Amara Khaled, Clay Elizabeth, Yeo Lorraine, Ramsköld Daniel, Spengler Julia, Sippl Natalie, Cameron James A, Israelsson Lena, Titcombe Philip J, Grönwall Caroline, Sahbudin Ilfita, Filer Andrew, Raza Karim, Malmström Vivianne, Scheel-Toellner Dagmar
Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-17176 Solna, Stockholm, Sweden.
Rheumatology Research Group, RACE AR UK Centre of Excellence in RA Pathogenesis, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
J Autoimmun. 2017 Jul;81:34-43. doi: 10.1016/j.jaut.2017.03.004. Epub 2017 Mar 24.
The clinical efficacy of B cell targeting therapies highlights the pathogenic potential of B cells in inflammatory diseases. Expression of Fc Receptor like 4 (FcRL4) identifies a memory B cell subset, which is enriched in the joints of patients with rheumatoid arthritis (RA) and in mucosa-associated lymphoid tissue. The high level of RANKL production by this B cell subset indicates a unique pathogenic role. In addition, recent work has identified a role for FcRL4 as an IgA receptor, suggesting a potential function in mucosal immunity. Here, the contribution of FcRL4+ B cells to the specific autoimmune response in the joints of patients with RA was investigated. Single FcRL4+ and FcRL4- B cells were sorted from synovial fluid and tissue from RA patients and their immunoglobulin genes characterized. Levels of hypermutation in the variable regions in both populations were largely consistent with memory B cells selected by an antigen- and T cell-dependent process. Recombinant antibodies were generated based on the IgH and IgL variable region sequences and investigated for antigen specificity. A significantly larger proportion of the recombinant antibodies generated from individual synovial FcRL4+ B cells showed reactivity towards citrullinated autoantigens. Furthermore, both in analyses based on heavy chain sequences and flow cytometric detection, FcRL4+ B cells have significantly increased usage of the IgA isotype. Their low level of expression of immunoglobulin and plasma cell differentiation genes does not suggest current antibody secretion. We conclude that these activated B cells are a component of the local autoimmune response, and through their RANKL expression, can contribute to joint destruction. Furthermore, their expression of FcRL4 and their enrichment in the IgA isotype points towards a potential role for these cells in the link between mucosal and joint inflammation.
B细胞靶向疗法的临床疗效凸显了B细胞在炎症性疾病中的致病潜力。Fc受体样4（FcRL4）的表达可识别一种记忆B细胞亚群，该亚群在类风湿关节炎（RA）患者的关节以及黏膜相关淋巴组织中富集。此B细胞亚群高水平的RANKL产生表明其具有独特的致病作用。此外，最近的研究确定FcRL4作为一种IgA受体发挥作用，提示其在黏膜免疫中具有潜在功能。在此，研究了FcRL4 + B细胞对RA患者关节中特异性自身免疫反应的贡献。从RA患者的滑液和组织中分离出单个FcRL4 +和FcRL4 - B细胞，并对其免疫球蛋白基因进行表征。两个群体可变区的高突变水平在很大程度上与通过抗原和T细胞依赖性过程选择的记忆B细胞一致。基于IgH和IgL可变区序列产生重组抗体，并研究其抗原特异性。从单个滑膜FcRL4 + B细胞产生的重组抗体中，有显著更大比例显示出对瓜氨酸化自身抗原的反应性。此外，无论是基于重链序列的分析还是流式细胞术检测，FcRL4 + B细胞IgA同种型的使用都显著增加。它们免疫球蛋白和浆细胞分化基因的低表达水平并不表明当前存在抗体分泌。我们得出结论，这些活化的B细胞是局部自身免疫反应的一个组成部分，并且通过其RANKL表达，可导致关节破坏。此外，它们的FcRL4表达及其在IgA同种型中的富集表明这些细胞在黏膜炎症与关节炎症之间的联系中具有潜在作用。
