Altered B cell signalling in autoimmunity

In this Review, the authors propose that disease-associated genetic variants modulate signalling downstream of B cell receptors, Toll-like receptors and cytokine receptors in B cells to drive autoimmune responses. This altered signalling favours a naive B cell repertoire that is skewed towards self-reactivity and promotes the peripheral activation of autoreactive B cell clones. Recent work has provided new insights into how altered B cell-intrinsic signals — through the B cell receptor (BCR) and key co-receptors — function together to promote the pathogenesis of autoimmunity. These combined signals affect B cells at two distinct stages: first, in the selection of the naive repertoire; and second, during extrafollicular or germinal centre activation responses. Thus, dysregulated signalling can lead to both an altered naive BCR repertoire and the generation of autoantibody-producing B cells. Strikingly, high-affinity autoantibodies predate and predict disease in several autoimmune disorders, including type 1 diabetes and systemic lupus erythematosus. This Review summarizes how, rather than being a downstream consequence of autoreactive T cell activation, dysregulated B cell signalling can function as a primary driver of many human autoimmune diseases.