Genetics of autoimmune polyendocrine syndrome II

自身免疫性多内分泌综合征II型（APS-II）的特征是在个体中同时发生两种或多种自身免疫性疾病，并且通常也在其家族成员中发生，最典型的是Addison病、自身免疫性甲状腺疾病（格雷夫斯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，但在某些家族中还可能包括狼疮性肾炎、幼年型类风湿性关节炎、多发性硬化症和其它疾病。我们的分析强烈表明，APS-II的自身免疫是由非MHC基因的易感HLA基因型的背景下控制。我们建议对这种非MHC APS-II基因进行定位，确定其在不同临床亚型的APS-II中的作用，确定这种2-位点模型解释了APS-II的哪些自身免疫表现，并最终鉴定非MHC APS-II基因。我们的方法是确定和分析大型APS-II家系，以确定文书异质性，可能反映潜在的遗传异质性。我们已经进行了一系列的大型初步临床调查，确定了三个不同的APS-Ⅱ家族，其中特定的自身免疫性疾病似乎发生为常染色体显性遗传特征;家庭与多个案件的阿狄森氏病和其他自身免疫性疾病，家庭与多个案件的白癜风和其他自身免疫性疾病，和家庭与成人发病1型糖尿病和其他自身免疫性疾病。在多发性阿狄森氏病家族中，我们已经确定了特定的HLA基因型，似乎是必要的，但不足以发生疾病。考虑到易感的HLA基因型，这些家族中阿狄森氏病的发生似乎是由MHC外的常染色体显性遗传位点决定的。我们将通过最初的10-cM基因组筛选来定位这个非MHC APS-II位点，以确定连锁的候选区域，然后我们将使用额外的家族和额外的标记来完善这个定位，以构建该区域的物理图谱，我们最终将确定非MHC APS-II易感基因。我们还计划从白癜风/APS-II和糖尿病/APS-II家族中收集样本，并确定这些家族中的各种自身免疫表现中哪些是由该基因引起的。对易患各种形式的APS-II的基因的定义将极大地提高我们对自身免疫的遗传学和病因的理解。在某些家族中发生的狼疮性肾炎、幼年型类风湿性关节炎和多发性硬化症与APS-II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，识别参与这些自身免疫性疾病的基因和相应的基因产物无疑将开辟治疗甚至预防这些疾病的新途径。

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.