Chronic BCR signaling generates and maintains age-associated B cells from anergic B cells

Accumulation of age-associated B cells (ABCs) with autoreactive properties contributes to the pathogenesis of autoimmune diseases[1][1]–[5][2]. However, the mechanisms whereby ABCs are generated and maintained are not understood[1][1], [2][3], [4][4]. Here, we show that continuous stimulation of the B-cell receptor (BCR) with self-antigens plays a crucial role in ABC generation from anergic B cells and that this signal is vital for sustaining ABCs during aging and autoimmunity. In ABCs, BCR signaling was constitutively activated and the surface BCR was internalized in vivo , as occurs in autoreactive B cells chronically exposed to self-antigens[6][5]. With aging, ABCs were generated from autoreactive anergic B cells, but not from B cells expressing non-self-reactive BCR. In vitro stimulation of anergic B cells with self-antigen, interleukin-21, and Toll-like receptor 7/9 agonists promoted their differentiation to ABCs. Furthermore, the cellular phenotype of ABCs in Bm12-induced lupus mice[7][6], [8][7] resembled that of ABCs in aged mice, showing activation of BCR signaling, expression of activation markers, and BCR internalization. Importantly, Btk was persistently activated in ABCs of aged/autoimmune mice and humans with lupus. Pharmacological Btk inhibition resulted in a marked reduction in the number of ABCs and pathogenicity in lupus mice. Our findings have implications for accumulating ABCs and developing therapies for autoimmune diseases. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-5 [3]: #ref-2 [4]: #ref-4 [5]: #ref-6 [6]: #ref-7 [7]: #ref-8