Pathogenesis of NOD diabetes is initiated by reactivity to the insulin B chain 9-23 epitope and involves functional epitope spreading

• Published in: Journal of autoimmunity 2012-12, Vol.39 (4), p.347-353
• Main Authors: Prasad, Suchitra, Kohm, Adam P, McMahon, Jeffrey S, Luo, Xunrong, Miller, Stephen D
• Format: Article
• Language: English
• Subjects: Allergy and Immunology; Animals; Autoantigens; Autoantigens - genetics; Autoantigens - immunology; Autoimmune disease; Autoimmunity; Beta cells; Biological and medical sciences; CD4 antigen; CD8 antigen; Cell Movement; Cross-Linking Reagents - chemistry; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - pathology; Diabetes. Impaired glucose tolerance; Disease Progression; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Epitope spreading; Epitopes; Epitopes - genetics; Epitopes - immunology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Glucose; Glucose-6-Phosphatase - genetics; Glucose-6-Phosphatase - immunology; Glutamate Decarboxylase - genetics; Glutamate Decarboxylase - immunology; Homeostasis; Immune Tolerance; Immunological tolerance; Immunoregulation; Injections, Intravenous; Insulin; Insulin - genetics; Insulin - immunology; Insulin-Secreting Cells - immunology; Insulin-Secreting Cells - pathology; Islets of Langerhans; Lymphocytes T; Medical sciences; Mice; Mice, Inbred NOD; Pancreas; Pancreatic β-cells; Peptide Fragments - genetics; Peptide Fragments - immunology; Proteins - genetics; Proteins - immunology; Spleen - immunology; Spleen - pathology; Splenocytes; T cell activation; T lymphocytes; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - pathology; Tolerance
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2012.04.005

Abstract Type 1 diabetes (T1D) is mediated by destruction of pancreatic β-cells by CD4 and CD8 T cells specific for epitopes on numerous diabetogenic autoantigens resulting in loss of glucose homeostasis. Employing antigen-specific tolerance induced by i.v. administration of syngeneic splenocytes ECDI cross-linked to various diabetogenic antigens/epitopes (Ag-SP), we show that epitope spreading plays a functional role in the pathogenesis of T1D in NOD mice. Specifically, Ag-SP coupled with intact insulin, Ins B9-23 or Ins B15-23 , but not GAD65509-528 , GAD65524-543 or IGRP206-214 , protected 4–6 week old NOD mice from the eventual development of clinical disease; infiltration of immune cells to the pancreatic islets; and blocked the induction of DTH responses in a Treg-dependent, antigen-specific manner. However, tolerance induction in 19–21 week old NOD mice was effectively accomplished only by Ins-SP, suggesting Ins B9-23 is a dominant initiating epitope, but autoimmune responses to insulin epitope(s) distinct from Ins B9-23 emerge during disease progression.