Shinagawa H
Department of Genetics, Kyushu University, Fukuoka.
Fukuoka Igaku Zasshi. 1990 Feb;81(2):97-111.
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.
对115例日本格雷夫斯病患者的免疫遗传因素，如人类白细胞抗原（HLA）、补体C4、T细胞受体和免疫球蛋白同种异型进行了研究。患者与HLA - A2（相对危险度=3.45，卡方值=14.93，Pc＜0.002）、Bw46（相对危险度=6.47，卡方值=16.25，Pc＜0.002）、Cw11（相对危险度=4.47，卡方值=9.19，Pc＜0.04）和DRw8（相对危险度=2.22，卡方值=5.62，P＜0.03，Pc：无显著意义）呈强阳性关联，由于强连锁不平衡，这些构成了日本人群典型的HLA单倍型之一。另一方面，患者与HLA - B7（相对危险度=0.15，卡方值=7.15）、Bw52（相对危险度=0.24，卡方值=7.86）、DR1（相对危险度=0.07，卡方值=9.71）和DQw1（相对危险度=0.45，卡方值=5.62）呈阴性关联，这些构成HLA - B7 - DR1 - DQw1和Bw52 - DR2 - DQw1单倍型。因为据报道HLA - A2 - Bw46 - Cw11 - DR9单倍型与中国格雷夫斯病患者相关，且因为Bw46与日本患者的关联最强，所以提示HLAⅠ类抗原Bw46可能是参与格雷夫斯病发病机制的主要免疫遗传因素。由于据报道HLA - DQw6与桥本甲状腺炎呈负相关，与目前在格雷夫斯病中的观察结果相同，所以提示HLA - DQw6可能决定对自身免疫性甲状腺炎的抵抗力。因此，使用DQw6转基因小鼠，研究了HLA - DQw6基因对实验性自身免疫性小鼠甲状腺炎（EAMT）的影响。与C3H小鼠杂交的F1代，以及F1代与对EAMT敏感的C3H小鼠之间的回交后代。抗甲状腺球蛋白抗体的检测表明，C3H小鼠、（C3H×DQ - B6）F1代以及F1代与C3H小鼠的回交后代对甲状腺球蛋白是高反应者，而B6小鼠和DQ - B6小鼠是低反应者。对这些小鼠甲状腺的组织学检查未能显示它们对EAMT易感性的显著差异。这些结果提示，对甲状腺球蛋白的免疫反应受H - 2k单倍型控制，且HLA - DQw6基因对甲状腺球蛋白免疫反应和自身免疫性甲状腺炎的影响很小。
