Pathogenesis of NOD diabetes is initiated by reactivity to the insulin B chain 9-23 epitope and involves functional epitope spreading.
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 B(9-23) or Ins B(15-23), but not GAD65(509-528), GAD65(524-543) or IGRP(206-214), 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 B(9-23) is a dominant initiating epitope, but autoimmune responses to insulin epitope(s) distinct from Ins B(9-23) emerge during disease progression.
Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Suchitra
S
Prasad
Adam P
AP
Kohm
Jeffrey S
JS
McMahon
Xunrong
X
Luo
Stephen D
SD
Miller
D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity; D002465:Cell Movement; D003432:Cross-Linking Reagents / Q000737:chemistry; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018450:Disease Progression; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D005260:Female; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000276:immunology; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance; D007275:Injections, Intravenous; D007328:Insulin / Q000235:genetics / Q000276:immunology*; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology*; D011506:Proteins / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
D001324:Autoantigens; D003432:Cross-Linking Reagents; D000939:Epitopes; D007328:Insulin; D010446:Peptide Fragments; D011506:Proteins; C097877:insulin B (9-23); D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse; D005968:Glutamate Decarboxylase