A Study on the Role of Genes of Innate Immunity in Type 1 Diabetes

Type 1 diabetes (T1D) is caused by autoimmune destruction of insulin-producing pancreatic β-cells. It is a polygenic disease in which maximal genetic susceptibility is conferred by the presence of MHC class II genes. Circulating autoantibodies against islet cell antigens and mononuclear cell infiltrates, especially CD4 + and CD8 + T cells, are characteristic of the disease. Recent evidence suggests innate immunity may be involved in the disease pathogenesis. The aim of this thesis is to identify the genes of innate immunity associated with T1D. In papers I and II, we tested the association of Killer immunoglobulin-like receptor (KIR) genes with T1D in two Caucasian populations (Swedish and Latvian). In the Swedish population, we demonstrated a negative association of KIRs 2DL1 and 3DS1 with T1D. Extensive stratification and interaction analyses showed that the frequency of KIRs 2DL2 and 3DS1 were higher in HLA-DR3/DR4 heterozygous T1D patients, but the difference was not significant. The presence of KIRs 2DL5 and 2DS5 conferred an increased risk to coxsackie B virus infection in T1D patients. In the Latvian cohort, we demonstrated that the presence of KIR 2DL2 and its ligand HLA-C1 conferred susceptibility to the disease. To test the overall association of KIR with T1D we performed a meta-analysis of all published data and found that KIRs 2DL5 and 3DS1 were negatively associated with T1D. These findings indicate that KIR genes are important in regulating innate immune responses and KIR-HLA-C ligand interactions can confer susceptibility to T1D. In papers III and IV, we tested the association of the small ubiquitin-related modifier 4 (SUMO4) M55V polymorphism with T1D in a Swedish (Caucasian) and an AsianIndian population. SUMO4 was not directly associated with T1D in both populations. However, in the Swedish population, presence of the SUMO4 M55V SNP increased the susceptibility (Odds ratio) caused by HLA-DR3/DR4. In paper V, we tested the association of SNPs in the exons of Toll-like receptor (TLR) genes with T1D. SNPs in TLR-1 (rs4833095), TLR-6 (rs5743808) and TLR-8 (rs2159377) were associated with T1D in subjects belonging to the 0-14 year age group. No significant association was observed in the 15-34 year age group. These findings suggest that dysregulation of the immune response, especially in children below the age of 15 years, may contribute to the development of autoimmunity. In conclusion, this thesis reports novel associations of three innate immunity components with T1D. LIST OF PUBLICATIONS I. Sedimbi SK, Kockum I and Sanjeevi CB. Killer Immunoglobulin-like Receptor genes confer susceptibility to type 1 diabetes in Swedish patients.