Molecular mechanisms controlling age‐associated B cells in autoimmunity*

Abstract

Age-associated B cells (ABCs) have emerged as critical components of immune responses. Their inappropriate expansion and differentiation have increasingly been linked to the pathogenesis of autoimmune disorders, aging-associated diseases, and infections. ABCs exhibit a distinctive phenotype and, in addition to classical B cell markers, often express the transcription factor T-bet and myeloid markers like CD11c; hence, these cells are also commonly known as CD11c + T-bet + B cells. Formation of ABCs is promoted by distinctive combinations of innate and adaptive signals. In addition to producing antibodies, these cells display antigen-presenting and proinflammatory capabilities. It is becoming increasingly appreciated that the ABC compartment exhibits a high degree of heterogeneity, plasticity, and sex-specific regulation and that ABCs can differentiate into effector progeny via several routes particularly in autoimmune settings. In this review, we will discuss the initial insights that have been obtained on the molecular machinery that controls ABCs and we will highlight some of the unique aspects of this control system that may enable ABCs to fulfill their distinctive role in immune responses. Given the expanding array of autoimmune disorders and pathophysiological settings in which ABCs are being implicated, a deeper understanding of this machinery could have important and broad therapeutic implications for the successful, albeit daunting, task of targeting these cells.

Age-associated B cells contribute to the pathogenesis of rheumatoid arthritis by inducing activation of fibroblast-like synoviocytes via TNF-α-mediated ERK1/2 and JAK-STAT1 pathways

“…The formation of ABCs is regulated by both innate and adaptive signals 41. Early studies in the murine system have revealed a critical role for innate signals, TLR7 and TLR9 engagement, in promoting the differentiation and generation of ABCs 10 11.…”

Age-Associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade

“…TRA expression in the thymus is a central tolerance mechanism, whereby stimulation of developing T cells by antigens usually expressed in non-thymic tissues directs these cells away from fates with the potential for harmful self-antigen driven autoimmune responses. Previous reports have suggested that AIRE is not functional in the small proportion of peripheral lymphocytes in which it can be detected(35-37), although AIRE function has never been assessed in ABCs (a peripheral B cell subset specifically associated with autoimmune disease(16,38,39)). AIRE-expressing cells also upregulated a set of genes previously defined as AIRE targets in thymic B cells(34) ( Fig.…”

Autoantibodies during infectious diseases: Lessons from malaria applied to COVID-19 and other infections

“…Additionally, these cells have been reported to express chemokine receptors such as CXCR3 and other markers. A summary of the nomenclature and markers described for this population has been summarized in previous reviews ( 36 , 37 ). Further evidence that ABCs and atypical B cells generated during infection and autoimmune disorders are closely related comes from scRNAseq analysis of these cells in malaria patients, which share similar transcriptional profiles with HIV patients, but also with patients from different autoimmune disorders (SLE, rheumatoid arthritis or common variable immunodeficiency), suggesting they share common drivers of expansion and function ( 38 ).…”