101
| | - David J Rawlings
- Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, WA 98101;
- Department of Pediatrics, University of Washington, Seattle, WA 98109; and
- Department of Immunology, University of Washington, Seattle, WA 98109
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32
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Lam S, Zuo T, Ho M, Chan FKL, Chan PKS, Ng SC. Review article: fungal alterations in inflammatory bowel diseases. Aliment Pharmacol Ther 2019; 50:1159-1171. [PMID: 31648369 DOI: 10.1111/apt.15523] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/08/2019] [Accepted: 09/11/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Emerging data suggest that alterations in gut fungi may be associated with the pathogenesis of inflammatory bowel disease (IBD). In healthy individuals, gut commensal fungi act synergistically with other members of the microbiota to maintain homeostasis but their role in IBD is less clear. AIM To review the role of gut fungi and their trans-kingdom interactions with bacteria in IBD METHODS: A literature search was conducted on Ovid and Pubmed to select relevant animal and human studies that have reported fungi and IBD. RESULTS There is an increased total fungal load particularly of Candida and Malassezia species in the faeces and mucosa of Crohn's disease patients, and a lower fungal diversity in the faeces of ulcerative colitis patients. Caspase recruitment domain-containing protein (CARD)-9 polymorphism in Crohn's disease patients favours Malassezia colonisation that worsens gut inflammation. Diet high in carbohydrates increased the total abundance of Candida species, whereas protein-rich diet had the opposite effect. Anti-fungal therapies are mostly used to treat Candida albicans or Histoplasma capsulatum infections in IBD, whereas pilot studies of supplementing fungal probiotics Saccharomycopsis fibuligera, Saccharomyces boulardii and Saccharomyces cerevisiae CNCM I-3856 strain showed therapeutic effects in IBD. CONCLUSIONS Gut fungi are altered in patients with Crohn's disease and ulcerative colitis. Modulation of the fungal microbiota can be considered as a therapeutic approach for IBD. Future research should focus on understanding how the fungal microbiota interacts with other components of the gut microbiota in association with the pathogenesis and development of IBD.
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Affiliation(s)
- Siu Lam
- Center for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Department of Medicine and Therapeutics, Institute of Digestive Disease, LKS Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.,Department of Microbiology, The Chinese University of Hong Kong, Hong Kong, China
| | - Tao Zuo
- Center for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Department of Medicine and Therapeutics, Institute of Digestive Disease, LKS Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China
| | - Martin Ho
- Department of Life Sciences, Imperial College London, London, UK
| | - Francis K L Chan
- Center for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Department of Medicine and Therapeutics, Institute of Digestive Disease, LKS Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China
| | - Paul K S Chan
- Center for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Department of Microbiology, The Chinese University of Hong Kong, Hong Kong, China
| | - Siew C Ng
- Center for Gut Microbiota Research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Department of Medicine and Therapeutics, Institute of Digestive Disease, LKS Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China
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Beyond the Cell Surface: Targeting Intracellular Negative Regulators to Enhance T cell Anti-Tumor Activity. Int J Mol Sci 2019; 20:ijms20235821. [PMID: 31756921 PMCID: PMC6929154 DOI: 10.3390/ijms20235821] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 11/04/2019] [Accepted: 11/07/2019] [Indexed: 02/07/2023] Open
Abstract
It is well established that extracellular proteins that negatively regulate T cell function, such as Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4) and Programmed Cell Death protein 1 (PD-1), can be effectively targeted to enhance cancer immunotherapies and Chimeric Antigen Receptor T cells (CAR-T cells). Intracellular proteins that inhibit T cell receptor (TCR) signal transduction, though less well studied, are also potentially useful therapeutic targets to enhance T cell activity against tumor. Four major classes of enzymes that attenuate TCR signaling include E3 ubiquitin kinases such as the Casitas B-lineage lymphoma proteins (Cbl-b and c-Cbl), and Itchy (Itch), inhibitory tyrosine phosphatases, such as Src homology region 2 domain-containing phosphatases (SHP-1 and SHP-2), inhibitory protein kinases, such as C-terminal Src kinase (Csk), and inhibitory lipid kinases such as Src homology 2 (SH2) domain-containing inositol polyphosphate 5-phosphatase (SHIP) and Diacylglycerol kinases (DGKs). This review describes the mechanism of action of eighteen intracellular inhibitory regulatory proteins in T cells within these four classes, and assesses their potential value as clinical targets to enhance the anti-tumor activity of endogenous T cells and CAR-T cells.
