Immunogenetics and Immunopathogenesis of Type 1 Diabetes and associated autoimmune disorders

The major goal of our laboratory is to define the genes and pathogenic processes that lead to type 1 diabetes and a series of related autoimmune disorders with the particular goal of prediction and prevention. Our studies deal primarily with patients and their families with type 1 diabetes and the NOD mouse model of type 1 diabetes. In 1986 our laboratory proposed that type 1 diabetes was a chronic autoimmune disorder and thus amenable to disease prediction. We have recently found that children with the genotype DQ8/DQ2 as young as 1/2 year of age develop autoantibodies reacting with a series of islet autoantigens. In addition to HLA molecules contributing to disease, we are pursuing a locus on chromosome 10q25.1, that combined with high risk HLA alleles confers a risk of diabetes of approximately 40%. Autoantibody prediction of type 1 diabetes is now carried out for both first degree relatives of patients as well as the general population. The DAISY study centered in Colorado has HLA typed more than 21,000 newborns from the general population and followed children at risk for type 1 diabetes and celiac disease. A major predictor of type 1 diabetes is the presence of autoantibodies reacting with multiple autoantigens, and multiple epitopes of given autoantigens. We favor the hypothesis that insulin may be a primary autoantigen for type 1 diabetes, and are studying spontaneous and induced models of anti-insulin autoimmunity with T cell clones recognizing the B:9-23 peptide of insulin. Altered peptide ligands of this peptide prevent diabetes of the NOD mouse and are being studied in man.

Selected References:

• Moriyama H., et al. Evidence for a primary islet autoantigen (presporinsulin 1) for insulitiis and diabetes in the NOD mouse. Proc Natl Acad Sci 100: 10376-10381, 2003
• Moriyama,H, Wen,L, Abiru,N, Liu,E, Yu,L, Miao,D, Gianani,R, Wong,F.S, Eisenbarth,G.S. Induction and acceleration of insulitis/diabetes in mice with a viral mimic (polyinosinic-polycytidylic acid) and an insulin self-peptide. Proc Natl Acad Sci 2002; 99:5539-5544.
• Abiru N, Wegmann D, Kawasaki E, Gottlieb P, Simone E, Eisenbarth GS. Dual overlapping peptides recognized by insulin peptide B:9-23 reactive T cell receptor AV13S3 T cell clones of the NOD mouse. J Autoimmun 2000; 14: 231-237.
• Bao F, Yu L, Babu S, Wang T, Hoffenberg EJ, Rewers M, et al. One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease associated transglutaminase autoantibodies. J Autoimmunity 1999; 13:143-148.
• Yu L, Robles DT, Abiru N, Kaur P, Rewers M, Kelemen K, et al. Early expression of anti-insulin autoantibodies of man and the NOD mouse: evidence for early determination of subsequent diabetes. Proc Natl Acad Sci USA 2000; 97:1701-1706.
• Redondo MJ, Rewers M, Yu L, Garg S, Pilcher CC, Elliott RB, et al. Genetic determination of islet cell autoimmunity in monozygotic twin, dizygotic twin, and non-twin siblings of patients with type 1 diabetes: prospective twin study. BMJ 1999; 318:698- 702.
• Simone E, Daniel D, Schloot N, Gottlieb P, Babu S, Kawasaki E, et al. T cell receptor restriction of diabetogenic autoimmune NOD T cells. Proc Natl Acad Sci USA 1997; 94:2518-2521.
• Verge CF, Vardi P, Babu S, Bao F, Erlich HA, Bugawan T, et al. Evidence for oligogenic inheritance of type 1A diabetes in a large Bedouin Arab family. J Clin Invest 1998; 102:1569-1575.
• Verge CF, Gianani R, Kawasaki E, Yu L, Pietropaolo M, Jackson RA, et al. Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes 1996; 45:926-933.

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