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 diseases1-5. However, the mechanisms whereby ABCs are generated and maintained are not understood1, 2, 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-antigens6. 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 mice7, 8 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.