Immunogenetic Studies of Autoimmune Disease

描述(申请人提供)：在西方国家，自身免疫性疾病共同影响着大约5%的人口，是导致残疾的主要原因。这组疾病包括各种各样的情况，具有不同的临床表现和自然病史。有令人信服的证据表明，遗传和非遗传影响都参与其中，女性受到的影响不成比例。尽管进行了数十年的深入研究，但自身免疫性疾病的病因尚不清楚。 微嵌合体(MC)和母胎关系在自身免疫中的作用已被提出。母亲和胎儿之间的双向细胞交换发生在怀孕期间，这些胎儿细胞被发现长期存在于母体循环中。强有力的证据表明，这种发生在胎儿发育过程中的非宿主暴露，可能通过胎儿细胞在母亲体内的长期存在，具有生物学意义，并可能在自身免疫性疾病的发病机制中发挥作用。母子之间共享或相容的人类白细胞抗原可能会调节这一过程，也可能以其他方式影响疾病风险或临床结果。 我们提出了一种大型、全面和多分析的方法来确定非遗传性母婴人类白细胞抗原机制是否是三种常见的与人类白细胞抗原相关的自身免疫性疾病的危险因素，这三种疾病是多发性硬化症(MS)、类风湿性关节炎(RA)和系统性红斑狼疮(SLE)。我们将使用大量针对每种疾病的严格确定的患者、对照组和其他家庭成员来研究胎儿来源的(父亲的)II类HLA等位基因和单倍型对母亲(患有MS、RA或SLE)的影响。我们将包括使用详细的临床和生殖病史以及人类白细胞抗原分析。这项应用利用了MS、RA和SLE家族的三个特征良好且正在进行的收集，并提出了一种新的实验方法来确定复杂自身免疫性疾病的潜在病因。本研究的结果将为未来自身免疫中MC和母胎关系的分子研究提供强有力的和急需的基础。

DESCRIPTION (provided by applicant): Autoimmune disorders, collectively, affect approximately 5% of the population in Western countries and are a major cause of disability. This group of diseases includes a wide variety of conditions with differing clinical presentations and natural histories. There is compelling evidence for the involvement of both genetic and non-genetic influences, and females are disproportionately affected. Despite decades of intensive investigation, the etiology of autoimmune disease is unknown. A role for microchimerism (MC) and maternal-fetal HLA relationships has been proposed for autoimmunity. Bi-directional cell traffic between mother and fetus occurs during pregnancy, and these fetal cells have been found to persist long-term in the maternal circulation. Strong evidence suggests that this non-host exposure occurring during fetal development, and perhaps through long term persistence of fetal cells in the mother, is biologically relevant, and may play a role in autoimmune disease pathogenesis. HLA sharing or compatibility between mother and offspring may mediate this process, and may also operate in other ways to influence disease risk or clinical outcome. We propose a large, comprehensive and multi-analytical approach to determine whether non-inherited maternal-fetal HLA mechanisms are risk factors in three common HLA-associated autoimmune diseases for which women are at greater risk: multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We will study the influence of fetally derived (paternal) class II HLA alleles and haplotypes on the mother (who has MS, RA or SLE) using a large number of stringently ascertained patients, controls and other family members for each disease. We will include the use of detailed clinical and reproductive histories and HLA profiling. This application takes advantage of three well-characterized and ongoing collections of MS, RA and SLE families and proposes a novel experimental approach for identifying the underlying etiology of complex autoimmune diseases. The results obtained from this study will provide a strong and much needed foundation for future molecular studies of MC and maternal-fetal relationships in autoimmunity.