(a) B cells in autoimmune diseases. B cells have antibody-dependent and antibody-independent pathogenic functions. Secreted autoantibodies specific to receptors or receptor ligands can activate or inhibit receptor functions. Deposited immune complexes can activate complement and effector cells. Autoantibodies can bind to basic structural molecules and interfere with the synthesis of structural elements and facilitate the uptake of antigen. Independent of antibody secretion B cells secrete proinflammatory cytokines, support the formation of ectopic GCs, and serve as antigen presenting cells. Both secreted autoantibodies and BCR on B cells can modulate the processing and presentation of antigen and thereby affect the nature of presented T-cell determinants. (b) Pathogenic effects of deposited immune complexes. The Fc portion of antibodies in immune complexes can be bound by C1q of the classical complement pathway, which eventually leads to the release of C5a and C3a. These anaphylatoxins promote release of proinflammatory cytokines and serve as chemoattractants for effector cells. Moreover they induce the upregulation of activating FcR on effector cells. Binding of the Fc portion of the antibodies to FcR leads to activation of effector cells and further release of proinflammatory cytokines and proteolytic enzymes, mediators of antibody-dependent cell-mediated cytotoxicity (ADCC). (c) Effect of antibodies and antigen-specific B cells on antigen uptake. Left panel: antigen bound by antibody is taken up via FcR on APCs such as dendritic cells or macrophages. After processing, antigen is presented on MHC molecules. This FcR-mediated antigen uptake is more efficient than antigen uptake by pinocytosis. Right panel: antigen binds to the BCR of antigen-specific B cells and is internalized. B cells are highly efficient APCs in situations of low antigen concentrations. (d) Effect of antibodies and antigen-specific B cells on antigen processing and presentation. BCR-mediated antigen uptake can influence antigen processing and the nature of MHC-displayed T-cell determinants. Likewise, antigen/antibody complexes are bound by the FcR of APCs and processed in a unique fashion dependent on the epitope specificity of the bound antibody. The BCR or antibody can shield certain protein determinants from the proteolytic attack in endocytic compartments (represented as scissors in this figure). Presentation of some determinants may thereby be suppressed, while others are boosted. Thereby cryptic pathogenic peptides may be presented and stimulate autoreactive T cells.
