Genetics of autoimmune polyendocrine syndrome II

自身免疫性多内分泌综合征II型（APS-II）以两种或两种以上自身免疫性疾病在个体及家族成员中同时出现为特征，最典型的是Addison病、自身免疫性甲状腺疾病（Graves病和甲状腺功能减退）、I型糖尿病、乳糜泻、性腺功能减退、白癜风、脱发、恶性贫血和重症肌无力，但在一些家族中也可能包括红斑狼疮、幼年类风湿性关节炎、多发性硬化症和其他疾病。我们的分析强烈表明，APS-II的自身免疫是由易感HLA基因型的非mhc基因控制的。我们拟对该非MHC APS-II基因进行定位，确定其在不同临床亚型APS-II中的作用，并通过该2位点模型确定APS-II的哪些自身免疫表现，最终鉴定非MHC APS-II基因。我们的方法是识别和分析大型APS-II谱系，以定义可能反映潜在遗传异质性的神职人员异质性。我们进行了一系列大型初步临床调查，确定了三组不同的APS-II家族，其中特异性自身免疫性疾病似乎作为常染色体显性性状发生；多例Addison病和其他自身免疫性疾病的家庭，多例白癜风和其他自身免疫性疾病的家庭，以及成人发病的1型糖尿病和其他自身免疫性疾病的家庭。在多重Addison病家族中，我们已经确定了特定的HLA基因型，这些基因型对于疾病的发生似乎是必要的，但不是充分的。鉴于易感HLA基因型，Addison病在这些家族中的发生似乎是由MHC外的常染色体显性遗传位点决定的。我们将通过一个初始的10厘米基因组筛选来定位这个非mhc APS-II位点，以确定一个候选的连锁区域，然后我们将使用其他家族和其他标记来完善这个定位，直到构建该区域的物理图谱，我们将最终确定非mhc APS-II易感基因。我们还计划收集白癜风/APS-II和糖尿病/APS-II家族的样本，并确定这些家族的各种自身免疫表现中哪些是由该基因引起的。定义易患各种形式APS-II的基因将大大提高我们对自身免疫的遗传学和病因的理解。APS-II家族中狼疮红斑、幼年类风湿性关节炎和多发性硬化症的发生表明，APS-II基因的鉴定也可能揭示这些自身免疫性疾病的发病机制。从长远来看，识别与这些自身免疫性疾病有关的基因和相应的基因产物无疑将为其治疗甚至预防开辟新的途径。

Autoimmune polyendocrine syndrome type II (APS-II) is characterized by the co-occurrence of two or more of various autoimmune disorders in individuals, and often also in their family members, most typically Addison's disease, autoimmune thyroid disease (Graves' disease and hypothyroidism), type I diabetes mellitus celiac disease, hypogonadism, vitiligo, alopecia, pernicious anemia, and myasthenia gravis, but in some families may also include lupus erythematosis, juvenile rheumatoid arthritis, multiple sclerosis, and other disorders. Our analyses strong indicate that autoimmunity in APS-II is controlled by a non-MHC gene in the context of a susceptible HLA genotype. We propose to map this non- MHC APS-II gene, determine its role in different clinical subtypes of APS-II, determine which autoimmune manifestations of APS-II are accounted for by this 2-locus model, and ultimately to identify the non- MHC APS-II gene. Our approach is to identify and analyze large APS-II pedigrees to define clerical heterogeneity that may reflect underlying genetic heterogeneity. We have carried out a series of large preliminary clinical surveys identifying three distinct groups of APS-II families in whom specific autoimmune disorders appear to occur as autosomal dominant traits; families with multiple cases of Addison's disease and other autoimmune disorders, families with multiple cases of vitiligo and other autoimmune disorders, and families with adult-onset type 1diabetes mellitus and other autoimmune disorders. In the multiplex Addison's disease families, we have identified specific HLA genotypes that appear to be necessary but not sufficient for the occurrence of disease. Given a susceptible HLA genotype, the occurrence of Addison's disease in these families appears to be determined by an autosomal dominantly inherited locus outside the MHC. We will map this non-MHC APS-II locus by an initial 10-cM genome screen to identify a candidate region of linkage, we will then refine this localization using additional families and additional markers, to the point of constructing a physical map of the region, and we will eventually identify the non-MHC APS-II susceptibility gene. We also plan to collect samples from vitiligo/APS-II and diabetes/APS-II families and to determine which of the various autoimmune manifestations in these families are accounted for by this gene. Definition of genes that predispose to various forms of APS-II will greatly enhance our understanding of the genetics and causation of autoimmunity in general. The occurrence of lupus erythematosis, juvenile rheumatoid arthritis, and multiple sclerosis in some families with APS-II suggests that the identification of APS-II genes may also shed light on the pathogenesis of these autoimmune disorders. In the long run, identification of genes and corresponding gene products that are involved in these autoimmune disorders will undoubtedly open up new avenues of approach to their treatment and even prevention.