Acquisition of the rheumatoid arthritis HLA shared epitope through microchimerism

Abstract

HLA-DRB1 alleles associated with risk of rheumatoid arthritis (RA) encode similar HLA-DRB1 sequences, called the shared epitope (SE). The most common SE sequences are QKRAA and QRRAA. Nevertheless, a substantial number of RA patients lack the SE. Bidirectional fetal-maternal trafficking results in long-term persistence of fetal cells in the mother and maternal cells in her offspring, a process known as microchimerism. This study was undertaken to discover whether RA patients who lack the SE can acquire it through microchimerism. We studied a total of 86 female subjects who were genotypically negative for the SE, comprising 52 patients with RA and 34 healthy controls. We developed specific real-time quantitative polymerase chain reaction assays for the SE-encoded sequences QKRAA and QRRAA, and used them to test DNA extracted from peripheral blood mononuclear cells. Microchimerism with the SE was found significantly more often in RA patients than controls (odds ratio 4.1 [95% confidence interval 1.6-10.0], P = 0.003). Concentrations of SE microchimerism were also significantly higher among RA patients than controls (P = 0.002). In separate analyses for SE type, the prevalence of QKRAA microchimerism in RA patients versus healthy controls was 17% versus 3% (9 of 52 versus 1 of 34; P = 0.03) and the prevalence of QRRAA microchimerism was 40% versus 18% (21 of 52 versus 6 of 34; P = 0.04), respectively. Microchimerism concentrations were also higher in RA patients than healthy subjects for QKRAA (P = 0.03) and QRRAA (P = 0.03). These results indicate that RA patients who genotypically lack the SE can acquire the SE as persistent microchimerism from fetal-maternal cell exchange, suggesting that SE-encoding microchimerism could be a risk factor for RA.