Pathogenesis of Lupus Nephritis

Renal disease ranks as the foremost cause of morbidity and mortality in systemic lupus erythematosus (SLE). Although several different end organs can be targeted in SLE, the pathogenic events leading to disease are fairly similar, involving both infiltrating leukocytes as well as resident nonimmune cells. The deposition of autoantibodies and immune complexes in the kidneys can initiate tissue injury, followed by recruitment of inflammatory leukocytes into the kidneys. Cytokines, chemokines, and various mediators released by the infiltrating leukocytes as well as resident renal cells can lead to a vicious cycle of inflammation, leading to acute, then chronic tissue injury. Among the spectrum of autoantibodies present in lupus patients, anti-DNA antibodies emerge as a key diagnostic and prognostic marker, being actively involved in the pathogenesis of lupus nephritis owing to their ability to bind to cell surface antigens or components of the glomerular matrix either directly (cross-reactivity) or indirectly (via chromatin-containing bridges). Furthermore, nucleosomes can induce lupus-like syndromes, accompanied by autoantibody production and immune-mediated glomerulonephritis. A growing body of evidence also indicates that B cells can contribute to the pathogenesis of lupus nephritis in both antibody-dependent and antibody-independent ways. With ongoing transcriptomic profiling studies and genome-wide association studies in human and murine lupus, the potential list of culprit molecules is likely to grow exponentially over the next decade. Decoding the intricate tapestry of intrarenal mechanisms and molecules that drive the pathogenesis of lupus nephritis is absolutely key for the discovery of better-rationalized therapeutics for this devastating disease.