Fetal-Maternal Histocompatibility and Autoimmune Disease

胎儿-母体组织相容性和自身免疫性疾病

• 批准号: 8987418
• 负责人: Giovanna Cruz
• 金额: $ 3.79万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8987418
• 关键词: Aborted Fetus; Accounting; Address; Affect; Age; Age of Onset; Alleles; Antigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biological; Birth; Blood Circulation; Cells; Characteristics; Child; Chronic; Clinical; Confidence Intervals; Cox Proportional Hazards Models; DNA; Diagnosis; Digit structure; Disease; Disease susceptibility; Etiology; European; Event; Exposure to; Fathers; Female; Fetus; Genes; Genetic; Genome; Genotype; HLA Antigens; Histocompatibility; Hormonal; Immunologics; Incidence; Individual; Infection; Investigation; Kidney; Live Birth; Logistic Regressions; Major Histocompatibility Complex; Measures; Mediating; Medical Records; Microchimerism; Morbidity - disease rate; Mothers; Nature; Odds Ratio; Onset of illness; Organ; Outcome; Partner in relationship; Pathogenesis; Patients; Pattern; Play; Population; Predisposition; Pregnancy; Pregnancy Histories; Process; Recording of previous events; Reporting; Resolution; Rheumatoid Arthritis; Rheumatoid Factor; Risk; Risk Factors; Risk Reduction; Role; Scleroderma; Smoking; Source; Stratification; Symptoms; Systemic Lupus Erythematosus; Testing; Therapeutic; Time; Tissues; Transplantation; United States; Woman; abstracting; base; carrier status; case control; cell mediated immune response; child bearing; cyclic citrullinated peptide; disease phenotype; disorder risk; fetal; fetus cell; graft vs host disease; hazard; human leukocyte antigen gene; insight; interest; mortality; offspring; parity; public health relevance; reproductive; risk variant; success

 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.

 描述（由适用提供）：该项目的目的是研究胎儿 - 伴侣组织相容性和其他HLA关系在母体自身免疫性疾病中的潜在作用。女性占主导地位，在生育年份的发作以及与移植物抗宿主疾病的相似之处，导致假设是，怀孕期间的自然过程，例如母亲和胎儿之间的双向细胞交换可能与某些自身免疫性条件的病因有关。源自另一个个体的细胞或组织的存在称为微chimerism（MC）。与健康对照组相比，在出生后几年中，在母体循环中发现，在硬皮病，类风湿关节炎（RA）和全身性红斑狼疮（SLE）的研究发现了更高的胎儿细胞或MC。胎儿细胞可能会引起移植物与宿主或宿主 - 移植作用触发自身免疫性条件。但是，与平等相关的RA和SLE风险的总体降低以及怀孕期间RA症状的改善，表明暴露于胎儿DNA也可能是有益的。总体而言，MC在病因学中的确切作用仍然未知。人白细胞抗原（HLA）分子在免疫功能中起关键作用，对自我和非自身的免疫认识很重要。假设组织相容性关系在胎儿细胞的有效和持久性中起作用。该项目的总体假设是胎儿母亲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4位HLA基因型，详细的妊娠历史以及从约900例RA病例，SLE病例和健康对照（每组300例），1,500名儿童和400名父亲从医疗记录中提取的临床特征，以解决三个相关假设。首先，与对照组相比，案例更有可能在八个经典HLA基因座上共享更多等位基因。病例对照差异将使用逻辑回归进行测试，调整已知的混杂因素和遗传血统。其次，与具有兼容后代的女性相比，与任何后代的组织相容性没有提高的女性具有RA和SLE的发病年龄。危害比率将使用COX-Prortiate危害模型估算，并将其诊断为感兴趣。第三，由于羊乳酪损失与母亲和儿童之间的组织相容性增加有关，但案例与对照组相比，与对照组相比，案例更有可能与对照组相似。我们将首先估算报告的妊娠数量导致胎儿丧失和疾病风险之间的关联。其次，我们将通过估计相关性系数R.通过经典HLA基因型介导的胎儿伴侣的影响来衡量交配伴侣之间的遗传相似性程度，可以为这些衰弱状况的病因和其他相关因素的病因提供新的见解。