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Ferreira RC, Castro Dopico X, Oliveira JJ, Rainbow DB, Yang JH, Trzupek D, Todd SA, McNeill M, Steri M, Orrù V, Fiorillo E, Crouch DJM, Pekalski ML, Cucca F, Tree TI, Vyse TJ, Wicker LS, Todd JA. Chronic Immune Activation in Systemic Lupus Erythematosus and the Autoimmune PTPN22 Trp 620 Risk Allele Drive the Expansion of FOXP3 + Regulatory T Cells and PD-1 Expression. Front Immunol 2019; 10:2606. [PMID: 31781109 PMCID: PMC6857542 DOI: 10.3389/fimmu.2019.02606] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 10/21/2019] [Indexed: 02/01/2023] Open
Abstract
In systemic lupus erythematosus (SLE), perturbed immunoregulation underpins a pathogenic imbalance between regulatory and effector CD4+ T-cell activity. However, to date, the characterization of the CD4+ regulatory T cell (Treg) compartment in SLE has yielded conflicting results. Here we show that patients have an increased frequency of CD4+FOXP3+ cells in circulation owing to a specific expansion of thymically-derived FOXP3+HELIOS+ Tregs with a demethylated FOXP3 Treg-specific demethylated region. We found that the Treg expansion was strongly associated with markers of recent immune activation, including PD-1, plasma concentrations of IL-2 and the type I interferon biomarker soluble SIGLEC-1. Since the expression of the negative T-cell signaling molecule PTPN22 is increased and a marker of poor prognosis in SLE, we tested the influence of its missense risk allele Trp620 (rs2476601C>T) on Treg frequency. Trp620 was reproducibly associated with increased frequencies of thymically-derived Tregs in blood, and increased PD-1 expression on both Tregs and effector T cells (Teffs). Our results support the hypothesis that FOXP3+ Tregs are increased in SLE patients as a consequence of a compensatory mechanism in an attempt to regulate pathogenic autoreactive Teff activity. We suggest that restoration of IL-2-mediated homeostatic regulation of FOXP3+ Tregs by IL-2 administration could prevent disease flares rather than treating at the height of a disease flare. Moreover, stimulation of PD-1 with specific agonists, perhaps in combination with low-dose IL-2, could be an effective therapeutic strategy in autoimmune disease and in other immune disorders.
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Affiliation(s)
- Ricardo C. Ferreira
- JDRF/Wellcome Diabetes and Inflammation Laboratory, Nuffield Department of Medicine, Wellcome Centre for Human Genetics, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
| | - Xaquin Castro Dopico
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
| | - João J. Oliveira
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
| | - Daniel B. Rainbow
- JDRF/Wellcome Diabetes and Inflammation Laboratory, Nuffield Department of Medicine, Wellcome Centre for Human Genetics, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
| | - Jennie H. Yang
- Department of Immunobiology, NIHR Biomedical Research Centre, King's College London, London, United Kingdom
| | - Dominik Trzupek
- JDRF/Wellcome Diabetes and Inflammation Laboratory, Nuffield Department of Medicine, Wellcome Centre for Human Genetics, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
| | - Sarah A. Todd
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
| | - Mhairi McNeill
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
| | - Maristella Steri
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Rome, Italy
| | - Valeria Orrù
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Rome, Italy
| | - Edoardo Fiorillo
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Rome, Italy
| | - Daniel J. M. Crouch
- JDRF/Wellcome Diabetes and Inflammation Laboratory, Nuffield Department of Medicine, Wellcome Centre for Human Genetics, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
| | - Marcin L. Pekalski
- JDRF/Wellcome Diabetes and Inflammation Laboratory, Nuffield Department of Medicine, Wellcome Centre for Human Genetics, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
| | - Francesco Cucca
- Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Rome, Italy
- Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy
| | - Tim I. Tree
- Department of Immunobiology, NIHR Biomedical Research Centre, King's College London, London, United Kingdom
| | - Tim J. Vyse
- Department of Medical & Molecular Genetics, King's College London, Guy's Hospital, London, United Kingdom
| | - Linda S. Wicker
- JDRF/Wellcome Diabetes and Inflammation Laboratory, Nuffield Department of Medicine, Wellcome Centre for Human Genetics, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
| | - John A. Todd
- JDRF/Wellcome Diabetes and Inflammation Laboratory, Nuffield Department of Medicine, Wellcome Centre for Human Genetics, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
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Ghorban K, Ezzeddini R, Eslami M, Yousefi B, Sadighi Moghaddam B, Tahoori MT, Dadmanesh M, Salek Farrokhi A. PTPN22 1858 C/T polymorphism is associated with alteration of cytokine profiles as a potential pathogenic mechanism in rheumatoid arthritis. Immunol Lett 2019; 216:106-113. [PMID: 31669381 DOI: 10.1016/j.imlet.2019.10.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Revised: 10/12/2019] [Accepted: 10/20/2019] [Indexed: 01/17/2023]
