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Walker SL, Leete P, Boldison J. Tissue Resident and Infiltrating Immune Cells: Their Influence on the Demise of Beta Cells in Type 1 Diabetes. Biomolecules 2025; 15:441. [PMID: 40149976 PMCID: PMC11939886 DOI: 10.3390/biom15030441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 03/11/2025] [Accepted: 03/17/2025] [Indexed: 03/29/2025] Open
Abstract
Type 1 diabetes (T1D) is an organ-specific autoimmune disease that results in the selective loss of pancreatic beta cells and an eventual deficit in insulin production to maintain glucose homeostasis. It is now increasingly accepted that this dynamic disease process is multifactorial; involves a variety of immune cells which contribute to an inflamed pancreatic microenvironment; and that the condition is heterogenous, resulting in variable rates of subsequent beta cell damage. In this review, we will explore the current understanding of the cellular interactions between both resident and infiltrating immune cells within the pancreatic environment, highlighting key mechanisms which may promote the beta cell destruction and islet damage associated with T1D.
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Affiliation(s)
| | | | - Joanne Boldison
- Department of Clinical and Biomedical Sciences, University of Exeter, RILD Building (Level 4), Barrack Road, Exeter EX2 5DW, UK; (S.L.W.); (P.L.)
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2
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Xu ZR, Xi L, Wu J, Ni JW, Luo FH, Zhang MY. COVID-19 infection and inactivated vaccination: Impacts on clinical and immunological profiles in Chinese children with type 1 diabetes. World J Diabetes 2024; 15:2276-2284. [PMID: 39676798 PMCID: PMC11580597 DOI: 10.4239/wjd.v15.i12.2276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 08/27/2024] [Accepted: 10/22/2024] [Indexed: 11/18/2024] Open
Abstract
BACKGROUND The coronavirus disease 2019 (COVID-19) pandemic has been linked to an increased incidence of diabetes and diabetic ketoacidosis (DKA). However, the relationship between COVID-19 infection and progression to type 1 diabetes (T1D) in children has not been well defined. AIM To evaluate the influence of COVID-19 infection and inactivated vaccine administration on the progression of T1D among Chinese children. METHODS A total of 197 newly diagnosed patients with T1D were retrospectively enrolled from Children's Hospital of Fudan University between September 2020 and December 2023. The patients were divided into three groups based on their history of COVID-19 infection and vaccination: the infection group, the vaccination-only group, and the non-infection/non-vaccination group. Comprehensive clinical assessments and detailed immunological evaluations were performed to delineate the characteristics and immune responses of these groups. RESULTS The incidence of DKA was significantly higher in the COVID-19 infection group (70.2%) compared to the non-infection/non-vaccination group (62.5%) and vacscination-only group (45.6%; P = 0.015). Prior COVID-19 infection was correlated with increased DKA risk (OR: 1.981, 95%CI: 1.026-3.825, P = 0.042), while vaccination was associated with a reduced risk (OR: 0.558, 95%CI: 0.312-0.998, P = 0.049). COVID-19 infection mildly altered immune profiles, with modest differences in autoantibody positivity, lymphocyte distribution, and immunoglobulin levels. Notably, HLA-DR3 positive children with a history of COVID-19 infection had an earlier T1D onset and lower fasting C-peptide levels than the HLA-DR3 negative children with a history of infection (both P < 0.05). CONCLUSION COVID-19 infection predisposes children to severe T1D, characterized by enhanced DKA risk. Inactivated vaccination significantly lowers DKA incidence at T1D onset. These findings are valuable for guiding future vaccination and T1D risk surveillance strategies in epidemic scenarios in the general pediatric population.
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Affiliation(s)
- Zhen-Ran Xu
- Department of Pediatric Endocrinology and Inherited Metabolic Diseases, National Children’s Medical Center, Children's Hospital of Fudan University, Shanghai 201102, China
| | - Li Xi
- Department of Pediatric Endocrinology and Inherited Metabolic Diseases, National Children’s Medical Center, Children's Hospital of Fudan University, Shanghai 201102, China
| | - Jing Wu
- Department of Pediatric Endocrinology and Inherited Metabolic Diseases, National Children’s Medical Center, Children's Hospital of Fudan University, Shanghai 201102, China
| | - Jin-Wen Ni
- Department of Pediatric Endocrinology and Inherited Metabolic Diseases, National Children’s Medical Center, Children's Hospital of Fudan University, Shanghai 201102, China
| | - Fei-Hong Luo
- Department of Pediatric Endocrinology and Inherited Metabolic Diseases, National Children’s Medical Center, Children's Hospital of Fudan University, Shanghai 201102, China
| | - Miao-Ying Zhang
- Department of Pediatric Endocrinology and Inherited Metabolic Diseases, National Children’s Medical Center, Children's Hospital of Fudan University, Shanghai 201102, China
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3
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Rampazzo Morelli N, Pipella J, Thompson PJ. Establishing evidence for immune surveillance of β-cell senescence. Trends Endocrinol Metab 2024; 35:576-585. [PMID: 38307810 DOI: 10.1016/j.tem.2024.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 01/13/2024] [Accepted: 01/15/2024] [Indexed: 02/04/2024]
Abstract
Cellular senescence is a programmed state of cell cycle arrest that involves a complex immunogenic secretome, eliciting immune surveillance and senescent cell clearance. Recent work has shown that a subpopulation of pancreatic β-cells becomes senescent in the context of diabetes; however, it is not known whether these cells are normally subject to immune surveillance. In this opinion article, we advance the hypothesis that immune surveillance of β-cells undergoing a senescence stress response normally limits their accumulation during aging and that the breakdown of these mechanisms is a driver of senescent β-cell accumulation in diabetes. Elucidation and therapeutic activation of immune surveillance mechanisms in the pancreas holds promise for the improvement of approaches to target stressed senescent β-cells in the treatment of diabetes.
