Fetal-Maternal Histocompatibility and Autoimmune Disease

University Of California Berkeley, Berkeley CA

Investigators

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Abstract

? 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.