Antibodies and B cells recognising citrullinated proteins display a broad cross-reactivity towards other post-translational modifications
Antibodies and B cells recognising citrullinated proteins display a broad cross-reactivity towards other post-translational modifications
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DOI：
10.1136/annrheumdis-2019-216499
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发表时间：
2020-04-01
影响因子：
27.4
通讯作者：
Toes, R. E. M.
中科院分区：
文献类型：
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作者：
Kissel, T.;Reijm, S.;Toes, R. E. M.
目的抗带有不同翻译后修饰(PTM)抗原的自身抗体，如瓜氨酸、高瓜氨酸或乙酰赖氨酸，是类风湿关节炎(RA)的标志。这些抗修饰蛋白抗体(AMPA)类之间的关系还不清楚，因为不同的PTM抗原激活针对瓜氨酸蛋白(CP)的B细胞受体(BCR)的能力。对能够激活这种B细胞的PTM的本质的洞察对于理解这种疾病背后可能发生的自身免疫反应的“进化”至关重要。在这里，我们研究了单抗AMPA的交叉反应性以及不同类型的PTM抗原激活CP反应性BCR的能力。方法用瓜氨酸化或乙酰化抗原从B细胞中分离BCR序列，制备单抗，并详细分析它们与PTM抗原的交叉反应。构建表达CP反应性Ig G bcr的Ramos B细胞转基因细胞，并检测其在PTM抗原刺激下的活化情况。携带CP反应性BCR的B细胞在不同类型的PTM抗原的刺激下表现出激活。结论我们的研究表明AMPA与至少两个PTM具有高度的交叉反应，表明它们的识别模式并不局限于一种修饰。此外，我们的数据表明，CP反应性B细胞不仅可以被瓜氨酸激活，还可以被氨甲酰化和/或乙酰化抗原激活。这些数据对于了解B细胞对PTM抗原的耐受性被打破以及这些抗原在RA发病机制中的可能作用是至关重要的。
ObjectiveAutoantibodies against antigens carrying distinct post-translational modifications (PTMs), such as citrulline, homocitrulline or acetyllysine, are hallmarks of rheumatoid arthritis (RA). The relation between these anti-modified protein antibody (AMPA)-classes is poorly understood as is the ability of different PTM-antigens to activate B-cell receptors (BCRs) directed against citrullinated proteins (CP). Insights into the nature of PTMs able to activate such B cells are pivotal to understand the 'evolution' of the autoimmune response conceivable underlying the disease. Here, we investigated the cross-reactivity of monoclonal AMPA and the ability of different types of PTM-antigens to activate CP-reactive BCRs.MethodsBCR sequences from B cells isolated using citrullinated or acetylated antigens were used to produce monoclonal antibodies (mAb) followed by a detailed analysis of their cross-reactivity towards PTM-antigens. Ramos B-cell transfectants expressing CP-reactive IgG BCRs were generated and their activation on stimulation with PTM-antigens investigated.ResultsMost mAbs were highly cross-reactive towards multiple PTMs, while no reactivity was observed to the unmodified controls. B cells carrying CP-reactive BCRs showed activation on stimulation with various types of PTM-antigens.ConclusionsOur study illustrates that AMPA exhibit a high cross-reactivity towards at least two PTMs indicating that their recognition pattern is not confined to one type of modification. Furthermore, our data show that CP-reactive B cells are not only activated by citrullinated, but also by carbamylated and/or acetylated antigens. These data are vital for the understanding of the breach of B-cell tolerance against PTM-antigens and the possible contribution of these antigens to RA-pathogenesis.