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is one of the most common prevalent autoimmune diseases. The 1858 C/T (rs2476601) single nucleotide polymorphism (SNP) within the PTPN22 gene has been associated with susceptibility to inflammatory based diseases in several populations. It is implicated that altered cytokine production has a potential pathogenic role in the development of RA. The aim of this work was to analyze the association of 1858 C/T PTPN22 polymorphism in RA patients with cytokine profiles. MATERIALS AND METHODS This study was performed on 120 RA patients who were referred to the Rheumatology Research Centre, Shariati Hospital (Tehran, Iran), and 120 healthy controls. Genomic DNA was extracted and genotyped for 1858 C/T PTPN22 gene SNP using the PCR-RFLP technique. Serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ as well as Anti-CCP and RF was measured by ELISA method. RESULTS Results showed that 1858 C/T PTPN22 SNP significantly (P = 0.007, OR = 2.321, 95% CI = 1.063-5.067) associated with RA. The 1858 T allele frequency was also significantly increased in RA patients in comparison to the controls (P = 0.008, OR = 3.583, 95% CI = 1.3-9.878). Our data demonstrated a significant reduction of IL-4 and IL-10 in PTPN22 1858C/T compared to 1858C/C RA patients. In addition, upregulation of IL-6, IFN-γ, and TNF-α was observed in PTPN22 1858C/T vs. 1858C/C RA patients. DISCUSSION Our findings implicate altered cytokine profiles as a possible pathogenic mechanism by which the 1858 T allele may contribute to the progress of RA.
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Affiliation(s)
- Khodayar Ghorban
- Department of Immunology, Faculty of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Rana Ezzeddini
- Department of Clinical Biochemistry, School of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Majid Eslami
- Department of Bacteriology and Virology, Semnan University of Medical Sciences, Semnan, Iran
| | - Bahman Yousefi
- Department of Immunology, School of Medical Sciences, Semnan University of Medical Sciences, Semnan, Iran
| | - Bizhan Sadighi Moghaddam
- Department of Immunology, School of Medical Sciences, Semnan University of Medical Sciences, Semnan, Iran
| | - Mohammad-Taher Tahoori
- Department of Immunology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Maryam Dadmanesh
- Department of Infectious Diseases, Faculty of Medicine, Aja University of Medical Sciences, Tehran, Iran
| | - Amir Salek Farrokhi
- Department of Immunology, School of Medical Sciences, Semnan University of Medical Sciences, Semnan, Iran.
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Thude H, Tiede P, Marget M, Peine S, Nashan B, Koch M. Protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene polymorphisms in liver transplant donors and impact on acute cellular liver transplant rejection. HLA 2019; 95:40-44. [PMID: 31577847 DOI: 10.1111/tan.13706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 09/13/2019] [Accepted: 09/19/2019] [Indexed: 11/28/2022]
Abstract
The PTPN22 gene encodes the lymphoid protein tyrosine phosphatase involved in regulation the immune response. The single nucleotide polymorphisms (SNPs) rs1217388, rs1310182, rs2476601, and rs2488457 are located within the PTPN22 gene. We investigated whether these SNPs in liver transplant donors are associated with acute cellular rejection in the recipients. The SNPs were analyzed in donors (n = 104) of recipients who did not develop an acute cellular rejection and in donors (n = 53) of corresponding recipients developing an acute cellular rejection. No significant differences in genotype and allele frequencies of these SNPs were detected in either of the group. Our data suggest that these SNPs in liver transplant donors have no impact on the susceptibility of acute cellular liver transplant rejection.
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Affiliation(s)
- Hansjörg Thude
- Institute of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Petra Tiede
- Institute of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Matthias Marget
- Institute of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sven Peine
- Institute of Transfusion Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Björn Nashan
- Department of Hepatobiliary and Transplant Surgey, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martina Koch
- Department of Hepatobiliary and Transplant Surgey, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Jofra T, Galvani G, Cosorich I, De Giorgi L, Annoni A, Vecchione A, Sorini C, Falcone M, Fousteri G. Experimental colitis in IL-10-deficient mice ameliorates in the absence of PTPN22. Clin Exp Immunol 2019; 197:263-275. [PMID: 31194881 DOI: 10.1111/cei.13339] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/30/2019] [Indexed: 02/06/2023] Open
Abstract
Interleukin (IL)-10 plays a key role in controlling intestinal inflammation. IL-10-deficient mice and patients with mutations in IL-10 or its receptor, IL-10R, show increased susceptibility to inflammatory bowel diseases (IBD). Protein tyrosine phosphatase, non-receptor type 22 (PTPN22) controls immune cell activation and the equilibrium between regulatory and effector T cells, playing an important role in controlling immune homoeostasis of the gut. Here, we examined the role of PTPN22 in intestinal inflammation of IL-10-deficient (IL-10-/- ) mice. We crossed IL-10-/- mice with PTPN22-/- mice to generate PTPN22-/- IL-10-/- double knock-out mice and induced colitis with dextran sodium sulphate (DSS). In line with previous reports, DSS-induced acute and chronic colitis was exacerbated in IL-10-/- mice compared to wild-type (WT) controls. However, PTPN22-/- IL-10-/- double knock-out mice developed milder disease compared to IL-10-/- mice. IL-17-promoting innate cytokines and T helper type 17 (Th17) cells were markedly increased in PTPN22-/- IL-10-/- mice, but did not provide a protctive function. CXCL1/KC was also increased in PTPN22-/- IL-10-/- mice, but therapeutic injection of CXCL1/KC in IL-10-/- mice did not ameliorate colitis. These results show that PTPN22 promotes intestinal inflammation in IL-10-deficient mice, suggesting that therapeutic targeting of PTPN22 might be beneficial in patients with IBD and mutations in IL-10 and IL-10R.
