B Cell Biology and Dysfunction in Sle (Systemic Lupus Erythematosus) (Clinical Report‪)‬

Abstract Systemic lupus erythematosus (SLE) is a complex disease characterized by the production of autoantibodies and clinical involvement in multiple organ systems. The immunological events triggering the onset of clinical manifestations have not yet been fully defined, but a central role for B cells in the pathogenesis of this disease has been brought to the fore in the last several years by work performed at multiple laboratories in both mice and humans. B cell defects that have been defined include abnormal expression or function of key signaling molecules, dysregulation of cytokines with key B cell effects, and perturbations in B cell developmental subsets. Many of these defects may contribute to or be reflective of abnormalities in B cell tolerance. Both antibody-dependent and antibody-independent mechanisms of B cells are important in SLE. Thus, autoantibodies contribute to autoimmunity by multiple mechanisms, including immune-complex mediated type III hypersensitivity reactions and type II antibody-dependent cytotoxicity, and by instructing innate immune cells to produce pathogenic cytokines, including IFN[alpha], TNF, and IL-1. Autoantibody-independent B cell functions have been postulated to include antigen-presentation, T-cell activation and polarization, and dendritic cell (DC) modulation. Several of these functions are mediated by the ability of B cells to produce immuno-regulatory cytokines, chemokines, and lymphangiogenic growth factors and by their critical contribution to lymphoid tissue development and organization, including the development of ectopic tertiary lymphoid tissue. Given the large body of evidence implicating abnormalities in the B cell compartment in SLE, there has been a recent therapeutic focus on developing interventions that target the B cell compartment by multiple mechanisms.