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Affiliation(s)
- Nayara Rampazzo Morelli
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children's Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada; Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Jasmine Pipella
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children's Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada; Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Peter J Thompson
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme, Children's Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada; Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
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4
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Roe K. Immunoregulatory natural killer cells. Clin Chim Acta 2024; 558:117896. [PMID: 38583553 DOI: 10.1016/j.cca.2024.117896] [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: 02/29/2024] [Revised: 03/28/2024] [Accepted: 03/29/2024] [Indexed: 04/09/2024]
Abstract
This review discusses a broader scope of functional roles for NK cells. Despite the well-known cytolytic and inflammatory roles of NK cells against tumors and pathogenic diseases, extensive evidence demonstrates certain subsets of NK cells have defacto immunoregulatory effects and have a role in inducing anergy or lysis of antigen-activated T cells and regulating several autoimmune diseases. Furthermore, recent evidence suggests certain subsets of immunoregulatory NK cells can cause anergy or lysis of antigen-activated T cells to regulate hyperinflammatory diseases, including multisystem inflammatory syndrome. Several pathogens induce T cell and NK cell exhaustion and/or suppression, which impair the immune system's control of the replication speed of virulent pathogens and tumors and result in extensive antigens and antigen-antibody immune complexes, potentially inducing to some extent a Type III hypersensitivity immune reaction. The Type III hypersensitivity immune reaction induces immune cell secretion of proteinases, which can cleave specific proteins to create autoantigens which activate T cells to initiate autoimmune and/or hyperinflammatory diseases. Furthermore, pathogen induced NK cell exhaustion and/or suppression will inhibit NK cells which would have induced the anergy or lysis of activated T cells to regulate autoimmune and hyperinflammatory diseases. Autoimmune and hyperinflammatory diseases can be consequences of the dual lymphocyte exhaustion and/or suppression effects during infections, by creating autoimmune and/or hyperinflammatory diseases, while also impairing immunoregulatory lymphocytes which otherwise would have regulated these diseases.
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Affiliation(s)
- Kevin Roe
- Retired USPTO, San Jose, CA, United States of America.
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5
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Wood EK, Reid BM, Sheerar DS, Donzella B, Gunnar MR, Coe CL. Lingering Effects of Early Institutional Rearing and Cytomegalovirus Infection on the Natural Killer Cell Repertoire of Adopted Adolescents. Biomolecules 2024; 14:456. [PMID: 38672472 PMCID: PMC11047877 DOI: 10.3390/biom14040456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 03/26/2024] [Accepted: 04/05/2024] [Indexed: 04/28/2024] Open
Abstract
Adversity during infancy can affect neurobehavioral development and perturb the maturation of physiological systems. Dysregulated immune and inflammatory responses contribute to many of the later effects on health. Whether normalization can occur following a transition to more nurturing, benevolent conditions is unclear. To assess the potential for recovery, blood samples were obtained from 45 adolescents adopted by supportive families after impoverished infancies in institutional settings (post-institutionalized, PI). Their immune profiles were compared to 39 age-matched controls raised by their biological parents (non-adopted, NA). Leukocytes were immunophenotyped, and this analysis focuses on natural killer (NK) cell populations in circulation. Cytomegalovirus (CMV) seropositivity was evaluated to determine if early infection contributed to the impact of an atypical rearing. Associations with tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), two cytokines released by activated NK cells, were examined. Compared to the NA controls, PI adolescents had a lower percent of CD56bright NK cells in circulation, higher TNF-α levels, and were more likely to be infected with CMV. PI adolescents who were latent carriers of CMV expressed NKG2C and CD57 surface markers on more NK cells, including CD56dim lineages. The NK cell repertoire revealed lingering immune effects of early rearing while still maintaining an overall integrity and resilience.
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Affiliation(s)
- Elizabeth K. Wood
- Department of Psychiatry, Oregon Health & Science University, Portland, OR 97239, USA
| | - Brie M. Reid
- Department of Psychiatry and Human Behavior, Brown University, Providence, RI 02906, USA;
| | - Dagna S. Sheerar
- Wisconsin Institute of Medical Research, University of Wisconsin Comprehensive Carbone Cancer Center, Madison, WI 53706, USA;
| | - Bonny Donzella
- Institute of Child Development, University of Minnesota, Minneapolis, MN 55455, USA; (B.D.); (M.R.G.)
| | - Megan R. Gunnar
- Institute of Child Development, University of Minnesota, Minneapolis, MN 55455, USA; (B.D.); (M.R.G.)