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Affiliation(s)
- T Jofra
- Division of Immunology Transplantation and Infectious Diseases (DITID), Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - G Galvani
- Division of Immunology Transplantation and Infectious Diseases (DITID), Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - I Cosorich
- Division of Immunology Transplantation and Infectious Diseases (DITID), Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - L De Giorgi
- Division of Immunology Transplantation and Infectious Diseases (DITID), Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - A Annoni
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - A Vecchione
- Division of Immunology Transplantation and Infectious Diseases (DITID), Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - C Sorini
- Division of Immunology Transplantation and Infectious Diseases (DITID), Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - M Falcone
- Division of Immunology Transplantation and Infectious Diseases (DITID), Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - G Fousteri
- Division of Immunology Transplantation and Infectious Diseases (DITID), Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Milan, Italy
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PTPN22 Gene Polymorphisms Are Associated with Susceptibility to Large Artery Atherosclerotic Stroke and Microembolic Signals. DISEASE MARKERS 2019; 2019:2193835. [PMID: 31191743 PMCID: PMC6525845 DOI: 10.1155/2019/2193835] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 03/24/2019] [Accepted: 04/01/2019] [Indexed: 11/18/2022]
Abstract
Large artery atherosclerotic stroke (LAAS) is the most common ischemic stroke (IS) subtype, and microemboli may be clinically important for indicating increased risk of IS. The inflammatory process of atherosclerosis is well known, and lymphoid phosphatase (Lyp), which is encoded by the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene, plays an important role in the inflammatory response. Our study was intended to evaluate the relationship between PTPN22 gene and LAAS and microembolic signals (MES). Three loci of the PTPN22 gene (rs2476599, rs1217414, and rs2488457) were analyzed in 364 LAAS patients and 369 control subjects. A genotyping determination was performed using the TaqMan assay. The G allele of rs2488457 might be related to a higher risk for developing LAAS and MES (odds ratio (OR) = 1.456, 95% confidence interval (CI) 1.156-1.833, P = 0.001; OR = 1.652, 95% CI 1.177-2.319, P = 0.004, respectively). In the LAAS group, the prevalence of the GTG haplotype was higher (P < 0.001) and the prevalence of the GCC haplotype was lower (P = 0.001). An interaction analysis of rs2488457 with smoking showed that smokers with the CG/GG genotypes had a higher risk of LAAS, compared to nonsmokers with the rs2488457 CC genotype (OR = 2.492, 95% CI 1.510–4.114, P < 0.001). Our research indicated that the PTPN22 rs2488457 might be related to the occurrence of LAAS and MES in the Han Chinese population. In addition, the rs2488457 polymorphism and the environmental factor of smoking jointly influenced the susceptibility of LAAS.
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Pellegrino M, Ceccacci F, Petrini S, Scipioni A, De Santis S, Cappa M, Mancini G, Fierabracci A. Exploiting novel tailored immunotherapies of type 1 diabetes: Short interfering RNA delivered by cationic liposomes enables efficient down-regulation of variant PTPN22 gene in T lymphocytes. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2019; 18:371-379. [PMID: 30439564 DOI: 10.1016/j.nano.2018.11.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 10/08/2018] [Accepted: 11/01/2018] [Indexed: 12/16/2022]
Abstract
In autoimmune diseases as Type 1 diabetes, the actual treatment that provides the missing hormones is not able, however, to interrupt the underlining immunological mechanism. Importantly, novel immunotherapies are exploited to protect and rescue the remaining hormone producing cells. Among probable targets of immunotherapy, the C1858T mutation in the PTPN22 gene, which encodes for the lymphoid tyrosine phosphatase (Lyp) variant R620W, reveals an autoimmunity related pathophysiological role. Our scope was to establish new C1858T PTPN22 siRNA duplexes delivered by liposomal carriers (lipoplexes) to patients' PBMC. Following lipoplexes treatment, CD3+ and CD3- immunotypes were efficiently transfected; cell integrity and viability were preserved. Specific target mRNA down-modulation was observed. After T cell receptor stimulation, in lipoplexes-treated PBMC Lyp function was restored by increased release of IL-2 in cultures. Results set-up the stage for ultimate trials in the treatment of autoimmunity based on the specific inhibitory targeting of C1858T PTPN22 by lipoplexes.
