German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany.
Blood. 2010 Dec 9;116(24):5181-90. doi: 10.1182/blood-2010-01-266536. Epub 2010 Sep 9.
The anti-CD20 antibody rituximab depletes human B cells from peripheral blood, but it remains controversial to what extent tissue-resident B cells are affected. In representative patients with rheumatoid arthritis, we here demonstrate that recently activated presumably short-lived plasmablasts expressing HLA-DR(high) and Ki-67 continuously circulate in peripheral blood after B-cell depletion by rituximab at 26%-119% of their initial numbers. They circulate independent of splenectomy, express immunoglobulin A (IgA), β₇ integrin, and C-C motif receptor 10 (CCR10) and migrate along CCL28 gradients in vitro, suggesting their mucosal origin. These plasmablasts express somatically hypermutated V(H) gene rearrangements and spontaneously secrete IgA, exhibiting binding to microbial antigens. Notably, IgA(+) plasmablasts and plasma cells were identified in the lamina propria of patients treated with rituximab during peripheral B-cell depletion. Although a relation of these "steady state"-like plasmablasts with rheumatoid arthritis activity could not be found, their persistence during B-cell depletion indicates that their precursors, that is, B cells resident in the mucosa are not deleted by this treatment. These data suggest that a population of mucosal B cells is self-sufficient in adult humans and not replenished by CD20(+) B cells immigrating from blood, lymphoid tissue, or bone marrow, that is, B cells depleted by rituximab.
抗 CD20 抗体利妥昔单抗可从外周血中清除人 B 细胞，但组织驻留 B 细胞受到多大程度的影响仍存在争议。在有代表性的类风湿关节炎患者中，我们在此证明，在 B 细胞耗竭后，最近被激活的、可能是短暂寿命的浆母细胞以其初始数量的 26%-119%持续在外周血中循环。它们的循环与脾切除术无关，表达免疫球蛋白 A（IgA）、β₇ 整联蛋白和 C-C 基序受体 10（CCR10），并在体外沿 CCL28 梯度迁移，提示其黏膜起源。这些浆母细胞表达体细胞超突变的 V(H)基因重排，并自发分泌 IgA，表现出与微生物抗原的结合。值得注意的是，在接受利妥昔单抗外周 B 细胞耗竭治疗的患者的固有层中鉴定出 IgA(+)浆母细胞和浆细胞。虽然这些“稳态”样浆母细胞与类风湿关节炎活动之间的关系尚未找到，但它们在外周 B 细胞耗竭期间的持续存在表明，其前体，即驻留在黏膜中的 B 细胞未被这种治疗所删除。这些数据表明，在成人中存在一种黏膜 B 细胞群体，其自身是充足的，而不是由从血液、淋巴组织或骨髓中迁入的 CD20(+)B 细胞补充的，也就是说，利妥昔单抗耗竭的 B 细胞。
