Altered B cell signalling in autoimmunity

Key Points Human genetic variants associated with the development of systemic autoimmunity modulate B cell receptor (BCR) and co-receptor signalling, suggesting a role for dysregulated B cell signalling in promoting disease pathogenesis. Altered B cell signalling probably facilitates a breach in B cell tolerance through distinct effects on B cell selection during the establishment of the naive BCR repertoire and on peripheral activation responses. BCR signalling functions as a 'master regulator' of coordinate co-receptor signalling, facilitating central and peripheral B cell tolerance mechanisms throughout B cell development. Hypomorphic and/or hypermorphic signalling variants affect both the negative and positive selection of autoreactive BCR specificities. During humoral autoimmunity, autoantibody-producing plasma cells are generated through parallel extrafollicular and germinal centre (GC) B cell activation pathways. Activated autoreactive B cells orchestrate the formation of spontaneous, autoimmune GCs by initiating breaks in T cell tolerance and by promoting subsequent T follicular helper cell differentiation. These events are mediated by B cell antigen presentation to cognate CD4 + T cells, probably in concert with B cell co-stimulatory and cytokine signalling.