| | - Christopher L. Coe
- Department of Psychology, University of Wisconsin-Madison, Madison, WI 54706, USA;
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6
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Mohammadi V, Maleki AJ, Nazari M, Siahmansouri A, Moradi A, Elahi R, Esmaeilzadeh A. Chimeric Antigen Receptor (CAR)-Based Cell Therapy for Type 1 Diabetes Mellitus (T1DM); Current Progress and Future Approaches. Stem Cell Rev Rep 2024; 20:585-600. [PMID: 38153634 DOI: 10.1007/s12015-023-10668-1] [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] [Accepted: 12/17/2023] [Indexed: 12/29/2023]
Abstract
Type 1 diabetes mellitus (T1DM) is an autoimmune disease that destroys insulin-producing pancreatic β-cells. Insulin replacement therapy is currently the mainstay of treatment for T1DM; however, treatment with insulin does not ameliorate disease progression, as dysregulated immune response and inflammation continue to cause further pancreatic β-cell degradation. Therefore, shifting therapeutic strategies toward immunomodulating approaches could be effective to prevent and reverse disease progression. Different immune-modulatory therapies could be used, e.g., monoclonal-based immunotherapy, mesenchymal stem cell, and immune cell therapy. Since immune-modulatory approaches could have a systemic effect on the immune system and cause toxicity, more specific treatment options should target the immune response against pancreatic β-cells. In this regard, chimeric antigen receptor (CAR)-based immunotherapy could be a promising candidate for modulation of dysregulated immune function in T1DM. CAR-based therapy has previously been approved for a number of hematologic malignancies. Nevertheless, there is renewed interest in CAR T cells' " off-the-shelf " treatment for T1DM. Several pre-clinical studies demonstrated that redirecting antigen-specific CAR T cells, especially regulatory CAR T cells (CAR Tregs), toward the pancreatic β-cells, could prevent diabetes onset and progression in diabetic mice models. Here, we aim to review the current progress of CAR-based immune-cell therapy for T1DM and the corresponding challenges, with a special focus on designing CAR-based immunomodulatory strategies to improve its efficacy in the treatment of T1DM.
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Affiliation(s)
- Vahid Mohammadi
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | | | - Mahdis Nazari
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Amir Siahmansouri
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Amirhosein Moradi
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Reza Elahi
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Abdolreza Esmaeilzadeh
- Department of Immunology, Zanjan University of Medical Sciences, Zanjan, Iran.
- Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran.
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7
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Gomez-Muñoz L, Dominguez-Bendala J, Pastori RL, Vives-Pi M. Immunometabolic biomarkers for partial remission in type 1 diabetes mellitus. Trends Endocrinol Metab 2024; 35:151-163. [PMID: 37949732 DOI: 10.1016/j.tem.2023.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 10/13/2023] [Accepted: 10/13/2023] [Indexed: 11/12/2023]
Abstract
Shortly after diagnosis of type 1 diabetes mellitus (T1DM) and initiation of insulin therapy, many patients experience a transient partial remission (PR) phase, also known as the honeymoon phase. This phase presents a potential therapeutic opportunity due to its association with immunoregulatory and β cell-protective mechanisms. However, the lack of biomarkers makes its characterization difficult. In this review, we cover the current literature addressing the discovery of new predictive and monitoring biomarkers that contribute to the understanding of the metabolic, epigenetic, and immunological mechanisms underlying PR. We further discuss how these peripheral biomarkers reflect attempts to arrest β cell autoimmunity and how these can be applied in clinical practice.
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Affiliation(s)
- Laia Gomez-Muñoz
- Immunology Section, Germans Trias i Pujol Research Institute, Universitat Autònoma de Barcelona, 08916 Badalona, Spain
| | - Juan Dominguez-Bendala
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Ricardo L Pastori
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Marta Vives-Pi
- Immunology Section, Germans Trias i Pujol Research Institute, Universitat Autònoma de Barcelona, 08916 Badalona, Spain; Ahead Therapeutics SL, 08193, Bellaterra, Barcelona, Spain.
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8
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Shapiro MR, Dong X, Perry DJ, McNichols JM, Thirawatananond P, Posgai AL, Peters LD, Motwani K, Musca RS, Muir A, Concannon P, Jacobsen LM, Mathews CE, Wasserfall CH, Haller MJ, Schatz DA, Atkinson MA, Brusko MA, Bacher R, Brusko TM. Human immune phenotyping reveals accelerated aging in type 1 diabetes. JCI Insight 2023; 8:e170767. [PMID: 37498686 PMCID: PMC10544250 DOI: 10.1172/jci.insight.170767] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 07/19/2023] [Indexed: 07/29/2023] Open
Abstract
The proportions and phenotypes of immune cell subsets in peripheral blood undergo continual and dramatic remodeling throughout the human life span, which complicates efforts to identify disease-associated immune signatures in type 1 diabetes (T1D). We conducted cross-sectional flow cytometric immune profiling on peripheral blood from 826 individuals (stage 3 T1D, their first-degree relatives, those with ≥2 islet autoantibodies, and autoantibody-negative unaffected controls). We constructed an immune age predictive model in unaffected participants and observed accelerated immune aging in T1D. We used generalized additive models for location, shape, and scale to obtain age-corrected data for flow cytometry and complete blood count readouts, which can be visualized in our interactive portal (ImmScape); 46 parameters were significantly associated with age only, 25 with T1D only, and 23 with both age and T1D. Phenotypes associated with accelerated immunological aging in T1D included increased CXCR3+ and programmed cell death 1-positive (PD-1+) frequencies in naive and memory T cell subsets, despite reduced PD-1 expression levels on memory T cells. Phenotypes associated with T1D after age correction were predictive of T1D status. Our findings demonstrate advanced immune aging in T1D and highlight disease-associated phenotypes for biomarker monitoring and therapeutic interventions.
