Immunogenetic Studies of Autoimmune Disease

描述（由申请人提供）：自身免疫性疾病，共同影响西方国家约5%的人口，是残疾的主要原因。这组疾病包括具有不同临床表现和自然史的各种各样的病症。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。尽管数十年的深入研究，自身免疫性疾病的病因是未知的。 微嵌合体（MC）和母胎HLA关系的作用已经提出了自身免疫。母亲和胎儿之间的双向细胞运输发生在怀孕期间，这些胎儿细胞已被发现长期存在于母体循环中。强有力的证据表明，在胎儿发育期间发生的这种非宿主暴露，以及可能通过胎儿细胞在母体中的长期存在，具有生物学相关性，并且可能在自身免疫性疾病发病机制中发挥作用。母亲和后代之间的HLA共享或相容性可能介导这一过程，也可能以其他方式影响疾病风险或临床结果。 我们提出了一个大的，全面的和多分析的方法，以确定是否非遗传性母胎HLA机制的危险因素，在三个常见的HLA相关的自身免疫性疾病的妇女是在更大的风险：多发性硬化症（MS），类风湿性关节炎（RA）和系统性红斑狼疮（SLE）。我们将使用大量严格确定的患者、对照和每种疾病的其他家庭成员，研究胎儿衍生（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史和HLA分析。本申请利用MS、RA和SLE家族的三个良好表征和正在进行的收集，并提出了一种新的实验方法用于鉴定复杂自身免疫性疾病的潜在病因。本研究的结果将为今后MC和自身免疫中母胎关系的分子研究提供强有力的基础。

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.