B lymphocytopenia in rheumatoid arthritis is associated with the DRB1 shared epitope and increased acute phase response

The influence of HLA DRB1 alleles on B-cell homeostasis was analyzed in 164 patients with rheumatoid arthritis (RA). The percentages of CD19(+) B lymphocytes determined in the peripheral circulation of 94 retrospectively recruited RA patients followed a bimodal distribution. Two frequency peaks (B-cell(low) patients and B-cell(high) patients) were separated by the population median of a B-cell frequency of 8.5% of all lymphocytes. Human leucocyte antigen genotyping revealed that the B-cell(low) patients were more frequently positive for the RA-associated HLA DRB1 shared epitope (SE) than were B-cell(high) patients. Accordingly, SE-positive patients had lower CD19 percentages in the rank-sum analysis when compared with SE-negative patients, and were markedly B lymphocytopenic when compared with a healthy control group. To confirm the differential frequencies of CD19(+) B cells, absolute numbers in peripheral blood were determined prospectively in a cohort of 70 RA patients with recent onset disease. SE-positive patients were found to have lower absolute numbers of circulating CD19(+) B cells. B-cell counts below the mean of the study population were associated with higher acute phase response and with increased levels of rheumatoid factor IgA. No correlation between absolute numbers of circulating B cells and radiographic progression of joint destruction was seen. The influence of immunogenetic parameters on B-cell homeostasis in RA reported here has not been described previously. The clinical relevance of B lymphocytopenia in SE-positive RA will be further investigated in longitudinal studies.

本研究针对164例类风湿关节炎（rheumatoid arthritis, RA）患者，分析了人类白细胞抗原DRB1（HLA DRB1）等位基因对B细胞稳态的影响。本研究对94例回顾性招募的RA患者外周血中CD19⁺B淋巴细胞占比进行检测，结果显示其呈现双峰分布。该双峰分布以所有淋巴细胞中B细胞占比8.5%的人群中位数为界，分为低B细胞组与高B细胞组两类患者。人类白细胞抗原基因分型结果显示，相较于高B细胞组患者，低B细胞组患者携带RA相关HLA DRB1共同表位（shared epitope, SE）的比例更高。据此，秩和分析结果显示，SE阳性患者的CD19⁺细胞占比低于SE阴性患者；与健康对照组相比，SE阳性患者存在显著的B淋巴细胞减少。为验证CD19⁺B细胞占比的差异，本研究对70例新发RA患者队列的外周血B细胞绝对计数进行了前瞻性检测。结果证实，SE阳性患者的循环CD19⁺B细胞绝对计数更低。本研究人群中，B细胞计数低于平均值的患者，其急性期反应更强，血清IgA型类风湿因子水平也更高。未观察到循环B细胞绝对计数与关节破坏的影像学进展存在相关性。本研究揭示的免疫遗传参数对RA患者B细胞稳态的影响，此前尚无相关报道。SE阳性RA患者中B淋巴细胞减少的临床相关性，将在后续纵向研究中进一步探究。