Balázs Csaba
Budai Irgalmasrendi Kórház Belgyógyászati-Endokrin Osztály Budapest Frankel L. út 17-19. 1029.
Orv Hetil. 2012 Jul 1;153(26):1013-22. doi: 10.1556/OH.2012.29370.
Autoimmune thyroid diseases are the most common organ-specific autoimmune disorders affecting 5% to 10% of the population in Western countries. The clinical presentation varies from hyperthyroidism in Graves' disease to hypothyroidism in Hashimoto's thyroiditis. While the exact etiology of thyroid autoimmunity is not known, the interaction between genetic susceptibility and environmental factors appears to be of fundamental importance to initiate the process of thyroid autoimmunity. The identified autoimmune thyroid disease susceptibility genes include immune-modulating genes, such as the major histocompatibility complex, and thyroid-specific genes, including TSH receptor, thyroglobulin and thyroid peroxidase. The majority of the anti-TSH-receptor antibodies have a stimulating capacity and are responsible for hyperthyroidism. The anti-thyroglobulin- and anti-thyroid peroxidase antibodies belonging to the catalytic type of antibodies destroy the thyrocytes resulting in hypothyroidism. The appearance of anti-thyroid peroxidase antibodies precedes the induction of thyroiditis and the manifestation of hypothyroidism. The molecular analysis of thyroglobulin gene polymorphism is important in the mechanism of autoimmune thyroiditis. The autoantigen presentation by major histocompatibility complex molecules is a key point of the autoimmune mechanism. It has been shown that a HLA-DR variant containing arginine at position 74 of the DRβ1 chain confers a strong genetic susceptibility to autoimmune thyroid diseases, Graves' disease and Hashimoto's thyroiditis, while glutamine at position DRβ1-74 is protective. Human thyroglobulin 2098 peptide represents a strong and specific DRβ1-Arg74 binder, while a non-binding control peptide, thyroglobulin 2766 fails to induce this response. Moreover, thyroglobulin 2098 stimulated T-cells from individuals who were positive for thyroglobulin antibodies, demonstrating that thyroglobulin 2098 is an immunogenic peptide capable of being presented in vivo and activating T-cells in autoimmune thyroid diseases. Taken together these findings suggest that thyroglobulin 2098, a strong and specific binder to the disease-associated HLA-DRβ1-Arg74, is a major human T-cell epitope and it participates in the pathomechanism of the autoimmune thyroid disease. The exact nature of the role of environmental factors in the autoimmune thyroid disease is still not well known, but the importance of several factors such as iodine, drugs and infections has been reported. Further knowledge of the precise mechanisms of interaction between environmental factors and genes in inducing thyroid autoimmunity could result in the development of new strategies for diagnosis, prevention and treatment.
自身免疫性甲状腺疾病是最常见的器官特异性自身免疫性疾病，在西方国家影响着5%至10%的人口。临床表现从格雷夫斯病的甲状腺功能亢进到桥本甲状腺炎的甲状腺功能减退各不相同。虽然甲状腺自身免疫的确切病因尚不清楚，但遗传易感性与环境因素之间的相互作用似乎对启动甲状腺自身免疫过程至关重要。已确定的自身免疫性甲状腺疾病易感基因包括免疫调节基因，如主要组织相容性复合体，以及甲状腺特异性基因，包括促甲状腺激素受体、甲状腺球蛋白和甲状腺过氧化物酶。大多数抗促甲状腺激素受体抗体具有刺激能力，是导致甲状腺功能亢进的原因。属于催化型抗体的抗甲状腺球蛋白和抗甲状腺过氧化物酶抗体破坏甲状腺细胞，导致甲状腺功能减退。抗甲状腺过氧化物酶抗体的出现先于甲状腺炎的诱导和甲状腺功能减退的表现。甲状腺球蛋白基因多态性的分子分析在自身免疫性甲状腺炎的机制中很重要。主要组织相容性复合体分子呈递自身抗原是自身免疫机制的关键环节。研究表明，DRβ1链第74位含有精氨酸的HLA - DR变体赋予对自身免疫性甲状腺疾病、格雷夫斯病和桥本甲状腺炎的强烈遗传易感性，而DRβ1 - 74位的谷氨酰胺具有保护作用。人甲状腺球蛋白2098肽是一种强而特异的DRβ1 - Arg74结合物，而非结合对照肽甲状腺球蛋白2766则不能诱导这种反应。此外，甲状腺球蛋白2098刺激了甲状腺球蛋白抗体呈阳性个体的T细胞，表明甲状腺球蛋白2098是一种能够在体内呈递并激活自身免疫性甲状腺疾病中T细胞的免疫原性肽。综合这些发现表明，甲状腺球蛋白2098是与疾病相关的HLA - DRβ1 - Arg74的强而特异的结合物，是主要的人类T细胞表位，它参与了自身免疫性甲状腺疾病的发病机制。环境因素在自身免疫性甲状腺疾病中的确切作用性质仍不清楚，但已报道了碘、药物和感染等几种因素的重要性。进一步了解环境因素与基因在诱导甲状腺自身免疫中相互作用的精确机制，可能会导致开发出新的诊断、预防和治疗策略。