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Affiliation(s)
- Melanie R. Shapiro
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, and
- Diabetes Institute and
| | - Xiaoru Dong
- Diabetes Institute and
- Department of Biostatistics, College of Public Health and Health Professions, University of Florida, Gainesville, Florida, USA
| | - Daniel J. Perry
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, and
- Diabetes Institute and
| | - James M. McNichols
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, and
- Diabetes Institute and
| | - Puchong Thirawatananond
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, and
- Diabetes Institute and
| | - Amanda L. Posgai
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, and
- Diabetes Institute and
| | - Leeana D. Peters
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, and
- Diabetes Institute and
| | - Keshav Motwani
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, and
- Diabetes Institute and
| | - Richard S. Musca
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, and
- Diabetes Institute and
| | - Andrew Muir
- Department of Pediatrics, Emory University, Atlanta, Georgia, USA
| | - Patrick Concannon
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, and
- Diabetes Institute and
- Genetics Institute and
| | - Laura M. Jacobsen
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, and
- Diabetes Institute and
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Clayton E. Mathews
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, and
- Diabetes Institute and
| | - Clive H. Wasserfall
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, and
- Diabetes Institute and
| | - Michael J. Haller
- Diabetes Institute and
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Desmond A. Schatz
- Diabetes Institute and
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Mark A. Atkinson
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, and
- Diabetes Institute and
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Maigan A. Brusko
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, and
- Diabetes Institute and
| | - Rhonda Bacher
- Diabetes Institute and
- Department of Biostatistics, College of Public Health and Health Professions, University of Florida, Gainesville, Florida, USA
| | - Todd M. Brusko
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, and
- Diabetes Institute and
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida, USA
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9
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Tang R, Zhong T, Lei K, Lin X, Li X. Recovery of intracellular glucose uptake in T cells during partial remission of type 1 diabetes. Diabetologia 2023; 66:1532-1543. [PMID: 37300581 DOI: 10.1007/s00125-023-05938-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 04/21/2023] [Indexed: 06/12/2023]
Abstract
AIMS/HYPOTHESIS Notwithstanding the irreversible beta cell failure seen in type 1 diabetes, some individuals may experience a special phase named 'partial remission' or 'the honeymoon period', in which there is a transient recovery of beta cell function. Importantly, this stage of partial remission shows spontaneous immune downregulation, although the exact mechanisms are unclear. Intracellular energy metabolism is crucial for the differentiation and function of T cells, and provides promising targets for immunometabolic intervention strategies, but its role during partial remission is unknown. In this study, we aim to investigate the association between T cell intracellular glucose and fatty acid metabolism and the partial remission phase. METHODS This is a cross-sectional study with a follow-up component. Intracellular uptake of glucose and fatty acids by T cells was detected in participants with either new-onset type 1 diabetes or type 1 diabetes that was already in partial remission, and compared with heathy individuals and participants with type 2 diabetes. Subsequently, the participants with new-onset type 1 diabetes were followed up to determine whether they experienced a partial remission (remitters) or not (non-remitters). The trajectory of changes in T cell glucose metabolism was observed in remitters and non-remitters. Expression of programmed cell death-1 (PD-1) was also analysed to investigate possible mechanisms driving altered glucose metabolism. Partial remission was defined when patients had convalescent fasting or 2 h postprandial C-peptide >300 pmol/l after insulin treatment. RESULTS Compared with participants with new-onset type 1 diabetes, intracellular glucose uptake by T cells decreased significantly in individuals with partial remission. The trajectory of these changes during follow-up showed that intracelluar glucose uptake in T cells fluctuated during different disease stages, with a decreased uptake during partial remission that rebounded after remission. This dynamic in T cell glucose uptake was only detected in remitters and not in non-remitters. Further analysis demonstrated that changes of intracellular glucose uptake were found in subsets of CD4+ and CD8+ T cells, including Th17, Th1, CD8+ naive T cells (Tn) and CD8+ terminally differentiated effector memory T cells (Temra). Moreover, glucose uptake in CD8+ T cells was negatively related to PD-1 expression. The intracellular metabolism of fatty acids was not found to be different between new-onset participants and those in partial remission. CONCLUSIONS/INTERPRETATION Intracellular glucose uptake in T cells was specifically decreased during partial remission in type 1 diabetes and may be related to PD-1 upregulation, which may be involved in the down-modulation of immune responses during partial remission. This study suggests that altered immune metabolism could be a target for interventions at the point of diagnosis of type 1 diabetes.
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Affiliation(s)
- Rong Tang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Ting Zhong
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Kang Lei
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Xiaoxi Lin
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Xia Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
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10
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Viswanathan A, Wood JR, Hatipoglu BA. What Is a Honeymoon in Type 1, Can It Go into Remission? Endocrinol Metab Clin North Am 2023; 52:175-185. [PMID: 36754493 DOI: 10.1016/j.ecl.2022.08.001] [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] [Indexed: 11/19/2022]
Abstract
Type 1 diabetes is a chronic autoimmune disorder that results in destruction of insulin-producing cells in the pancreas. The autoimmune process is thought to be waxing and waning resulting in variable endogenous insulin secretion ability. An example of this is the honeymoon phase or partial remission phase of type 1 diabetes, during which optimal control of blood glucoses can be maintained with significantly reduced exogenous insulin, and occasionally exogenous insulin can be temporarily discontinued altogether. Understanding this phase is important because even fairly small amounts of endogenous insulin secretion is associated with reduced risk of severe hypoglycemia and microvascular complications.
