scholarly journals Non-Genetically Encoded Epitopes Are Relevant Targets in Autoimmune Diabetes

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 202
Author(s):  
Hai Nguyen ◽  
Perrin Guyer ◽  
Ruth A. Ettinger ◽  
Eddie A. James
Keyword(s):  
T Cells ◽  
Beta Cell ◽  
Cd4 T Cells ◽  
Disease Risk ◽  
Autoimmune Diabetes ◽  
Peripheral Tolerance ◽  
Islet Autoimmunity ◽  
Beta Cell Destruction ◽  
Specific Antigens ◽  
Islet Antigen

Islet antigen reactive T cells play a key role in promoting beta cell destruction in type 1 diabetes (T1D). Self-reactive T cells are typically deleted through negative selection in the thymus or deviated to a regulatory phenotype. Nevertheless, those processes are imperfect such that even healthy individuals have a reservoir of potentially autoreactive T cells. What remains less clear is how tolerance is lost to insulin and other beta cell specific antigens. Islet autoantibodies, the best predictor of disease risk, are known to recognize classical antigens such as proinsulin, GAD65, IA-2, and ZnT8. These antibodies are thought to be supported by the expansion of autoreactive CD4+ T cells that recognize these same antigenic targets. However, recent studies have identified new classes of non-genetically encoded epitopes that may reflect crucial gaps in central and peripheral tolerance. Notably, some of these specificities, including epitopes from enzymatically post-translationally modified antigens and hybrid insulin peptides, are present at relatively high frequencies in the peripheral blood of patients with T1D. We conclude that CD4+ T cells that recognize non-genetically encoded epitopes are likely to make an important contribution to the progression of islet autoimmunity in T1D. We further propose that these classes of neo-epitopes should be considered as possible targets for strategies to induce antigen specific tolerance.

scholarly journals Failure to Censor Forbidden Clones of CD4 T Cells in Autoimmune Diabetes

2002 ◽  
Vol 196 (9) ◽  
pp. 1175-1188 ◽  
Author(s):  
Sylvie Lesage ◽  
Suzanne B. Hartley ◽  
Srinivas Akkaraju ◽  
Judith Wilson ◽  
Michelle Townsend ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Autoimmune Diabetes ◽  
High Titre ◽  
High Avidity ◽  
Autoantibody Production ◽  
Inherited Susceptibility ◽  
Organ Specific ◽  
Nonobese Diabetic Mice ◽  
Islet Antigen

Type 1 diabetes and other organ-specific autoimmune diseases often cluster together in human families and in congenic strains of NOD (nonobese diabetic) mice, but the inherited immunoregulatory defects responsible for these diseases are unknown. Here we track the fate of high avidity CD4 T cells recognizing a self-antigen expressed in pancreatic islet β cells using a transgenic mouse model. T cells of identical specificity, recognizing a dominant peptide from the same islet antigen and major histocompatibility complex (MHC)-presenting molecule, were followed on autoimmune susceptible and resistant genetic backgrounds. We show that non-MHC genes from the NOD strain cause a failure to delete these high avidity autoreactive T cells during their development in the thymus, with subsequent spontaneous breakdown of CD4 cell tolerance to the islet antigen, formation of intra-islet germinal centers, and high titre immunoglobulin G1 autoantibody production. In mixed bone marrow chimeric animals, defective thymic deletion was intrinsic to T cells carrying diabetes susceptibility genes. These results demonstrate a primary failure to censor forbidden clones of self-reactive T cells in inherited susceptibility to organ-specific autoimmune disease, and highlight the importance of thymic mechanisms of tolerance in organ-specific tolerance.

scholarly journals Soluble FAS ligand is not required for pancreatic islet inflammation or beta-cell destruction in non-obese diabetic mice

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Prerak M. Trivedi ◽  
Stacey Fynch ◽  
Lucy M. Kennedy ◽  
Jonathan Chee ◽  
Balasubramanian Krishnamurthy ◽  
...  
Keyword(s):  
T Cells ◽  
Beta Cell ◽  
Fas Ligand ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Target Cells ◽  
Beta Cell Destruction ◽  
Soluble Fasl ◽  
Membrane Bound ◽  
Islet Inflammation

Abstract CD8+ T cells play a central role in beta-cell destruction in type 1 diabetes. CD8+ T cells use two main effector pathways to kill target cells, perforin plus granzymes and FAS ligand (FASL). We and others have established that in non-obese diabetic (NOD) mice, perforin is the dominant effector molecule by which autoreactive CD8+ T cells kill beta cells. However, blocking FASL pharmacologically was shown to protect NOD mice from diabetes, indicating that FASL may have some role. FASL can engage with its receptor FAS on target cells either as membrane bound or soluble FASL. It has been shown that membrane-bound FASL is required to stimulate FAS-induced apoptosis in target cells, whereas excessive soluble FASL can induce NF-κB-dependent gene expression and inflammation. Because islet inflammation is a feature of autoimmune diabetes, we tested whether soluble FASL could be important in disease pathogenesis independent of its cell death function. We generated NOD mice deficient in soluble FASL, while maintaining expression of membrane-bound FASL due to a mutation in the FASL sequence required for cleavage by metalloproteinase. NOD mice lacking soluble FASL had normal numbers of lymphocytes in their spleen and thymus. Soluble FASL deficient NOD mice had similar islet inflammation as wild-type NOD mice and were not protected from diabetes. Our data indicate that soluble FASL is not required in development of autoimmune diabetes.

