Do follicular dendritic cells regulate lupus-specific B cells?

•SSB/La specific B cells escape tolerance at the transitional stage in the absence of complement C4.•C4 deficient mice develop elevated germinal centers to lupus antigen in autoimmune strain.•Follicular dendritic cells retain lupus antigen IC in the early endosomal compartment.•Propose model that FDC secrete IFNa on internalization of RNP.

The factors that allow self-reactive B cells to escape negative selection and become activated remain poorly defined. In this review we describe recently published results in which a B cell receptor-knock-in mouse strain specific for nucleolar self-antigens was bred with mice deficient in complement C4 and discuss the implications for the lupus field. Absence of C4 leads to a breakdown in the elimination of autoreactive B cell clones at the transitional stage. This is characterized by a relative increase in their response to a range of stimuli, entrance into follicles and a greater propensity to form self-reactive germinal centers. In this review, a model is proposed in which, in the absence of complement C4, inappropriate clearance of apoptotic debris promotes chronic activation of myeloid cells and follicular dendritic cells, resulting in secretion of Type I interferon. This allows for the maturation and activation of self-reactive B cell clones leading to increased spontaneous formation of germinal centers and subsequent generation of autoantibodies.