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Affiliation(s)
- Anuradha Viswanathan
- Section for Pediatric Endocrinology, Cleveland Clinic Children's, 9500 Euclid Avenue, R Building- R-3, Cleveland, OH 44195, USA.
| | - Jamie R Wood
- University Hospitals Cleveland Medical Center, Rainbow Babies and Children's Hospital, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106, USA
| | - Betul A Hatipoglu
- University Hospitals Cleveland Medical Center, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106, USA
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11
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Sieniawska J, Krzewska A, Skowronek A, Wrobel W, Tomczyk Z, Pach E, Rosolowska I, Wilczynska B, Beń-Skowronek I. Lower percentages of natural killer cells in children with type 1 diabetes and their siblings. Pediatr Endocrinol Diabetes Metab 2023; 29:214-224. [PMID: 38282490 PMCID: PMC10826694 DOI: 10.5114/pedm.2023.132029] [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: 07/10/2023] [Accepted: 09/04/2023] [Indexed: 01/30/2024]
Abstract
INTRODUCTION One of the most common children's endocrine and autoimmune diseases in the world is type 1 diabetes mellitus (T1DM). The incidence of type 1 diabetes is constantly increasing, and according to current estimates, the number of children with T1DM in the world has exceeded 542,000. There are 3 main components emphasized in the pathogenesis: genetic and environmental factors, and the patient's immune system. Many publications have confirmed the role of natural killer cells (NK) in the pathogenesis of type 1 diabetes and other autoimmune diseases. AIM The aim of the study was to evaluate the population of NK cells and pancreatic β cell autoantibodies in a group of children with T1DM and their healthy siblings in comparison with children from families with no history of autoimmune diseases. MATERIAL AND METHODS The research included 76 children with T1DM, 101 children from the sibling group, and 30 children from the control group. Peripheral blood was analysed on a FACSCalibur flow cytometer (Becton Dickinson) to evaluate the NK cell population. The results were presented as the percentage of NK cells among lymphocytes. Statistical analysis was performed using STATIS-TICA 10 PL software. RESULTS The mean percentage of NK cells in children with T1D (10.59 ±5.37) and in the sibling group (11.93 ±5.62) was statistically reduced in comparison to the control group (14.89 ±7.78) in sequence (Student's t -test: t = -3.24; df = 103; p = 0.002) (Stu-dent's t -test: t = -2.30; df = 128; p = 0.02). There was no statistically significant difference in the percentage of NK cells be-tween the group of children with T1DM and their siblings (Student's t -test: t = -1.59; df = 173; p = 0.11). In the group of sib-lings, the younger the child, the lower the reported percentage of NK cells. This relationship was statistically significant (test for the Pearson correlation coefficient t = 3.41; p = 0.0009; r = 0.33). In the group of children with type 1 diabetes, a similar relationship was not found. The concentration of anti-IA2 and anti-Znt8 antibodies was statistically significantly higher in the sibling group compared to the control group (anti-IA2 p = 0.0000001; anti-ZnT8 p = 0.00001), and the concentration of anti-GAD antibodies was comparable in both groups. In the group of children with type 1 diabetes, a positive correlation was demonstrated between the reduced percentage of NK cells and the coexistence of anti-GAD and anti-ZnT8 antibodies (Mann-Whitney U test Z = -2.02; p = 0.04). There was no similar relationship in the group of siblings. CONCLUSIONS The reduced percentage of NK cells in children with T1DM and in their siblings compared to the control group suggests the role of NK cells in the pathogenesis of T1DM. Genetic predisposition and dysfunction of NK cells probably underlie the pathogenesis of T1DM.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Iwona Beń-Skowronek
- Department of Paediatric Endocrinology and Diabetology with Laboratory of Endocrinology and Metabolism, Medical University of Lublin, Poland
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12
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Bechi Genzano C, Bezzecchi E, Carnovale D, Mandelli A, Morotti E, Castorani V, Favalli V, Stabilini A, Insalaco V, Ragogna F, Codazzi V, Scotti GM, Del Rosso S, Mazzi BA, De Pellegrin M, Giustina A, Piemonti L, Bosi E, Battaglia M, Morelli MJ, Bonfanti R, Petrelli A. Combined unsupervised and semi-automated supervised analysis of flow cytometry data reveals cellular fingerprint associated with newly diagnosed pediatric type 1 diabetes. Front Immunol 2022; 13:1026416. [PMID: 36389771 PMCID: PMC9647173 DOI: 10.3389/fimmu.2022.1026416] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 10/11/2022] [Indexed: 11/03/2023] Open
Abstract
An unbiased and replicable profiling of type 1 diabetes (T1D)-specific circulating immunome at disease onset has yet to be identified due to experimental and patient selection limitations. Multicolor flow cytometry was performed on whole blood from a pediatric cohort of 107 patients with new-onset T1D, 85 relatives of T1D patients with 0-1 islet autoantibodies (pre-T1D_LR), 58 patients with celiac disease or autoimmune thyroiditis (CD_THY) and 76 healthy controls (HC). Unsupervised clustering of flow cytometry data, validated by a semi-automated gating strategy, confirmed previous findings showing selective increase of naïve CD4 T cells and plasmacytoid DCs, and revealed a decrease in CD56brightNK cells in T1D. Furthermore, a non-selective decrease of CD3+CD56+ regulatory T cells was observed in T1D. The frequency of naïve CD4 T cells at disease onset was associated with partial remission, while it was found unaltered in the pre-symptomatic stages of the disease. Thanks to a broad cohort of pediatric individuals and the implementation of unbiased approaches for the analysis of flow cytometry data, here we determined the circulating immune fingerprint of newly diagnosed pediatric T1D and provide a reference dataset to be exploited for validation or discovery purposes to unravel the pathogenesis of T1D.
