Differences in B cell regulation in DRB1 shared epitope positive and negative rheumatoid arthritis

Introduction

Aim of the study was the analysis of systemic B cell activity and of the size of the B lymphocyte compartment in patients with rheumatoid arthritis (RA)

Material and methods

In 94 patients with RA according to the 1987 ACR criteria, clinical, radiographic and laboratory data were gathered in a cross-sectional, retrospective study. Besides standard laboratory test, concentration of serum IgM and IgG were determined. In peripheral blood mononuclear cells, the percentages of CD4+, CD8+ and CD19+ lymphocytes were determined by dual-color flow cytometry. For all patients, the presence of the RA associated shared epitope (SE) was determined by HLA DRB1 genotyping.

Results

The analysis of CD19+ B cell frequencies of RA patients revealed a bimodal distribution in the study population separating one group of patients with B cell counts below 8.5 % of all lymphocytes (B cell low patients, 62 % of the study population) from a second group with more than 8.5 % B cells (B cell high, 38 %). HLA genotyping revealed, that the two groups were immunogenetically distinct. B cell low patients were more frequently SE positive than B cell high patients (84.5 % vs. 50 %, P < 0.001), and SE positive patients had lower CD19 percentages in the rank-sum analysis when compared to SE negative ones (6.3 % vs. 14.0 %, P < 0.001). Comparative analysis of a healthy control group showed, that B cell frequencies were diminished in SE positive and increased in SE negative patients.

B cell low patients were found to have significantly lower concentrations of RF IgM, RF IgA, and serum IgM, but not of serum IgG, when compared to the B cell high group. Multivariate analysis revealed the presence of low B cell counts to be associated with the presence of the shared epitope sequence, RF IgM seronegativity and low concentrations of serum IgM, but not with disease activity, gender, age at disease onset or disease duration.

Conclusion

We have found a diminished size of the peripheral B cell pool in SE positive RA patients, that is associated with lower RF IgM titers and a suppression of the parameters of polyclonal IgM, but not IgG secretion. Suppression of polyclonal autoreactivity in SE positive RA patients by clonal deletion of autoreactive, IgM+ B lymphocytes is one possible explanation for decreased B cell counts in RA.