Mechanisms of autoimmune dysregulation in lipoic acid users at risk for NELL1 membranous nephropathy

Project Summary/Abstract We identified an association between lipoic acid and neural epidermal growth-factor like 1 (NELL1) membranous nephropathy (MN), an autoimmune kidney disease that causes urine protein loss (proteinuria), diffuse body swelling, and blood clots. If the condition is not detected early, NELL1 MN can lead to kidney failure. Lipoic acid is a widely available dietary supplement used for general wellness and a range of medical conditions including neuropathy and chronic pain. We have observed that 1/3 of NELL1 patients, mostly women (76%) with underlying autoimmunity (36%), report lipoic acid use. The long-term goal of our research is to investigate how lipoic acid promotes pathogenic autoimmune dysregulation so that we can detect early- stage disease in susceptible lipoic acid users, and deploy targeted treatment in those with NELL1 MN. Research suggests that approximately 70% of NELL1 MN patients have detectable anti-NELL1 antibodies in the blood, however we have an incomplete understanding about whether NELL1 antibodies can herald future disease. Furthermore, it is unclear how lipoic acid induces NELL1 antibody and the role of T cells in disease induction. Emerging data on T cell responses suggests a critical role for dysregulated CD4+ T regulatory cells and TH17 cells in another form of membranous nephropathy, and whether this dysregulated T cell signature is present in lipoic acid associated NELL1 MN is unknown. To begin to address these knowledge gaps, we first completed a study that demonstrates the feasibility of recruiting lipoic acid users, detecting circulating NELL1 antibody through Western blot, and examining peripheral T cell phenotype and function through flow cytometry. The feasibility study informs the design of this K23 career development award that will test the central hypothesis that circulating NELL1 antibodies and proinflammatory T cells predict proteinuria in susceptible lipoic acid users. We will test this hypothesis through two aims, 1) to determine whether NELL1 antibodies associate with proteinuria in lipoic acid users, and 2) to determine the phenotype and function of T cells in lipoic acid users who develop proteinuria. We will do this through an observational and longitudinal study where we will recruit 150 lipoic acid users at risk for NELL1 MN and measure circulating NELL1 antibodies through Western Blot, and collect peripheral blood mononuclear cells to examine T cell phenotype and function through flow cytometry, at pre-specified intervals over 2 years. This research has the potential to establish NELL1 antibody as a useful disease biomarker and demonstrate the role of T cells in disease induction, thereby unmasking possible treatment targets. The mentorship team of clinical and translational researchers with expertise in autoimmunity, lipoic acid, MN, and basic mechanisms of disease will support my training in autoimmunity, rare disease research, and leadership in science. This, combined with the ample resources at my institution for K awardees, will support my transition to research independence.