Age-associated B-cells across the rheumatoid arthritis continuum: from early immunopathogenesis to comorbidities

Age-associated B cells (ABCs) are a B-cell subset with distinct transcription and functional properties. Their functions include antibodies secretion, cytokine production, antigen presentation and T-cell stimulation. ABCs have been found expanded in aging, infections and autoimmune diseases such as systemic lupus erythematous, multiple sclerosis and rheumatoid arthritis (RA). ABCs have emerged as plausible mediators of autoimmunity by virtue of their ability to produce autoantibodies and proinflammatory cytokines, as well as trigger T-cell activation, although mechanisms may differ across diseases. Moreover, ABCs may represent a mechanistic link between immunosenescence, premature aging and disease outcomes. Herein, we describe the current knowledge of ABCs in RA with a special focus in the early stages and comorbidity development. Accumulating evidence from preclinical and clinical studies with RA patients have demonstrated disturbances within the ABCs pool. Animal models suggest that ABCs play an important role already in the early phases of the disease and data from RA patients seem to support this hypothesis. Besides, RA risk factors and disease activity may be linked to ABCs expansion, which is associated with high levels of proinflammatory cytokines and correlated with skewed helper T-cell profiles, potentially contributing to inflammaging. Moreover, ABCs may not only be involved in the RA immunopathology, but also in the clinical expression of this disease at synovial and systemic levels. Potential roles of ABCs in cardiovascular, lung, neurological, kidney and metabolic comorbidities are identified, although level of evidence is heterogeneous and limited in some cases. Future perspectives for research, clinical translation and therapeutic implications are discussed.