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Affiliation(s)
| | - Francesca Ceccacci
- CNR Chemical Methodologies Institute-Section Mechanisms of reaction (CNR-IMC-SMR) c/o Sapienza University
| | | | | | | | - Marco Cappa
- Division of Endocrinology, Bambino Gesù Children's Hospital, IRCCS.
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Solouki S, August A, Huang W. Non-receptor tyrosine kinase signaling in autoimmunity and therapeutic implications. Pharmacol Ther 2019; 201:39-50. [PMID: 31082431 DOI: 10.1016/j.pharmthera.2019.05.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 04/18/2019] [Indexed: 12/17/2022]
Abstract
Autoimmune diseases are characterized by impaired immune tolerance towards self-antigens, leading to enhanced immunity to self by dysfunctional B cells and/or T cells. The activation of these cells is controlled by non-receptor tyrosine kinases (NRTKs), which are critical mediators of antigen receptor and cytokine receptor signaling pathways. NRTKs transduce, amplify and sustain activating signals that contribute to autoimmunity, and are counter-regulated by protein tyrosine phosphatases (PTPs). The function of and interaction between NRTKs and PTPs during the development of autoimmunity could be key points of therapeutic interference against autoimmune diseases. In this review, we summarize the current state of knowledge of the functions of NRTKs and PTPs involved in B cell receptor (BCR), T cell receptor (TCR), and cytokine receptor signaling pathways that contribute to autoimmunity, and discuss their targeting for therapeutic approaches against autoimmune diseases.
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Affiliation(s)
- Sabrina Solouki
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Avery August
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
| | - Weishan Huang
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA; Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA.
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Okada Y, Eyre S, Suzuki A, Kochi Y, Yamamoto K. Genetics of rheumatoid arthritis: 2018 status. Ann Rheum Dis 2019; 78:446-453. [PMID: 30530827 DOI: 10.1136/annrheumdis-2018-213678] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 11/06/2018] [Accepted: 11/07/2018] [Indexed: 01/08/2023]
Abstract
Study of the genetics of rheumatoid arthritis (RA) began about four decades ago with the discovery of HLA-DRB1 Since the beginning of this century, a number of non-HLA risk loci have been identified through genome-wide association studies (GWAS). We now know that over 100 loci are associated with RA risk. Because genetic information implies a clear causal relationship to the disease, research into the pathogenesis of RA should be promoted. However, only 20% of GWAS loci contain coding variants, with the remaining variants occurring in non-coding regions, and therefore, the majority of causal genes and causal variants remain to be identified. The use of epigenetic studies, high-resolution mapping of open chromatin, chromosomal conformation technologies and other approaches could identify many of the missing links between genetic risk variants and causal genetic components, thus expanding our understanding of RA genetics.
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Affiliation(s)
- Yukinori Okada
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan
- Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Stephen Eyre
- Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, The University of Manchester, Manchester, UK
| | - Akari Suzuki
- Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Yuta Kochi
- Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Kazuhiko Yamamoto
- Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
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Mustelin T, Bottini N, Stanford SM. The Contribution of PTPN22 to Rheumatic Disease. Arthritis Rheumatol 2019; 71:486-495. [PMID: 30507064 PMCID: PMC6438733 DOI: 10.1002/art.40790] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 11/27/2018] [Indexed: 12/22/2022]
Abstract
One of the unresolved questions in modern medicine is why certain individuals develop a disorder such as rheumatoid arthritis (RA) or lupus, while others do not. Contemporary science indicates that genetics is partly responsible for disease development, while environmental and stochastic factors also play a role. Among the many genes that increase the risk of autoimmune conditions, the risk allele encoding the W620 variant of protein tyrosine phosphatase N22 (PTPN22) is shared between multiple rheumatic diseases, suggesting that it plays a fundamental role in the development of immune dysfunction. Herein, we discuss how the presence of the PTPN22 risk allele may shape the signs and symptoms of these diseases. Besides the emerging clarity regarding how PTPN22 tunes T and B cell antigen receptor signaling, we discuss recent discoveries of important functions of PTPN22 in myeloid cell lineages. Taken together, these new insights reveal important clues to the molecular mechanisms of prevalent diseases like RA and lupus and may open new avenues for the development of personalized therapies that spare the normal function of the immune system.
