Fetal-Maternal HLA Relationships and Autoimmune Disease

Autoimmune disease disproportionately affects more women than men. Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are two prototypic female-predominant autoimmune diseases. Despite different clinical manifestations, similarities exist. Both are characterized by a dysregulated immune response to self-tissues. For both diseases, the strongest genetic risk factors are linked to human leukocyte antigen (HLA) alleles. Pregnancy affects their course and may also contribute to risk. This dissertation investigates mother-child HLA relationships and risk of developing RA or SLE./nChapter 1 provides background on RA and SLE and a literature review outlining the rationale for the dissertation. The chapter states the hypotheses of the project and the specific aims addressed in each chapter./nChapter 2 addresses the question of mother-child histocompatibility and risk of RA or SLE. The study tests the hypothesis that having any children who are compatible from the perspective of the mother increases the risk of developing RA or SLE. Results show that having any histocompatible children at HLA-B and DPB1 increase risk of RA in the mother. Increased structural similarity as quantified by a sequence similarity matching score at DPB1 was associated with decreased risk of SLE. Mother-child compatibility at minor histocompatibility antigen ZAPHIR was likewise associated with decreased risk of SLE but compatibility at LB-WNK1 increased risk for mothers who were also HLA-compatible at HLA-A with their children. This is the first study investigating the relationship between minor histocompatibility antigen compatibility and risk of SLE. This study supports the hypothesis that mother-child HLA relationships are associated with risk of RA and SLE./nChapter 3 addresses the question of whether having children who carry HLA alleles associated with increased risk of SLE contributes to its development among mothers. The alleles investigated include DRB1*03:01, *15:01, *08:01. In addition, the study tests the hypothesis that molecular mimicry by means of exposure to DRB1*04:01 that codes for a similar amino acid sequence to the Epstein-Barr virus, a known SLE risk factor, increases risk among mothers. There was no association between SLE risk-associated alleles. However, increased risk of SLE was associated with having at least one child who carried the DRB1*04:01 allele among women negative for the allele but with at least one of the predisposing alleles. This study supports the hypothesis that a child’s alleles inherited from the father influence a mother’s subsequent risk of SLE./nChapter 4 investigates the association between having children who carry alleles encoding amino acids (AA) associated with RA including the “shared epitope”, the sequence DERAA at AA positions 70-74, AA valine, lysine, alanine at positions 11, 71, 74 of the HLA-DRB1 molecule, aspartic acid at position 9 of HLA-B and phenylalanine at position 8 of DPB1. The study finds increased risk of RA among mothers who had any child with SE, DERAA, valine, lysine and alanine encoding alleles, independent of maternal carrier status. Among non-carrier mothers, increased risk of RA was associated with having children who carried DERAA./nChapter 5 summarizes the key findings and results from each study and the conclusions of this work. Future directions are also addressed.

Advisor: Barcellos, Lisa F