Acquisition of the rheumatoid arthritis HLA shared epitope through microchimerism

Arthritis Rheum. 2011 Mar;63(3):640-4. doi: 10.1002/art.30160.

Abstract

Objective: 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.

Methods: 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.

Results: 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).

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Arthritis, Rheumatoid / epidemiology
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / immunology*
  • Chimerism* / statistics & numerical data
  • Epitopes / genetics
  • Epitopes / immunology
  • Female
  • Genetic Predisposition to Disease / epidemiology
  • HLA-DRB1 Chains / genetics
  • HLA-DRB1 Chains / immunology*
  • Humans
  • Leukocytes, Mononuclear / immunology
  • Male
  • Maternal-Fetal Exchange / genetics
  • Maternal-Fetal Exchange / immunology*
  • Middle Aged
  • Pregnancy
  • Prevalence
  • Real-Time Polymerase Chain Reaction
  • Risk Factors

Substances

  • Epitopes
  • HLA-DRB1 Chains