Dendritic cells in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) persists as a chronic inflammatory autoimmune disease and is characterized by the production of autoantibodies and immune complexes that affect multiple organs. The underlying mechanism that triggers and sustains disease are complex and involve certain susceptibility genes and environmental factors. There have been several immune mediators linked to SLE including cytokines and chemokines that have been reviewed elsewhere [ 1-3 ]. A number of articles have reviewed the role of B cells and T cells in SLE [ 4-10 ]. Here, we focus on the role of dendritic cells (DC) and innate immune factors that may regulate autoreactive B cells.

Figure 1

General model for potential roles of DCs in the regulation of autoreactive B cells in secondary lymphoid tissues. Normal immune homeostasis regulates autoreactive B cells. Plausible mechanisms that inhibit autoreactive B cells include B cell anergy due to a block in BCR signaling or to repression of chronically stimulated follicular B cells from the local production of IL-6, TNFα and CD40L by DCs and macrophages or marginal zone (MZ) B cells by macrophages. ACs may suppress DCs and macrophages from becoming hyperactive. Defects in clearing ACs by DCs and macrophages increase self antigens available to B cells and releases checks in DC (or macrophage) activity or survival. In addition, nucleic material from pathogens or ACs maybe endocytosed or they may form antigen-antibody immune complexes (IC) that bind Fc receptors (FcR) on several cell types and are internalized into endosomes. TLR7 and TLR9 sense RNA or DNA complex components and trigger IFNI (type I interferon) secretion particularly by pDC. High levels of IFNI production is associated with increased p202 that may affect several cells including B cells and FDC in germinal centers as well as cDC. The activated FDC have been shown to secrete MFG-E8 which binds PS on ACs and αvβ5 integrin on tingible-body macrophages to facilitate ingestion. Similarly, GAS6 binds both PS on ACs and Mertk on macrophages and cooperates with αvβ5 to facilitate efficient engulfment of dying cells. In addition, complement C1q deficiency results in impaired clearance by macrophages via CD91 and autoantibody formation. The lack of MFG-E8, Mertk or C1q results in autoantibody formation in animal models. The FDCs can also provide immune-complexed self antigens to autoreactive B cells. In the presence of IFNI, B cells will upregulate TLR7 or TLR9 and sufficient BCR and TLR stimulation may break tolerance of autoreactive follicular B cells. These follicular B cells migrate out into the circulation to become memory B cells or antibody-secreting cells. In the MZ, cDC may also become activated by IFNI and nuclear material which promotes cytokine production. These activated cDC may sufficiently stimulate BCR-, BAFF-, and TLR-mediated activation of MZ B cells that then migrate through the follicle to become antibody-secreting cells in the bridging channels or red pulp.