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Affiliation(s)
| | - Eugenia Bezzecchi
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
- Center for Omics Sciences, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Debora Carnovale
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | | | - Elisa Morotti
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
- Department of Pediatrics, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Valeria Castorani
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Valeria Favalli
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
- Department of Pediatrics, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Angela Stabilini
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Vittoria Insalaco
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Francesca Ragogna
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Valentina Codazzi
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | | | - Stefania Del Rosso
- Laboratory Medicine, Autoimmunity Section, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Benedetta Allegra Mazzi
- Immuno-Hematology and Transfusion Medicine (ITMS), IRCCS Ospedale San Raffaele, Milan, Italy
| | - Maurizio De Pellegrin
- Pediatric Orthopedic and Traumatology Unit, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Andrea Giustina
- Institute of Endocrine and Metabolic Sciences, IRCCS Ospedale San Raffaele, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Lorenzo Piemonti
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Emanuele Bosi
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
- Department of General Medicine, Diabetes and Endocrinology, IRCCS Ospedale San Raffaele, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Manuela Battaglia
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Marco J. Morelli
- Center for Omics Sciences, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Riccardo Bonfanti
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
- Department of Pediatrics, IRCCS Ospedale San Raffaele, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
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13
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Hypo-osmotic stress induces the epithelial alarmin IL-33 in the colonic barrier of ulcerative colitis. Sci Rep 2022; 12:11550. [PMID: 35798804 PMCID: PMC9263100 DOI: 10.1038/s41598-022-15573-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 06/27/2022] [Indexed: 11/08/2022] Open
Abstract
Epithelial alarmins are gaining interest as therapeutic targets for chronic inflammation. The nuclear alarmin interleukin-33 (IL-33) is upregulated in the colonic mucosa of acute ulcerative colitis (UC) and may represent an early instigator of the inflammatory cascade. However, it is not clear what signals drive the expression of IL-33 in the colonic mucosa, nor is the exact role of IL-33 elucidated. We established an ex vivo model using endoscopic colonic biopsies from healthy controls and UC patients. Colonic biopsies exposed to hypo-osmotic medium induced a strong nuclear IL-33 expression in colonic crypts in both healthy controls and UC biopsies. Mucosal IL33 mRNA was also significantly increased following hypo-osmotic stress in healthy controls compared to non-stimulated biopsies (fold change 3.9, p-value < 0.02). We observed a modest induction of IL-33 in response to TGF-beta-1 stimulation, whereas responsiveness to inflammatory cytokines TNF and IFN-gamma was negligible. In conclusion our findings indicate that epithelial IL-33 is induced by hypo-osmotic stress, rather than prototypic proinflammatory cytokines in colonic ex vivo biopsies. This is a novel finding, linking a potent cytokine and alarmin of the innate immune system with cellular stress mechanisms and mucosal inflammation.
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Ramírez-Sánchez AD, Chu X, Modderman R, Kooy-Winkelaar Y, Koletzko S, Korponay-Szabó IR, Troncone R, Wijmenga C, Mearin L, Withoff S, Jonkers IH, Li Y. Single-Cell RNA Sequencing of Peripheral Blood Mononuclear Cells From Pediatric Coeliac Disease Patients Suggests Potential Pre-Seroconversion Markers. Front Immunol 2022; 13:843086. [PMID: 35371081 PMCID: PMC8964997 DOI: 10.3389/fimmu.2022.843086] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 02/22/2022] [Indexed: 11/30/2022] Open
Abstract
Celiac Disease (CeD) is a complex immune disorder involving villous atrophy in the small intestine that is triggered by gluten intake. Current CeD diagnosis is based on late-stage pathophysiological parameters such as detection of specific antibodies in blood and histochemical detection of villus atrophy and lymphocyte infiltration in intestinal biopsies. To date, no early onset biomarkers are available that would help prevent widespread villous atrophy and severe symptoms and co-morbidities. To search for novel CeD biomarkers, we used single-cell RNA sequencing (scRNAseq) to investigate PBMC samples from 11 children before and after seroconversion for CeD and 10 control individuals matched for age, sex and HLA-genotype. We generated scRNAseq profiles of 9559 cells and identified the expected major cellular lineages. Cell proportions remained stable across the different timepoints and health conditions, but we observed differences in gene expression profiles in specific cell types when comparing patient samples before and after disease development and comparing patients with controls. Based on the time when transcripts were differentially expressed, we could classify the deregulated genes as biomarkers for active CeD or as potential pre-diagnostic markers. Pathway analysis showed that active CeD biomarkers display a transcriptional profile associated with antigen activation in CD4+ T cells, whereas NK cells express a subset of biomarker genes even before CeD diagnosis. Intersection of biomarker genes with CeD-associated genetic risk loci pinpointed genetic factors that might play a role in CeD onset. Investigation of potential cellular interaction pathways of PBMC cell subpopulations highlighted the importance of TNF pathways in CeD. Altogether, our results pinpoint genes and pathways that are altered prior to and during CeD onset, thereby identifying novel potential biomarkers for CeD diagnosis in blood.
