Genetic and Environmental Modifiers Of Autoimmune Disease

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

The main focus of our group is the identification of characterization of genes and environmental factors that contribute to the development of systemic autoimmune disease. We use mouse models of systemic lupus erythematosus (SLE) to determine the necessity of certain molecular pathways and cellular interactions in the spontaneous autoimmune pathology. In addition, we analyze the effect of external influences, such as infections, in the progression of SLE. New mechanistic insight obtained from these studies can guide future therapeutic strategies to treat SLE in human patients. We previously described mice deficient in the IgG receptor FcgammaRIIB as a well-established murine model for SLE. Characterization of other genetic modifiers of SLE in the FcgammaRIIB-deficient line allowed us to determine that several genes linked to anti-viral RNA sensors including TLR7, MDA5 and MAVS, were susceptibility factors for autoimmune disease. This concept has been validated by multiple groups that work with mouse models and human SLE patients. We recently uncovered a role for the mitochondrial antiviral signaling (MAVS) adaptor protein in the metabolic fitness of antigen-receptor stimulated B cells, with consequences in the prevention of autoimmunity. MAVS is well known as a mitochondrial-tethered signaling adaptor for sensing viral double-stranded RNA and type I interferon inducer. The role of MAVS downstream of B cell receptor stimulation was recognized in absence of interferon, suggesting a new pathway for MAVS activation that is independent of viral infection. As part of our investigation centered on environmental factors, we looked into interactions between infections and autoimmune disease in SLE mouse models. As an example, our work on the effect of malaria on SLE provided new insights into end-stage autoimmune nephritis. We observed that a single infection with a murine malaria parasite had a protective effect on lethal autoimmune glomerulonephritis while maintaining high levels of autoreactivity systemically. Recent experiments led to our finding of parasite-induced long-term skewing of the bone marrow with a protective effect in end-stage kidney disease in mouse models of SLE.