The effects of HLA class II genes on the susceptibility to autoimmune thyroid diseases

Immunogenetic factors such as HLA, C4, T cell receptor and immunoglobulin allotypes were investigated in 115 Japanese patients with Graves' disease. The patients showed strong positive association with HLA-A2 (R.R. = 3.45, chi 2 = 14.93, Pc less than 0.002), Bw46 (R.R. = 6.47, chi 2 = 16.25, Pc less than 0.002), Cw11 (R.R. = 4.47, chi 2 = 9.19, Pc less than 0.04) and DRw8 (R.R. = 2.22, chi 2 = 5.62, P less than 0.03, Pc: n.s.) which form one of the typical HLA haplotypes in Japanese population due to the strong linkage disequilibria. On the other hand, the patients showed negative association with HLA-B7 (R.R. = 0.15, chi 2 = 7.15), Bw52 (R.R. = 0.24, chi 2 = 7.86), DR1 (R.R. = 0.07, chi 2 = 9.71) and DQw1 (R.R. = 0.45, chi 2 = 5.62), which form HLA-B7-DR1-DQw1 and Bw52-DR2-DQw1 haplotypes. Because HLA-A2 -Bw46-Cw11-DR9 haplotype was reported to be associated with Chinese Graves' patients, and because Bw46 showed the strongest association with the Japanese patients, it was suggested that HLA class 1 antigen, Bw46, might be the primary immunogenetic factor involved in the pathogenesis of Graves' disease. Since HLA-DQw6 was reported to be associated negatively with Hashimoto's thyroiditis as same as the current observation in Graves' disease, it was suggested that HLA-DQw6 may determine the resistance to autoimmune thyroiditis. The effect of HLA-DQw6 gene, therefore, on the experimental autoimmune murine thyroiditis (EAMT) was examined, using DQw6-transgenic mouse. F1 with C3H mouse, and backcross progeny between the F1 and C3H mouse which is a susceptible strain to EAMT. The measurement of anti-thyroglobulin antibody indicated that C3H mouse, (C3H x DQ-B6) F1 and backcross progeny between the F1 and C3H were high responders to the thyroglobulin, but that B6 mouse and DQ-B6 mouse were low responders. The histological examination of the thyroid gland of these mice failed to demonstrate the significant difference in susceptibility to EAMT among these mice. These results suggested that the immune response to the thyroglobulin was controlled by H-2k haplotype and that the effect of HLA-DQw6 gene on the immune response to thyroglobulin and on the autoimmune thyroiditis was marginal.