HLA genes associated with autoimmunity and progression to disease in type 1 diabetes

• Published in: Tissue antigens Vol. 61; no. 2; pp. 146 - 153
• Main Authors: Tait, B.D., Colman, P.G., Morahan, G., Marchinovska, L., Dore, E., Gellert, S., Honeyman, M.C., Stephen, K., Loth, A.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Munksgaard International Publishers 01-02-2003
• Subjects: Alleles; Autoantibodies; Autoantibodies - blood; autoimmunity; Autoimmunity - genetics; Case-Control Studies; Diabetes Mellitus, Type 1 - etiology; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Female; GAD; Gene Frequency; Genes, MHC Class I; Genes, MHC Class II; Haplotypes; HLA Antigens - genetics; HLA class 1; HLA class 2; Humans; IA-2; insulin; Male; Prediabetic State - genetics; Prediabetic State - immunology; type 1 DM
• ISSN: 0001-2815; 1399-0039
• DOI: 10.1034/j.1399-0039.2003.00013.x

: 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.