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Affiliation(s)
- Aarón D Ramírez-Sánchez
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Xiaojing Chu
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.,Department of Computational Biology for Individualised Medicine, Centre for Individualised Infection Medicine (CiiM) & TWINCORE, Joint Ventures Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
| | - Rutger Modderman
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Yvonne Kooy-Winkelaar
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands
| | - Sibylle Koletzko
- Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München (LMU) Klinikum Munich, Munich, Germany.,Department of Pediatric Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland
| | - Ilma R Korponay-Szabó
- Coeliac Disease Center, Heim Pál National Paediatric Institute, Budapest, Hungary.,Department of Paediatrics, Faculty of Medicine and Clinical Center, University of Debrecen, Debrecen, Hungary
| | - Riccardo Troncone
- Department of Medical Translational Sciences and European Laboratory for the Investigation of Food Induced Diseases, University Federico II, Naples, Italy
| | - Cisca Wijmenga
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Luisa Mearin
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands
| | - Sebo Withoff
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Iris H Jonkers
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Yang Li
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.,Department of Computational Biology for Individualised Medicine, Centre for Individualised Infection Medicine (CiiM) & TWINCORE, Joint Ventures Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany.,Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
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15
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Barcenilla H, Pihl M, Wahlberg J, Ludvigsson J, Casas R. Intralymphatic GAD-alum Injection Modulates B Cell Response and Induces Follicular Helper T Cells and PD-1+ CD8+ T Cells in Patients With Recent-Onset Type 1 Diabetes. Front Immunol 2022; 12:797172. [PMID: 35095874 PMCID: PMC8791064 DOI: 10.3389/fimmu.2021.797172] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 12/20/2021] [Indexed: 12/21/2022] Open
Abstract
Antigen-specific immunotherapy is an appealing strategy to preserve beta-cell function in type 1 diabetes, although the approach has yet to meet its therapeutic endpoint. Direct administration of autoantigen into lymph nodes has emerged as an alternative administration route that can improve the efficacy of the treatment. In the first open-label clinical trial in humans, injection of aluminum-formulated glutamic acid decarboxylase (GAD-alum) into an inguinal lymph node led to the promising preservation of C-peptide in patients with recent-onset type 1 diabetes. The treatment induced a distinct immunomodulatory effect, but the response at the cell level has not been fully characterized. Here we used mass cytometry to profile the immune landscape in peripheral blood mononuclear cells from 12 participants of the study before and after 15 months of treatment. The immunomodulatory effect of the therapy included reduction of naïve and unswitched memory B cells, increase in follicular helper T cells and expansion of PD-1+ CD69+ cells in both CD8+ and double negative T cells. In vitro stimulation with GAD65 only affected effector CD8+ T cells in samples collected before the treatment. However, the recall response to antigen after 15 months included induction of CXCR3+ and CD11c+Tbet+ B cells, PD-1+ follicular helper T cells and exhausted-like CD8+ T cells. This study provides a deeper insight into the immunological changes associated with GAD-alum administration directly into the lymph nodes.
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Affiliation(s)
- Hugo Barcenilla
- Division of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Mikael Pihl
- Core Facility, Flow Cytometry Unit, Linköping University, Linköping, Sweden
| | - Jeanette Wahlberg
- Department of Health, Medicine and Caring Sciences (HMV), Linköping University, Linköping, Sweden.,Division of Diagnostics and Specialist Medicine and Faculty of Health Sciences, Örebro University, Örebro, Sweden
| | - Johnny Ludvigsson
- Division of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden.,Division of Pediatrics, Crown Princess Victoria Children's Hospital, Linköping, Sweden
| | - Rosaura Casas
- Division of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
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16
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Gomez-Muñoz L, Perna-Barrull D, Caroz-Armayones JM, Murillo M, Rodriguez-Fernandez S, Valls A, Vazquez F, Perez J, Corripio R, Castaño L, Bel J, Vives-Pi M. Candidate Biomarkers for the Prediction and Monitoring of Partial Remission in Pediatric Type 1 Diabetes. Front Immunol 2022; 13:825426. [PMID: 35280980 PMCID: PMC8904370 DOI: 10.3389/fimmu.2022.825426] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/31/2022] [Indexed: 01/10/2023] Open
Abstract
The partial remission (PR) phase, a period experienced by most patients with type 1 diabetes (T1D) soon after diagnosis, is characterized by low insulin requirements and improved glycemic control. Given the great potential of this phase as a therapeutic window for immunotherapies because of its association with immunoregulatory mechanisms and β-cell protection, our objective was to find peripheral immunological biomarkers for its better characterization, monitoring, and prediction. The longitudinal follow-up of 17 pediatric patients with new-onset T1D over one year revealed that, during the PR phase, remitter patients show increased percentages of effector memory (EM) T lymphocytes, terminally differentiated EM T lymphocytes, and neutrophils in comparison to non-remitter patients. On the contrary, remitter patients showed lower percentages of naïve T lymphocytes, regulatory T cells (TREG), and dendritic cells (DCs). After a year of follow-up, these patients also presented increased levels of regulatory B cells and transitional T1 B lymphocytes. On the other hand, although none of the analyzed cytokines (IL-2, IL-6, TGF-β1, IL-17A, and IL-10) could distinguish or predict remission, IL-17A was increased at T1D diagnosis in comparison to control subjects, and remitter patients tended to maintain lower levels of this cytokine than non-remitters. Therefore, these potential monitoring immunological biomarkers of PR support that this stage is governed by both metabolic and immunological factors and suggest immunoregulatory attempts during this phase. Furthermore, since the percentage of TREG, monocytes, and DCs, and the total daily insulin dose at diagnosis were found to be predictors of the PR phase, we next created an index-based predictive model comprising those immune cell percentages that could potentially predict remission at T1D onset. Although our preliminary study needs further validation, these candidate biomarkers could be useful for the immunological characterization of the PR phase, the stratification of patients with better disease prognosis, and a more personalized therapeutic management.
