B cell depletion with rituximab in patients with rheumatoid arthritis: Multiplex bead array reveals the kinetics of IgG and IgA antibodies to citrullinated antigens
B cell depletion with rituximab in patients with rheumatoid arthritis: Multiplex bead array reveals the kinetics of IgG and IgA antibodies to citrullinated antigens
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DOI：
10.1016/j.jaut.2016.03.010
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发表时间：
2016-06-01
影响因子：
12.8
通讯作者：
Sokolove, Jeremy
中科院分区：
文献类型：
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作者：
Cambridge, Geraldine;Leandro, Maria J.;Sokolove, Jeremy
类风湿关节炎(RA)患者的血清学特征是自身抗体水平持续升高：抗Ig G Fc的类风湿因子(RHF)和瓜氨酸(Cit)蛋白/肽序列：ACPA，识别多个Cit序列。以利妥昔单抗为基础的B细胞去除治疗对RA患者有良好的临床反应，特别是在血清阳性组，反应有时持续到B细胞重建阶段之后。一般而言，利妥昔单抗治疗后，ACPA水平下降，但在预测复发方面的波动已被证明令人失望。为了确定免疫球蛋白或免疫球蛋白ACPA中可能的免疫显性特异性，我们使用了一个基于多重微珠的阵列，该阵列由30个Cit-肽/蛋白质和22个相应的天然序列组成。在连续16例严重活动期类风湿关节炎患者的利妥昔单抗治疗的初始周期中，在关键时间点(基线、B细胞耗竭阶段、复发)测量了血清ACPA对个体特异性的反应动力学。所有患者的疾病活动性评分均显著降低-28分，外周血中B细胞持续耗竭(=1(高于人群平均水平))，每种血清中至少发现一种Cit抗原。对个体特异性的ACPA随后以3种不同的模式波动。大多数51/68(75%)的Ig G-和48/51的Ig A-ACPA(94%)在基线和耗竭之间，其中57%的Ig G-和65%的Ig A-ACPA在复发前反弹。有趣的是，有17/68人(25%)和一些人(3/51人；6%)的IgA-ACPA从基线一过性升高，随后在复发前下降。个体对特定Cit抗原表位的反应与特定的波动模式无关，但对单个Cit抗原的Ig G和Ig A ACPA通常遵循相似的过程。但有4例患者在复发时出现了针对不同Cit抗原的新的Ig G-和Ig A-ACPA。因此，利妥昔单抗后ACPA反应的复杂性可能反映了其耗尽或改变亲本B细胞克隆功能的能力，这一能力因患者而异。尽管利妥昔单抗的复发总是伴随着原始B细胞从骨髓中消失，但这些研究表明，新的和残留的自身反应性B细胞之间的相互作用可能是症状恢复的关键。缺乏任何免疫显性特异性的鉴定表明，驱动RA患者自身免疫反应的是瓜氨酸化过程，而不是任何特定的Cit抗原。(C)2016爱思唯尔有限公司。保留所有权利。
The serology of patients with Rheumatoid arthritis (RA) is characterized by persistently raised levels of autoantibodies: Rheumatoid Factors (RhF) against Fc of IgG, and to citrullinated (Cit) protein/peptide sequences: ACPA, recognizing multiple Cit-sequences. B cell depletion therapy based on rituximab delivers good clinical responses in RA patients, particularly in the seropositive group, with responses sometimes lasting beyond the phase of B cell reconstitution. In general, ACPA levels fall following rituximab, but fluctuations with respect to predicting relapse have proved disappointing. In order to identify possible immunodominant specificities within either IgG- or IgA-ACPA we used a Multiplex bead-based array consisting of 30 Cit-peptides/proteins and 22 corresponding native sequences. The kinetics of the serum ACPA response to individual specificities was measured at key points (Baseline, B cell depletion phase, Relapse) within an initial cycle of rituximab therapy in 16 consecutive patients with severe, active RA. All had achieved significant decreases in Disease Activity Scores-28 and maintained B cell depletion in the peripheral blood (= 1 (above population mean) were identified, with at least one Cit-antigen identified in each serum. ACPA to individual specificities subsequently fluctuated with 3 different patterns. Most 51/68 (75%) IgG- and 48/51 IgA-ACPA (94%) fell between Baseline and Depletion, of which 57% IgG- and 65% IgA-ACPA rebounded pre-Relapse. Interestingly, 17/68 IgG-ACPA (25%) and some IgA-ACPA (3/51; 6%) transiently increased from Baseline, subsequently falling pre-Relapse. Individual responses to particular Cit-epitopes were not linked to particular patterns of fluctuation, but IgG- and IgA-ACPA to individual Cit-antigens often followed similar courses. Some new IgG- and IgA-ACPA, generally to different Cit-antigens however, arose at Relapse in 4 patients. The complexities of the ACPA response after rituximab may therefore reflect its ability to deplete or modify the function of parent B cell clones, which varies between patients. Although relapse following rituximab invariably follows naive B cell exit from the bone marrow, these studies show that interactions between both 'new' and residual autoreactive memory B cells may be key to resumption of symptoms. The lack of identification of any immunodominant specificity suggests that the process of citrullination, rather than any particular Cit-antigen drives the autoimmune response in RA patients. (C) 2016 Elsevier Ltd. All rights reserved.