Cambon-Thomsen A, Roth M P
Centre de recherches sur le polymorphisme génétique des populations humaines, CNRS, UPR 8291, CHU Purpan, Toulouse.
Rev Prat. 1994 Jan 1;44(1):43-52.
Strategies for studying the genetics of autoimmune diseases have undergone a considerable evolution during the last years, especially due to molecular biology techniques and to systematic genome studies. Genetic factors account for 20 to 40% of the risk, and environmental elements play a major role. The major histocompatibility complex comprising HLA genes remains the immunogenetic system most studied and most closely associated with various autoimmune diseases. These associations are mainly observed with HLA class II genes polymorphisms; the precise knowledge of their structure has allowed to define HLA sequence polymorphisms which are themselves risk markers: specific combinations of HLA-DQA and DQB alleles in insulin-dependent diabetes mellitus or a given DR, DQ haplotype for multiple sclerosis. No strong association with HLA-DP has been demonstrated. In all cases the genes involved have a normal structure and the disease is secondary to the combination of a given set of genes with environmental factors. The present knowledge of insulin-dependent diabetes mellitus and multiple sclerosis genetics is rather advanced. Other genes of the HLA region might also be involved in the genetic susceptibility. Results about other immunogenetic systems (T cell receptor genes or heavy chain immunoglobulin genes) are still contradictory but no major gene for autoimmune susceptibility seems to exist in these regions; however autoimmune diseases are under polygenic control; susceptibility genes shared between different diseases often occurring within the same families (Graves' disease and insulin-dependent diabetes mellitus) and genes specific for a given disease (insulin gene region in diabetes) both exist. The present rapid progress in this area is due to the use of highly polymorphic markers randomly distributed across the genome (microsatellites being most informative) and that of animal models: the list of "candidate genes or regions" potentially involved in the genetics of autoimmune diseases is enlarging; the development of coordinated epidemiological studies of molecular genetics along with the sharing of biological resources between different teams allow to build up powerful informative studies which will confirm or refute those "candidates". However, once the list of genes involved is established their mechanism of action will still take time to elucidate.
在过去几年中，研究自身免疫性疾病遗传学的策略经历了相当大的演变，这尤其得益于分子生物学技术和系统的基因组研究。遗传因素占风险的20%至40%，环境因素起主要作用。包含HLA基因的主要组织相容性复合体仍然是研究最多且与各种自身免疫性疾病关系最密切的免疫遗传系统。这些关联主要见于HLA II类基因多态性；对其结构的精确了解使得能够定义HLA序列多态性，这些多态性本身就是风险标志物：胰岛素依赖型糖尿病中HLA - DQA和DQB等位基因的特定组合，或多发性硬化症的特定DR、DQ单倍型。尚未证明与HLA - DP有强关联。在所有情况下，所涉及的基因结构正常，疾病是特定基因组合与环境因素共同作用的结果。目前关于胰岛素依赖型糖尿病和多发性硬化症遗传学的知识相当先进。HLA区域的其他基因也可能参与遗传易感性。关于其他免疫遗传系统（T细胞受体基因或重链免疫球蛋白基因）的结果仍然相互矛盾，但这些区域似乎不存在自身免疫易感性的主要基因；然而，自身免疫性疾病受多基因控制；不同疾病之间共有的易感性基因（常出现在同一家族中的格雷夫斯病和胰岛素依赖型糖尿病）以及特定疾病的基因（糖尿病中的胰岛素基因区域）都存在。该领域目前的快速进展得益于使用随机分布在基因组中的高度多态性标记（微卫星最为信息丰富）以及动物模型：潜在参与自身免疫性疾病遗传学的“候选基因或区域”列表正在扩大；分子遗传学的协调流行病学研究的开展以及不同团队之间生物资源的共享使得能够开展强大的信息丰富的研究，从而证实或反驳这些“候选者”。然而，一旦确定了所涉及的基因列表，其作用机制仍需时间来阐明。
