B cells expressing the IgA receptor FcRL4 participate in the autoimmune response in patients with rheumatoid arthritis.
B cells expressing the IgA receptor FcRL4 participate in the autoimmune response in patients with rheumatoid arthritis.
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DOI：
10.1016/j.jaut.2017.03.004
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发表时间：
2017-07
影响因子：
12.8
通讯作者：
Scheel-Toellner D
中科院分区：
文献类型：
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作者：
Amara K;Clay E;Yeo L;Ramsköld D;Spengler J;Sippl N;Cameron JA;Israelsson L;Titcombe PJ;Grönwall C;Sahbudin I;Filer A;Raza K;Malmström V;Scheel-Toellner D
B细胞靶向治疗的临床疗效凸显了B细胞在炎症性疾病中的致病潜力。 Fc 受体样 4 (FcRL4) 的表达识别出记忆 B 细胞亚群，该亚群在类风湿性关节炎 (RA) 患者的关节和粘膜相关淋巴组织中丰富。该 B 细胞亚群产生的高水平 RANKL 表明其具有独特的致病作用。此外，最近的工作还确定了 FcRL4 作为 IgA 受体的作用，表明其在粘膜免疫中具有潜在功能。在此，研究了 FcRL4+ B 细胞对 RA 患者关节特异性自身免疫反应的贡献。从 RA 患者的滑液和组织中分选单个 FcRL4+ 和 FcRL4- B 细胞，并对其免疫球蛋白基因进行表征。两个群体中可变区的超突变水平与通过抗原和 T 细胞依赖性过程选择的记忆 B 细胞基本一致。根据 IgH 和 IgL 可变区序列生成重组抗体，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，显着更大比例显示出对瓜氨酸自身抗原的反应性。此外，在基于重链序列和流式细胞术检测的分析中，FcRL4+ B 细胞对 IgA 同种型的使用显着增加。它们的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有抗体分泌。我们得出的结论是，这些激活的 B 细胞是局部自身免疫反应的一个组成部分，并且通过它们的 RANKL 表达，可以导致关节破坏。此外，它们的 FcRL4 表达及其 IgA 同种型的富集表明这些细胞在粘膜和关节炎症之间的联系中具有潜在作用。在 RA 患者的关节中发现了表达 IgA 受体 FcRL4 的记忆 B 细胞。滑膜 FcRL4+ B 细胞上表达的 B 细胞受体通常属于 IgA 类。从 FcRL4+ B 细胞克隆的重组抗体与瓜氨酸蛋白具有更高的反应性。 FcRL4+ B 细胞的基因转录谱显示向浆细胞的低分化水平。这些细胞可能参与粘膜和关节自身免疫之间的联系。
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. Memory B cells expressing the IgA receptor FcRL4 are found in the joints of patients with RA. B cell receptors expressed on synovial FcRL4+ B cells more frequently belong to the IgA class. Among recombinant antibodies cloned from FcRL4+ B cells there is more reactivity with citrullinated proteins. The gene transcription profile of FcRL4+ B cells shows a low level of differentiation to plasma cells. These cells may be involved in the link between mucosal and joint autoimmunity.