Fetal-Maternal Histocompatibility and Autoimmune Disease

 描述(申请人提供)：这个项目的目标是调查胎儿-母体组织相容性和其他人类白细胞抗原在母体自身免疫性疾病中的潜在作用。女性的优势，在育龄期间发病，以及与移植物抗宿主病的相似之处，导致了怀孕期间的自然过程，如母亲和胎儿之间的双向细胞交换，可能参与了一些自身免疫疾病的病因。来自不同个体的细胞或组织的存在被称为微嵌合体(MC)。对硬皮病、类风湿性关节炎(RA)和系统性红斑狼疮(SLE)的研究发现，与健康对照组相比，出生后几年母体循环中的胎儿细胞或MC数量更多。胎儿细胞可能会引发移植物抗宿主或宿主抗移植物效应，从而触发自身免疫条件。然而，与产次相关的RA和SLE风险的总体降低以及妊娠期间RA症状的改善，表明接触胎儿DNA也可能是有益的。总体而言，MC在疾病病因中的确切作用仍不清楚。人类白细胞抗原(人类白细胞抗原)分子在免疫功能中起着关键作用，在自身和异体的免疫识别中起着重要作用。组织相容性关系被认为在胎儿细胞的效应和持久性中发挥作用。该项目的总体假设是，胎儿-母体组织相容性关系的性质决定了暴露于胎儿细胞对疾病风险的影响。该项目将使用从900名RA患者、SLE患者和健康对照组(每组300名)、他们的1500名子女和400名父亲的医疗记录中提取的4位数的人类白细胞抗原基因型别、详细的孕产史和临床特征来解决三个相关假设。首先，与对照组相比，患者更有可能在8个经典的人类白细胞抗原基因座上共享更多的等位基因。病例对照差异将使用Logistic回归进行检验，并对已知的混杂因素和遗传血统进行调整。其次，与任何后代没有增加组织相容性的女性，与有相容后代的女性相比，RA和SLE的发病年龄更晚。风险比将使用以诊断年龄为感兴趣事件的Cox比例风险模型来估计。第三，与对照组相比，病例更有可能是与其伴侣相似的人类白细胞抗原，因为胎儿丢失与母子之间组织相容性的增加有关，此外，类风湿关节炎和系统性红斑狼疮的风险增加。我们将首先评估报告的导致胎儿丢失的怀孕次数与疾病风险之间的关系。其次，我们将通过估计亲缘系数R来衡量交配伙伴之间的遗传相似程度。通过经典的HLA基因型别介导的胎儿-母体影响可以为这些衰弱疾病和其他可疑与怀孕有关的因素的病因学提供新的见解。

 DESCRIPTION (provided by applicant): The objective of this project is to investigate the potential role of fetal-maternal histocompatibility and other HLA relationships in maternal autoimmune disease. Female predominance, onset during childbearing years, and similarities to graft-versus-host disease have led to the hypothesis that natural processes during pregnancy such as the bi-directional cellular exchange between mother and fetus could be involved in the etiology of some autoimmune conditions. The presence of cells or tissues originating from a different individual is referred to as microchimerism (MC). Studies in scleroderma, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) have found higher number of fetal cells, or MC, in the maternal circulation years after birth compared to healthy controls. Fetal cells could potentially elicit a graft-versus-host or a host-versus-graft effect triggering autoimmune conditions. However, the overall reduction of risk of RA and SLE associated with parity and the amelioration of RA symptoms during pregnancy, suggest that exposure to fetal DNA could also be beneficial. Overall, the exact role of MC in disease etiology remains unknown. Human Leukocyte Antigen (HLA) molecules play a key role in immunologic function and are important in immune recognition of self and non-self. Histocompatibility relationships are hypothesized to play a role in effect and persistence of fetal cells. The overall hypothesis of this project is tha the nature of the fetal-maternal histocompatibility relationship determines the effect of exposure to fetal cells on risk of disease. This project will use 4-digit HLA genotypes, detailed pregnancy histories, and clinical characteristics abstracted from medical records from ~900 RA cases, SLE cases and healthy controls (300 in each group), 1,500 of their children and 400 fathers to address three related hypotheses. First, cases are more likely to share a larger number of alleles at eight classical HLA loci compared to controls. Case-control differences will be tested using logistic regression, adjusting for known confounders and genetic ancestry. Second, women who do not have increased histocompatibility with any of their offspring have a later age of onset of RA and SLE compared to women who have compatible offspring. Hazard ratios will be estimated using a Cox-proportional hazards model with age of diagnosis as the event of interest. Third, cases are more likely to be HLA similar to their partners than controls since feta loss is associated with increased histocompatibility between mother and child, in addition to increased risk of RA and SLE. We will first estimate the association between reported number of pregnancies resulting in fetal loss and risk of disease. Second, we will measure the degree of genetic similarity between mating partners by estimating a relatedness coefficient R. Fetal-maternal influences mediated through classical HLA genotypes could provide new insight into the etiology of these debilitating conditions and others where pregnancy related factors are suspected.