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Affiliation(s)
- Tomas Mustelin
- Division of Rheumatology, Department of Medicine, University of Washington, 750 Republican Street, Room E507, Seattle, WA 99108, phone (206) 616-6130,
| | - Nunzio Bottini
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, MC0656, La Jolla, CA 92093-0656, phone (858) 246-2398 (N.B.) and (858) 246-2397 (S.M.S.), (N.B.) and (S.M.S.)
| | - Stephanie M. Stanford
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, MC0656, La Jolla, CA 92093-0656, phone (858) 246-2398 (N.B.) and (858) 246-2397 (S.M.S.), (N.B.) and (S.M.S.)
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Shaik NA, Banaganapalli B. Computational Molecular Phenotypic Analysis of PTPN22 (W620R), IL6R (D358A), and TYK2 (P1104A) Gene Mutations of Rheumatoid Arthritis. Front Genet 2019; 10:168. [PMID: 30899276 PMCID: PMC6416176 DOI: 10.3389/fgene.2019.00168] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 02/15/2019] [Indexed: 12/31/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disorder of bone joints caused by the complex interplay between several factors like body physiology, the environment with genetic background. The recent meta-analysis of GWAS has expanded the total number of RA-associated loci to more than 100, out of which approximately ∼97% (98 variants) loci are located in non-coding regions, and the other ∼3% (3 variants) are in three different non-HLA genes, i.e., TYK2 (Prp1104Ala), IL6R (Asp358Ala), and PTPN22 (Trp620Arg). However, whether these variants prompt changes in the protein phenotype with regards to its stability, structure, and interaction with other molecules, remains unknown. Thus, we selected the three clinically pathogenic variants described above, as positive controls and applied diverse computational methods to scrutinize if those mutations cause changes in the protein phenotype. Both wild type and mutant protein structures of PTPN22 (W620R), IL6R (D358A), and TYK2 (P1104A) were modeled and studied for structural deviations. Furthermore, we have also studied the secondary structure characteristics, solvent accessibility and stability, and the molecular interaction deformities caused by the amino acid substitutions. We observed that simple nucleotide predictions of SIFT, PolyPhen, CADD and FATHMM yields mixed findings in screening the RA-missense variants which showed a ≥P-value threshold of 5 × 10-8 in genome wide association studies. However, structure-based analysis confirms that mutant structures shows subtle but significant changes at their core regions, but their functional domains seems to lose wild type like functional interaction. Our findings suggest that the multidirectional computational analysis of clinically potential RA-mutations could act as a primary screening step before undertaking functional biology assays.
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Affiliation(s)
- Noor Ahmad Shaik
- Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.,Princess Al-Jawhara Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Babajan Banaganapalli
- Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.,Princess Al-Jawhara Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia
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Fike AJ, Elcheva I, Rahman ZSM. The Post-GWAS Era: How to Validate the Contribution of Gene Variants in Lupus. Curr Rheumatol Rep 2019; 21:3. [DOI: 10.1007/s11926-019-0801-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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PTPN22 +788 G>A (R263Q) Polymorphism is Associated with mRNA Expression but it is not a Susceptibility Marker for Rheumatoid Arthritis Patients from Western Mexico. Biochem Genet 2019; 57:455-465. [PMID: 30637604 DOI: 10.1007/s10528-019-09902-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 01/04/2019] [Indexed: 02/01/2023]
Abstract
PTPN22 represents an important non-HLA gene that has been strongly associated with rheumatoid arthritis (RA) pathogenesis. Several studies have reported a specific genetic variant for PTPN22 (+788 G>A; rs33996649) that might be associated with decreased RA risk in Caucasian population; nevertheless, its specific role in western Mexican population has not been yet described. A case-control study with 443 RA patients and 317 control subjects (CS) was conducted. The genotyping was performed by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) technique and the PTPN22 mRNA expression was determined by SYBR Green-based real-time quantitative-PCR assay. No association between the PTPN22 +788 G>A polymorphism and RA susceptibility in western Mexican population was found when comparing genotype and allelic frequencies between RA patients and CS (G/G vs. G/A: OR 0.55, p = 0.14, 95% CI 0.22-1.32; G vs. A: OR 0.56, p = 0.14, 95% CI 0.23-1.36). The PTPN22 mRNA expression increased 4.6-fold more in RA patients than in CS, and RA patients, carriers of PTPN22 +788 G/A genotype, expressed 15.6-fold more than RA patients carrying the homozygous G/G genotype. Overall, these results showed that the PTPN22 +788 G>A polymorphism is not associated with RA susceptibility in western Mexican population, whereas the presence of G/A genotype is associated with increased PTPN22 mRNA expression in RA patients.