scholarly journals Spontaneous Autoimmune Diabetes in Monoclonal T Cell Nonobese Diabetic Mice

1997 ◽  
Vol 186 (10) ◽  
pp. 1663-1676 ◽  
Author(s):  
Joan Verdaguer ◽  
Dennis Schmidt ◽  
Abdelaziz Amrani ◽  
Brad Anderson ◽  
Nuzhat Averill ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Beta Cell ◽  
Beta Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Pancreatic Beta Cells ◽  
Autoimmune Diabetes ◽  
Nod Mice ◽  
Nonobese Diabetic

It has been established that insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice results from a CD4+ and CD8+ T cell–dependent autoimmune process directed against the pancreatic beta cells. The precise roles that beta cell–reactive CD8+ and CD4+ T cells play in the disease process, however, remain ill defined. Here we have investigated whether naive beta cell–specific CD8+ and CD4+ T cells can spontaneously accumulate in pancreatic islets, differentiate into effector cells, and destroy beta cells in the absence of other T cell specificities. This was done by introducing Kd– or I-Ag7–restricted beta cell–specific T cell receptor (TCR) transgenes that are highly diabetogenic in NOD mice (8.3- and 4.1-TCR, respectively), into recombination-activating gene (RAG)-2–deficient NOD mice, which cannot rearrange endogenous TCR genes and thus bear monoclonal TCR repertoires. We show that while RAG-2−/− 4.1-NOD mice, which only bear beta cell–specific CD4+ T cells, develop diabetes as early and as frequently as RAG-2+ 4.1-NOD mice, RAG-2−/− 8.3-NOD mice, which only bear beta cell–specific CD8+ T cells, develop diabetes less frequently and significantly later than RAG-2+ 8.3-NOD mice. The monoclonal CD8+ T cells of RAG-2−/− 8.3-NOD mice mature properly, proliferate vigorously in response to antigenic stimulation in vitro, and can differentiate into beta cell–cytotoxic T cells in vivo, but do not efficiently accumulate in islets in the absence of a CD4+ T cell–derived signal, which can be provided by splenic CD4+ T cells from nontransgenic NOD mice. These results demonstrate that naive beta cell– specific CD8+ and CD4+ T cells can trigger diabetes in the absence of other T or B cell specificities, but suggest that efficient recruitment of naive diabetogenic beta cell–reactive CD8+ T cells to islets requires the assistance of beta cell–reactive CD4+ T cells.

Efficacy of clonal deletion vs. anergy of self-reactive CD4 T-cells for the prevention and reversal of autoimmune diabetes

2005 ◽  
Vol 25 (1) ◽  
pp. 21-32 ◽  
Author(s):  
Anca Preda-Pais ◽  
Alexandru C. Stan ◽  
Sofia Casares ◽  
Constantin Bona ◽  
Teodor-D. Brumeanu
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Autoimmune Diabetes ◽  
Clonal Deletion

Analysis of pancreatic beta cell specific CD4+ T cells reveals a predominance of proinsulin specific cells

2019 ◽  
Vol 335 ◽  
pp. 68-75 ◽  
Author(s):  
Gabriele Blahnik ◽  
Hannes Uchtenhagen ◽  
I.-Ting Chow ◽  
Cate Speake ◽  
Carla Greenbaum ◽  
...  
Keyword(s):  
T Cells ◽  
Beta Cell ◽  
Cd4 T Cells ◽  
Pancreatic Beta Cell

scholarly journals Hybrid insulin peptides are neo-epitopes for CD4 T cells in autoimmune diabetes

2019 ◽  
Vol 26 (4) ◽  
pp. 195-200
Author(s):  
Rocky L. Baker ◽  
Braxton L. Jamison ◽  
Kathryn Haskins
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Autoimmune Diabetes

scholarly journals Autoimmune diabetes can be induced in transgenic major histocompatibility complex class II-deficient mice.

1993 ◽  
Vol 178 (2) ◽  
pp. 589-596 ◽  
Author(s):  
T M Laufer ◽  
M G von Herrath ◽  
M J Grusby ◽  
M B Oldstone ◽  
L H Glimcher
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class Ii ◽  
Cd4 T Cells ◽  
Islet Cells ◽  
Autoimmune Diabetes ◽  
Class Ii ◽  
Dependent Diabetes Mellitus ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease marked by hyperglycemia and mononuclear cell infiltration of insulin-producing beta islet cells. Predisposition to IDDM in humans has been linked to the class II major histocompatibility complex (MHC), and islet cells often become aberrantly class II positive during the course of the disease. We have used two recently described transgenic lines to investigate the role of class II molecules and CD4+ T cells in the onset of autoimmune insulitis. Mice that are class II deficient secondary to a targeted disruption of the A beta b gene were bred to mice carrying a transgene for the lymphocytic choriomenigitis virus (LCMV) glycoprotein (GP) targeted to the endocrine pancreas. Our results indicate that class II-deficient animals with and without the GP transgene produce a normal cytotoxic T lymphocyte response to whole LCMV. After infection with LCMV, GP-transgenic class II-deficient animals develop hyperglycemia as rapidly as their class II-positive littermates. Histologic examination of tissue sections from GP-transgenic class II-deficient animals reveals lymphocytic infiltrates of the pancreatic islets that are distinguishable from those of their class II-positive littermates only by the absence of infiltrating CD4+ T cells. These results suggest that in this model of autoimmune diabetes, CD4+ T cells and MHC class II molecules are not required for the development of disease.

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