Autoreactive B cells in autoimmune diseases: Mechanisms, functions and clinical implications

Autoreactive B cells play a key role in the pathophysiology of autoimmune diseases (AIDs). Still, due to their low frequency in the circulating blood, they are less well characterized than the global B cell pool. This review aims at describing the tools that allow the study of autoreactive B cells, deciphering their features and functions, and discussing the therapeutic implications that arise from these findings. The capacity to detect and analyze autoreactive B cells has been significantly improved by diverse techniques such as ELISpot and flow cytometry, shedding light on their roles in immune dysregulation. It reveals the multifaceted features of autoreactive B cells in terms of phenotypic and functional characteristics, that vary between different AIDs, and from one autoantigen to another. This heterogeneity may be influenced by factors such as the nature of the targeted autoantigen, or the costimulatory signals involved. These observations highlight that autoreactive B cells contribute not only to autoantibody production, but also to the perpetuation of autoimmunity through additional mechanisms, including antigen presentation and cytokine secretion. Recent therapeutic approaches have been developed to target autoreactive B cells, allowing an antigen-specific depletion of B cells, without causing widespread immunosuppression. Challenges remain, such as understanding the precise mechanisms by which the B cell tolerance breakdown occur, and the pathways by which autoreactive B cells activate (i.e. germinal centre or extrafollicular pathway). Ongoing research into the mechanisms regulating autoreactive B cells will be crucial for designing more targeted and effective therapies, leading to better outcomes for AID patients.