Toes Rene E M
Dept. Of Rheumatology, Leiden University Medical Center, 2333, ZA, Leiden, The Netherlands.
Semin Arthritis Rheum. 2025 Jun;72S:152699. doi: 10.1016/j.semarthrit.2025.152699. Epub 2025 Feb 26.
Many autoimmune diseases respond well to therapies targeting B cells, emphasizing the importance of autoreactive B cells in disease induction and progression. In some cases, autoantibodies from plasma cells are the main effectors, while in others, memory B cells are thought to modulate inflammatory responses through antigen presentation or cytokine secretion. Tolerance mechanisms usually prevent the development of autoantibodies, but when these systems fail, autoimmunity and subsequent autoimmune diseases can arise. Understanding the dynamics of autoreactive B cell responses is crucial for delineation the pathogenic pathways underlying disease. Rheumatoid arthritis (RA) is a prototypic autoimmune disease featuring autoreactive B cell responses against post-translationally modified (PTM) proteins. Especially, the Anti-Citrullinated Protein Antibody (ACPA) response, the autoimmune response hallmarking RA, is well characterized over the last two decades. ACPA target citrullinated proteins and their presence is associated with more severe disease progression. In recent years, it has become apparent that ACPA are very promiscuous and able to recognize both human and microbial PTM proteins. Likewise, it is now clear that these antibodies often carry Fab glycans that could, potentially, boost B cell activation and/or be involved in evasion of tolerance mechanisms. Although subjected to tolerance checkpoint, new technologies have shown that the secreted ACPA repertoire is highly polyclonal, unique to each patient, but also dominated by a few ACPA clones. In this synopsis, these and other findings are discussed. Overall, these shed light on the complexity and evolving nature of the ACPA response in RA, unveiling new insights into autoreactive B cell behavior.
许多自身免疫性疾病对靶向B细胞的疗法反应良好，这突出了自身反应性B细胞在疾病诱导和进展中的重要性。在某些情况下，浆细胞产生的自身抗体是主要效应物，而在其他情况下，记忆B细胞被认为通过抗原呈递或细胞因子分泌来调节炎症反应。耐受机制通常可防止自身抗体的产生，但当这些系统失效时，就会出现自身免疫及随后的自身免疫性疾病。了解自身反应性B细胞反应的动态过程对于描绘疾病潜在的致病途径至关重要。类风湿性关节炎（RA）是一种典型的自身免疫性疾病，其特征是针对翻译后修饰（PTM）蛋白的自身反应性B细胞反应。特别是，抗瓜氨酸化蛋白抗体（ACPA）反应作为RA的自身免疫反应标志，在过去二十年中已得到充分表征。ACPA靶向瓜氨酸化蛋白，其存在与更严重的疾病进展相关。近年来，很明显ACPA非常混杂，能够识别人类和微生物的PTM蛋白。同样，现在清楚的是，这些抗体通常携带Fab聚糖，这些聚糖可能会促进B细胞活化和/或参与逃避耐受机制。尽管受到耐受检查点的作用，但新技术表明，分泌的ACPA库是高度多克隆的，对每个患者都是独特的，但也由少数ACPA克隆主导。在本综述中，将讨论这些及其他发现。总体而言，这些发现揭示了RA中ACPA反应的复杂性和不断演变的性质，为自身反应性B细胞行为提供了新的见解。