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Abstract
INTRODUCTION Depression and posttraumatic stress disorder (PTSD) are two complex and debilitating psychiatric disorders that result in poor life and destructive behaviors against self and others. Currently, diagnosis is based on subjective rather than objective determinations leading to misdiagnose and ineffective treatments. Advances in novel neurobiological methods have allowed assessment of promising biomarkers to diagnose depression and PTSD, which offers a new means of appropriately treating patients. Areas covered: Biomarkers discovery in blood represents a fundamental tool to predict, diagnose, and monitor treatment efficacy in depression and PTSD. The potential role of altered HPA axis, epigenetics, NPY, BDNF, neurosteroid biosynthesis, the endocannabinoid system, and their function as biomarkers for mood disorders is discussed. Insofar, we propose the identification of a biomarker axis to univocally identify and discriminate disorders with large comorbidity and symptoms overlap, so as to provide a base of support for development of targeted treatments. We also weigh in on the feasibility of a future blood test for early diagnosis. Expert commentary: Potential biomarkers have already been assessed in patients' blood and need to be further validated through multisite large clinical trial stratification. Another challenge is to assess the relation among several interdependent biomarkers to form an axis that identifies a specific disorder and secures the best-individualized treatment. The future of blood-based tests for PTSD and depression is not only on the horizon but, possibly, already around the corner.
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Affiliation(s)
- Dario Aspesi
- a The Psychiatric Institute, Department of Psychiatry , University of Illinois at Chicago , Chicago , IL , USA
| | - Graziano Pinna
- a The Psychiatric Institute, Department of Psychiatry , University of Illinois at Chicago , Chicago , IL , USA
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Bray C, Wright D, Haupt S, Thomas S, Stauss H, Zamoyska R. Crispr/Cas Mediated Deletion of PTPN22 in Jurkat T Cells Enhances TCR Signaling and Production of IL-2. Front Immunol 2018; 9:2595. [PMID: 30483260 PMCID: PMC6240618 DOI: 10.3389/fimmu.2018.02595] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 10/22/2018] [Indexed: 01/25/2023] Open
Abstract
A single nucleotide polymorphism, C1858T, in the gene encoding the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) results in one of the strongest genetic traits associated with autoimmune disease outside of the Major Histocompatibility Complex (MHC) genes. However, the consequences of this polymorphism, which introduces an arginine to tryptophan substitution at amino acid 620, for the function of PTPN22 protein is unclear and conflicting results have been obtained in human compared to mouse cells expressing this variant phosphatase. In mouse the variant appears to be a loss-of-function allele resembling a milder form of the null allele, while studies in human cells have reported it to be a gain-of-function mutation. To address whether the phosphatase has distinct functions in mouse vs. human T cells, we used CRISPR gene-editing to generate the first example of human PTPN22-KnockOut (KO) T cells. By comparing isogenic human T cells which express or lack PTPN22, we showed that PTPN22 KO T cells displayed enhanced expression of IL-2 and CD69 upon stimulation with cognate antigen. PTPN22 KO cells also showed increased Erk phosphorylation upon stimulation with weak antigen, but the difference was diminished in response to strong antigen, indicating that PTPN22 plays a more critical role in regulating weak-antigen responses. These data are in keeping with a role for PTPN22 in determining the threshold of stimulation required to activate T cells, a critical function of autoimmune pathogenesis. Our data indicate that PTPN22 has comparable functions in mouse and human T cells, and that the conflicting results in the literature regarding the impact of the point mutation are not due to differences in the activity of PTPN22 itself, but may be related to interactions with other proteins or splice variation.
