Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition.

Synovial IgG-expressing B cells from patients with rheumatoid arthritis show specificity for citrullinated autoantigens. Antibodies targeting citrullinated proteins (ACPAs [anticitrullinated protein antibodies]) are commonly found in patients with rheumatoid arthritis (RA), strongly associate with distinct HLA-DR alleles, and predict a more aggressive disease course as compared with seronegative patients. Still, many features of these antibodies, including their site of production and the extent of MHC class II–driven T cell help, remain unclarified. To address these questions, we have used a single B cell–based cloning technology to isolate and express immunoglobulin (Ig) genes from joint-derived B cells of active RA patients. We found ∼25% of synovial IgG-expressing B cells to be specific for citrullinated autoantigens in the investigated ACPA+ RA patients, whereas such antibodies were not found in ACPA− patients. The citrulline-reactive monoclonal antibodies did not react with the unmodified arginine peptides, yet several reacted with more than one citrullinated antigen. A role for active antigen selection of the citrulline-reactive synovial B cells was supported by the strong bias toward amino acid replacement mutations in ACPA+ antibodies and by their loss of reactivity to citrullinated autoantigens when somatic mutations were reverted to the corresponding germline sequences.

类风湿关节炎患者表达IgG的滑膜B细胞对瓜氨酸化自身抗原具有特异性。 针对瓜氨酸化蛋白的抗体（抗瓜氨酸化蛋白抗体[ACPAs]）常见于类风湿关节炎（RA）患者，与特定的HLA - DR等位基因密切相关，并且与血清阴性患者相比，预示着更具侵袭性的疾病进程。然而，这些抗体的许多特性，包括其产生部位以及MHC II类分子驱动的T细胞辅助程度，仍不明确。为了解决这些问题，我们使用了一种基于单个B细胞的克隆技术，从活动性RA患者的关节来源B细胞中分离并表达免疫球蛋白（Ig）基因。我们发现，在所研究的抗瓜氨酸化蛋白抗体阳性的RA患者中，约25%表达IgG的滑膜B细胞对瓜氨酸化自身抗原具有特异性，而在抗瓜氨酸化蛋白抗体阴性的患者中未发现此类抗体。瓜氨酸反应性单克隆抗体不与未修饰的精氨酸肽反应，但有几种抗体可与不止一种瓜氨酸化抗原反应。抗瓜氨酸化蛋白抗体阳性抗体中氨基酸替换突变的强烈偏向，以及当体细胞突变恢复为相应的种系序列时它们对瓜氨酸化自身抗原反应性的丧失，都支持了瓜氨酸反应性滑膜B细胞存在主动抗原选择的作用。