HLA genes associated with autoimmunity and progression to disease in type 1 diabetes.
Insulin dependent diabetes mellitus (type I DM) is caused by an autoimmune process which culminates in destruction of pancreatic beta cells with resultant loss of insulin production. Preceding the clinical diagnosis of type I DM is a preclinical stage characterized by autoantibodies to insulin, glutamic acid decarboxylase (GAD) and a tyrosine phosphatase-like molecule (IA-2). We have studied both HLA class I and class 2 allele distributions in diabetic probands and autoantibody positive individuals in members of 452 families recruited for the Australian type I diabetes DNA repository. The results demonstrate that progression to autoimmunity as measured by the appearance of autoantibodies is strongly associated with the class 2 alleles DRB1*03 and DRB*04 and with DRB1*03/04 heterozygosity. In contrast, the progression to clinical disease appears associated with class I alleles A24, A30 and B18 while A1, A28, B14 and B56 appear negatively associated. The class 2 alleles appear to have a minimal role in the progression from autoantibody positivity to clinical disease. These results are consistent with the view that CD4+ T cells responding to peptides in the context of class 2 molecules are responsible for initiating autoantibody production, while the destruction of islet cells leading to clinical expression of the disease is the function of CD8+ T cells recognizing relevant peptides in the context of class I molecules.
Tait
B D
BD
Victorian Transplantation and Immunogenetics Service, Australian Red Cross Blood Service, Melbourne, Victoria, Australia.
Colman
P G
PG
Morahan
G
G
Marchinovska
L
L
Dore
E
E
Gellert
S
S
Honeyman
M C
MC
Stephen
K
K
Loth
A
A
D000483:Alleles; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity / Q000235:genetics*; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005787:Gene Frequency; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008297:Male; D011236:Prediabetic State / Q000235:genetics / Q000276:immunology
D001323:Autoantibodies; D006680:HLA Antigens