In many autoimmune diseases, including rheumatoid arthritis (RA), the presence of autoantibodies represents a break of tolerance to self-antigens that has resulted in the generation of auto-reactive B cells. Frequently, this defective control of B cell auto-reactivity occurs prior to the onset of clinical symptoms of disease and marks one of the earliest detectable events of disease-related immune disturbance.
Interestingly, studies of the last years have shown that auto-reactivity in healthy individuals is more frequent than previously anticipated, especially in the immature human B cell compartment. Defects in checkpoints that prevent the further maturation of auto-reactive B cell precursors have been postulated that favor the development of autoimmunity. However, once B cell precursors have passed these checkpoints, little is known about mechanisms that allow and control the maintenance of human auto-reactive B cell memory. In part, this is due to the fact that direct identification of auto-reactive B cells in humans has proven extremely difficult.
In RA, anti-citrullinated protein antibodies (ACPA) represent highly disease-specific biomarkers found in the majority of patients. As ACPA have been implicated in disease pathogenesis, it is of crucial relevance to understand the underlying auto-reactive B cell response. In this context, direct antigen-specific identification and isolation of ACPA-producing B cells would allow a detailed phenotypic and functional characterization of the immune response to better understand its development and maintenance. We now successfully developed, for the first time, a tetramer-based method to identify citrullinated antigen-specific B cells in RA patients. This technique revealed that RA patients harbor a remarkable frequency of circulating memory B cells reactive with citrullinated antigens. This finding can be taken as a surprise, as one could expect that citrullinated antigen-specific B cells would constantly differentiate towards antibody secreting cells due to ubiquitous availability of citrullinated antigens, resulting in absence of specific memory B cells. Therefore, these cells and their functional characteristics are of particular interest and focus of the studies presented. Moreover, the therapeutic efficacy of B cell depletion by monoclonal antibodies targeting CD20 points to an important role of this compartment in RA disease pathogenesis.
Disclosure of Interest None declared