Age-dependent loss of tolerance to an immunodominant epitope of glutamic acid decarboxylase in diabetic-prone RIP-B7/DR4 mice.
We have identified for the first time an age-dependent spontaneous loss of tolerance to two self-antigenic epitopes derived from putative diabetes-associated antigens glutamic acid decarboxylase (GAD65) and glial fibrillary acidic protein (GFAP) in RIP-B7/DRB1*0404 HLA transgenic mice. Diabetic and older non-diabetic mice exhibited a proliferative response to an immunodominant epitope from GAD65 (555-567) and also from GFAP (240-252) but not from an immunogenic epitope from diabetes-associated islet-specific glucose-6-phosphatase catalytic subunit-related protein. The response to both of these self-antigens is not observed in young mice but is observed in older non-diabetic mice and is accompanied by histological evidence of insulitis in the absence of overt diabetes. Islet infiltrates in older non-diabetic mice and diabetic mice contain CD4(+)/FoxP3(+) cells and suggest the presence of a regulatory mechanism prior and during diabetic disease. Diabetes penetrance in RIP-B7/DR0404 mice is 23% with a mean onset age of 40 weeks and is similar to that reported for RIP-B7/DR0401 mice. A gender preference is observed in that 38% of female mice become diabetic compared to 8% of male mice.
Gebe
John A
JA
Department of Immunology, Benaroya Research Institute at Virginia Mason, 1201 9th Avenue, Seattle WA 98101, USA. jgebe@benaroyaresearch.org
Unrath
Kellee A
KA
Falk
Ben A
BA
Ito
Kouichi
K
Wen
Li
L
Daniels
Terri L
TL
Lernmark
Ake
A
Nepom
Gerald T
GT
D000375:Aging / Q000276:immunology*; D000818:Animals; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D004198:Disease Susceptibility; D000939:Epitopes / Q000276:immunology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology* / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D018417:Th1 Cells / Q000276:immunology
D018106:CD28 Antigens; D017252:CD3 Complex; D000939:Epitopes; D005968:Glutamate Decarboxylase