Studying the pathogenesis of kidney and central nervous system disease in systemic lupus erythematosus

Abstract

TNF superfamily ligands and receptors are important in the pathogenesis of lupus nephritis, a major cause of mortality and morbidity in SLE. Previously we found that the novel TNFSF member TWEAK was increased in urine from patients with active lupus nephritis, and the levels correlated with renal disease activity. To investigate the role of TWEAK in the pathogenesis of lupus nephritis and other inflammatory nephritides, we examined the effects of TWEAK in human kidney cells including mesangial cells, podocytes and tubular cells, following our demonstration of the presence of the TWEAK receptor Fn14 on these cells. We found that TWEAK induces human kidney cells to express multiple inflammatory mediators, including RANTES, MCP-1, IP-10, MIP-1alpha, GM-CSF, IL-6, ICAM-1, and VCAM-1. Cytokine production is mediated through NF-kappaB activation, and is inhibited by anti-TWEAK antibodies. TWEAK-induced chemokines induce migration of PBMC, particularly monocytes. Furthermore, we found that TWEAK promotes kidney infiltration, and stimulates proliferation of kidney cells in vitro and in vivo. Thus, TWEAK may play an important pathogenic role in the development of nephritis by promoting a local inflammation and inducing renal proliferation. Blocking TWEAK/Fn14 interactions may be a promising therapeutic target in lupus nephritis and other immune-mediated renal diseases.;70% of SLE patients develop an autoimmune-associated neuropsychiatric disorder (NPSLE). Previous studies in lupus-prone MRL/lpr mice indicated some neuropsychiatric manifestations. Although the incidence of lupus is much higher in females than in males, female mice have not been systematically studied. We studied NPSLE in MRL/lpr females early in the onset of the disease. Compared to control MRL/+ females, MRL/lpr mice exhibited significant depression-like behavior at both 8 and 18 weeks of age. Interestingly, MRL/lpr mice had normal visual memory, locomotor coordination and social preference and were, in fact, less anxious than control mice. We also found a significant correlation between depression behavior and auto-antibody titers (alpha-dsDNA, chromatin, NMDA receptors or cardiolipin). Kidney dysfunction was not found to contribute to the NPSLE in the tested mice. MRI revealed metabolic difference in cortical and hippocampal regions between MRL/lpr and control mice. These results demonstrated that female MRL/lpr mice develope NPSLE very early in the course of disease, in the absence of substantial peripheral organ pathology, and autoantibodies potentially play a pathogenic role in the development of NPSLE.