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Affiliation(s)
- Cara Bray
- School of Biological Sciences, Institute for Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom
| | - David Wright
- School of Biological Sciences, Institute for Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Sonja Haupt
- School of Biological Sciences, Institute for Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Sharyn Thomas
- Institute of Immunity and Transplantation, Royal Free Hospital, University College London, London, United Kingdom
| | - Hans Stauss
- Institute of Immunity and Transplantation, Royal Free Hospital, University College London, London, United Kingdom
| | - Rose Zamoyska
- School of Biological Sciences, Institute for Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom
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Ruiz-Noa Y, Hernández-Bello J, Llamas-Covarrubias MA, Palafox-Sánchez CA, Oregon-Romero E, Sánchez-Hernández PE, Ramírez-Dueñas MG, Parra-Rojas I, Muñoz-Valle JF. PTPN22 1858C>T polymorphism is associated with increased CD154 expression and higher CD4+ T cells percentage in rheumatoid arthritis patients. J Clin Lab Anal 2018; 33:e22710. [PMID: 30402903 DOI: 10.1002/jcla.22710] [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: 09/14/2018] [Revised: 10/13/2018] [Accepted: 10/14/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND CD40 is a costimulatory molecule for B cells, and CD154 is a marker of CD4+ T cells activation. CD40-CD154 interaction promotes pro-inflammatory cytokines secretion and autoantibodies production. PTPN22 gene encodes LYP protein, an inhibitor of T- and B-cell activation. PTPN22 1858C>T polymorphism confers rheumatoid arthritis (RA) susceptibility. Hence, we evaluate the relationship between 1858C>T polymorphism with CD40 and CD154 expression and IFN-γ secretion in RA patients. METHODS PTPN22 1858C>T polymorphism was genotyped in 315 RA patients and 315 control subjects (CS) using PCR-RFLP method. Later, we selected only ten anti-CCP-positive RA patients, naïve to disease-modifying antirheumatic drugs and ten CS, all with known 1858C>T PTPN22 genotype. The CD40 and CD154 membrane expressions were determined by flow cytometry in peripheral B and T cells, correspondingly. RESULTS The B cells percentage and mCD40 expression were similar between RA and CS (P > 0.05) and we did not find an association between these variables and the 1858C>T polymorphism. The CD4+ T cells percentage was higher in RA patients than CS (P = 0.003), and in the RA group, the CD4+ T cells percentage and mCD154 expression were higher in the 1858 T allele carriers (P = 0.008 and P = 0.032, respectively). The IFN-γ levels were lower in RA patients carrying the PTPN22 risk allele (P = 0.032). CONCLUSION The PTPN22 1858 T risk allele is associated with increased CD4+ T cells percentage and high mCD154 expression in RA patients, which could favor the pro-inflammatory cytokine release and the establishment of the inflammatory response at the seropositive RA.
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Affiliation(s)
- Yeniley Ruiz-Noa
- Instituto de Investigación en Ciencias Biomédicas, CUCS, Universidad de Guadalajara, Guadalajara, México
| | - Jorge Hernández-Bello
- Instituto de Investigación en Ciencias Biomédicas, CUCS, Universidad de Guadalajara, Guadalajara, México
| | - Mara A Llamas-Covarrubias
- Instituto de Investigación en Ciencias Biomédicas, CUCS, Universidad de Guadalajara, Guadalajara, México
| | - Claudia A Palafox-Sánchez
- Instituto de Investigación en Ciencias Biomédicas, CUCS, Universidad de Guadalajara, Guadalajara, México
| | - Edith Oregon-Romero
- Instituto de Investigación en Ciencias Biomédicas, CUCS, Universidad de Guadalajara, Guadalajara, México
| | | | | | - Isela Parra-Rojas
- Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, México
| | - Jose Francisco Muñoz-Valle
- Instituto de Investigación en Ciencias Biomédicas, CUCS, Universidad de Guadalajara, Guadalajara, México
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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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Carmona FD, Martín J. The potential of PTPN22 as a therapeutic target for rheumatoid arthritis. Expert Opin Ther Targets 2018; 22:879-891. [PMID: 30251905 DOI: 10.1080/14728222.2018.1526924] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION PTPN22 encodes a lymphoid-specific tyrosine phosphatase (LYP) that is a master regulator of the immune response. This gene is a major susceptibility factor for a wide range of autoimmune conditions, including rheumatoid arthritis (RA) for which it represents the strongest non-HLA contributor to disease risk. A missense PTPN22 allele (R620W) affecting the protein-protein interaction of LYP with other relevant players was described as the functional variant of the association. This review will focus on the role of PTPN22 in the pathogenic mechanisms underlying RA predisposition and discuss the possibility of developing LYP-based treatment strategies with a potential application in clinical practice. Areas covered: This review covers the literature showing how PTPN22 is implicated in signalling pathways involved in the autoimmune and autoinflammatory processes underlying RA. Insights obtained from studies aimed at developing novel selective LYP suppressors for treating RA are summarized. Expert opinion: Targeting key risk factors during the early steps of the disease may represent a good strategy to accomplish complete disease remission. As cumulating evidences suggest that PTPN22 R620W is a gain-of-function variant, a growing interest in developing LYP inhibitors has arisen. The potential efficacy and possible application of such compounds are discussed.
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Affiliation(s)
- F David Carmona
- a Departamento de Genética e Instituto de Biotecnología , Universidad de Granada , Granada , Spain
| | - Javier Martín
- b Instituto de Parasitología y Biomedicina López-Neyra , Consejo Superior de Investigaciones Científicas, IPBLN-CSIC , Granada , Spain
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