Molecular pathogenesis of lupus nephritis and potential therapeutic targets. Multiple steps lead to the pathogenesis of systemic lupus erythematosus (SLE). Captioned are two key sets of events underlying lupus nephritis (LN): one that engenders systemic autoimmunity, and another that drives end-organ inflammation and damage, as discussed in the text. Many of the cells and molecules in these pathogenic cascades also serve as attractive therapeutic targets, as detailed below. (1), (2) Dendritic cell (DC):T-cell and T-cell:B-cell interactions involve multiple co-stimulatory molecules, including CD28/B7, ICOS/ICOSL, and CD40/CD40L; blockade of these co-stimulatory pathways is being tested as potential therapeutic strategies in lupus. (3) Blys/BAFF elaborated by myeloid cells binds to receptors on B cells, and drives autoantibody production in SLE. Blocking this axis is emerging as a promising therapeutic avenue, based on recent clinical trials. (4) CD20, CD22, and CD19 are receptors on B cells. Several trials are aimed at depleting B cells in SLE, using antibodies to these B-cell molecules. (5) The activation of autoreactive B cells (and other leukocytes) in SLE is mediated by several signaling axes; some of these have been therapeutically targeted with success in preclinical models of the disease, and in limited clinical trials. (6) Type 1 interferon-elicited gene signatures have emerged as a distinctive feature of SLE. Based on these exciting leads, therapeutics targeting this axis are currently in active trials. (7) Activated lymphocytes and myeloid cells utilize a variety of cell adhesion molecules in order to gain access to the target organs. Therapeutics targeting these adhesion molecules and/or vascular addressins have shown promise in preclinical models of lupus. (8) Clearance of immune complexes is mediated by complement (receptor) and Fc/FcR-mediated mechanisms; targeting these nodes has also shown promise in murine lupus. (9) Activated leukocytes (as well as resident renal cells) elaborate a large spectrum of disease mediators, including various cytokines and chemokines. Blockade of these mediators also hold promise in ameliorating LN, although we are in the infancy of these studies. CD40L, CD40 ligand; ICOS, inducible T-cell costimulator; ICOSL, inducible T-cell costimulator ligand; TCR, T-cell receptor.
Saxena et al. Arthritis Research & Therapy 2011 13:240 doi:10.1186/ar3378