The Autoantibody response in rheumatoid arthritis; what makes it unique?

Abstract

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.