Mother\u2212child histocompatibility and risk of rheumatoid arthritis and systemic lupus erythematosus among mothers

Giovanna I Cruz,Wendy S W Wong,John E Niederhuber,Kirsten Sterba,Lindsey A Criswell,Kimberly A Ho,Xiaorong Shao,Diana Quach,Benjamin D Solomon,Nikolaos A Patsopoulos,Nektarios Ladas,Janelle A Noble,Lisa F Barcellos,Darrell J Triulzi,Hong Quach,Michael P Busch,Rainer Blasczyk

doi:10.1038/s41435-018-0055-7

Abstract

The study objective was to test the hypothesis that having histocompatible children increases the risk of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), possibly by contributing to the persistence of fetal cells acquired during pregnancy. We conducted a case control study using data from the UC San Francisco Mother Child Immunogenetic Study and studies at the Inova Translational Medicine Institute. We imputed human leukocyte antigen (HLA) alleles and minor histocompatibility antigens (mHags). We created a variable of exposure to histocompatible children. We estimated an average sequence similarity matching (SSM) score for each mother based on discordant mother−child alleles as a measure of histocompatibility. We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals. A total of 138 RA, 117 SLE, and 913 control mothers were analyzed. Increased risk of RA was associated with having any child compatible at HLA-B (OR 1.9; 1.2–3.1), DPB1 (OR 1.8; 1.2–2.6) or DQB1 (OR 1.8; 1.2–2.7). Compatibility at mHag ZAPHIR was associated with reduced risk of SLE among mothers carrying the HLA-restriction allele B*07:02 (n = 262; OR 0.4; 0.2–0.8). Our findings support the hypothesis that mother−child histocompatibility is associated with risk of RA and SLE.

Highlights

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are two prototypic autoimmune conditions.Massachusetts Institute of Technology and Harvard, 415 Main Street, Cambridge, MA 02142, USA 7 Blood Systems Research Institute, 270 Masonic Avenue, San Francisco, CA 94118-4417, USA 8 Institute for Transfusion Medicine, Department of Pathology, University of Pittsburgh, 3636 Blvd. of the Allies, Pittsburgh, PA 15213, USA 9 Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany Division of Medical Genomics, Inova Translational Medicine Institute, 8110 Gatehouse Road, Falls Church, VA 22042, USA School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA California Institute for Quantitative Biosciences (QB3), University of California Berkeley, 174 Stanley Hall, Berkeley, CA 947203220, USADespite differing clinical manifestations, a common feature is the production of B- and T-cell responses directed against self-antigens
RA and SLE cases were older at the time of interview or electronic medical record (EMR) extraction compared to controls (Table 1)
Over the seven individual human leukocyte antigen (HLA) loci tested in RA and SLE separately, HLA-B, DPB1 and DQB1 were associated with increased risk of RA when mothers had one or more children prior to diagnosis who were histocompatible from the mother’s perspective (Table 2)

Summary

Introduction

A common feature is the production of B- and T-cell responses directed against self-antigens. Both diseases have strong associations with human leukocyte antigen (HLA) alleles [1] and predominately affect women [2, 3]. In contrast to RA, a recent birth is associated with a reduction in risk of developing SLE lasting up to 10 years [11]. HLA disparity has been associated with improvement of RA symptoms during the course of pregnancy [12,13,14] and with delayed onset of RA post-pregnancy [13]. One hypothesis is that the persistence of fetal cells in the mother’s body may be analogous to a graft and its immunological effect may be mediated by HLA relationships between mother and fetus [16]

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