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Affiliation(s)
- Laia Gomez-Muñoz
- Immunology Department, Germans Trias i Pujol Research Institute and University Hospital, Autonomous University of Barcelona, Badalona, Spain
| | - David Perna-Barrull
- Immunology Department, Germans Trias i Pujol Research Institute and University Hospital, Autonomous University of Barcelona, Badalona, Spain
| | - Josep M. Caroz-Armayones
- Department of Political and Social Sciences, Health Inequalities Research Group (GREDS-EMCONET), Pompeu Fabra University, Barcelona, Spain
- Johns Hopkins University–Pompeu Fabra University Public Policy Center, Barcelona, Spain
| | - Marta Murillo
- Pediatrics Department, Germans Trias i Pujol Research Institute and University Hospital, Autonomous University of Barcelona, Badalona, Spain
| | - Silvia Rodriguez-Fernandez
- Immunology Department, Germans Trias i Pujol Research Institute and University Hospital, Autonomous University of Barcelona, Badalona, Spain
| | - Aina Valls
- Pediatrics Department, Germans Trias i Pujol Research Institute and University Hospital, Autonomous University of Barcelona, Badalona, Spain
| | - Federico Vazquez
- Endocrinology Department, Germans Trias i Pujol Research Institute and University Hospital, Autonomous University of Barcelona, Badalona, Spain
| | - Jacobo Perez
- Pediatric Endocrinology Department, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, Autonomous University of Barcelona, Sabadell, Spain
| | - Raquel Corripio
- Pediatric Endocrinology Department, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, Autonomous University of Barcelona, Sabadell, Spain
| | - Luis Castaño
- Cruces University Hospital, Biocruces Bizkaia Research Institute, UPV/EHU, CIBERDEM, CIBERER, Endo-ERN, Bilbao, Spain
| | - Joan Bel
- Pediatrics Department, Germans Trias i Pujol Research Institute and University Hospital, Autonomous University of Barcelona, Badalona, Spain
| | - Marta Vives-Pi
- Immunology Department, Germans Trias i Pujol Research Institute and University Hospital, Autonomous University of Barcelona, Badalona, Spain
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Shi R, Dai F, He Y, Sun L, Xu M, Deng D, Zhang Q. Comprehensive Analyses of Type 1 Diabetes Ketosis- or Ketoacidosis-Related Genes in Activated CD56 +CD16 + NK Cells. Front Endocrinol (Lausanne) 2021; 12:750135. [PMID: 34899600 PMCID: PMC8656236 DOI: 10.3389/fendo.2021.750135] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 11/05/2021] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVES Alterations in natural killer (NK) cells activity cause damage to pancreatic islets in type 1 diabetes mellitus (T1DM). The aim of this study is to identify T1DM ketosis- or ketoacidosis-related genes in activated CD56+CD16+ NK cells. METHODS Microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were analyzed using the GEO2R tool. Enrichment analyses were performed using Metascape online database and GSEA software. Cell-specific gene co-expression network was built using NetworkAnalyst tools. Cytoscape software was used to identify hub genes and construct co-expressed networks. Target miRNAs were predicted based on the DIANA-micro T, miRDB, and miRWalk online databases. RESULTS A total of 70 DEGs were identified between T1DM patients recovered from ketosis or ketoacidosis and healthy control blood samples in GSE44314. Among the DEGs, 10 hub genes were screened out. The mature NK cell-specific gene co-expression network for DEGs in T1DM was built using NetworkAnalyst tools. DEGs between activated CD56+CD16+ NK cells and CD56brightCD16- NK cells were identified from GSE1511. After intersection, 13 overlapping genes between GSE44314 and GSE1511 microarray datasets were screened out, in which 7 hub genes were identified. Additionally, 59 target miRNAs were predicted according to the 7 hub genes. After validating with the exosome miRNA expression profile dataset of GSE97123, seven differentially expressed miRNAs (DEmiRNAs) in plasma-derived exosome were selected. Finally, a mRNA-miRNA network was constructed, which was involved in the T1DM ketosis or ketoacidosis process. CONCLUSION This work identified seven hub genes in activated CD56+CD16+ NK cells and seven miRNAs in plasma-derived exosome as potential predictors of T1DM ketoacidosis, which provided a novel insight for the pathogenesis at the transcriptome level.
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Affiliation(s)
| | | | | | | | | | | | - Qiu Zhang
- *Correspondence: Datong Deng, ; Qiu Zhang,
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