Chapter 5 - B-cell biology, tolerance, and autoantibodies

Abstract

Systemic lupus erythematosus (SLE) is a complex disease characterized by autoantibodies against nuclear antigens and clinical involvement in multiple organ systems. The breakdown of B-cell tolerance is a defining and early event in the disease process. B-cell tolerance is normally enforced centrally in the bone marrow and peripherally in lymphoid tissue by multiple mechanisms, including receptor editing, clonal deletion, anergy, follicular competition, germinal center elimination, and inhibition of differentiation by inhibitory receptors and Toll-like receptor 9 (TLR9). Subversion of tolerance in SLE likely results from genetic and environmental factors and involves multiple pathways, including alterations in factors that affect B-cell activation thresholds, B-cell longevity, and apoptotic cell processing. Both antibody-dependent and -independent mechanisms of B cells are important in SLE. Autoantibodies contribute to disease by multiple mechanisms, including the formation of damaging immune complexes (immune-complex-mediated Type III hypersensitivity reactions) and direct pathogenesis (Type II antibody-dependent cytotoxicity). Autoantibodies also can activate plasmacytoid dendritic cells because RNA- and DNA-containing immune complexes act as TLR ligands, stimulating the secretion of interferon-alpha, which can further promote B-cell activation and differentiation. Autoantibody-independent B-cell functions include antigen presentation and T-cell activation and polarization, in part mediated by the ability of B cells to produce immunoregulatory cytokines and chemokines and by their critical contribution to lymphoid tissue development and organization, including the development of ectopic tertiary lymphoid organs. This chapter will focus on the fundamental biology of B-lymphocyte subsets and their development, including key events in selection and tolerance abrogated in SLE.