Figure 2.

Follicular and extrafollicular origins of autoantibody-producing plasma cells. Autoreactive red pulp B cells and follicular (FO) B cells that encounter autoantigens in conjunction with Toll-like receptor and other innate signals differentiate to autoantibody (autoAb)-producing antibody-forming cells in extrafollicular bridging channels, where marginal zone (MZ) dendritic cells (DCs) may promote autoAb responses and plasma cell (PC) survival through direct antigen presentation and production of soluble mediators such as IL-6, BAFF, or APRIL. Extrafollicular autoAb responses involve activation-induced deaminase-dependent class-switch recombination and somatic hypermutation (SHM) that in some cases is also T-cell independent. FO B cells may additionally migrate to germinal centers (GCs) within follicles where autoreactive B cells arising through SHM may escape selection mechanisms via B-cell intrinsic or extrinsic factors to become additional sources of pathogenic autoAbs in genetically predisposed animals and humans. These cells include both short-lived and long-lived PC populations. APRIL, a proliferation-inducing ligand; BAFF, B-cell activating factor; BM, bone marrow.