Genetic and Environmental Modifiers Of Autoimmune Disease

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Our past work has uncovered several lupus susceptibility genes that, either by themselves or by interacting with a variety of other genetic factors, modify both the induction and progression of autoimmune disease. We previously described mice deficient in the IgG receptor FcgammaRIIB as a well-established murine model for SLE. Characterization of other genetic modifiers of lupus in the FcgammaRIIB-deficient line allowed us to determine that a mere duplication of the Tlr7 gene is sufficient to aggravate autoimmune disease and that the anti-viral adaptor MAVS is essential for the phenotype. We are continuing our studies on MAVS by characterizing its role in stabilizing mitochondrial responses during B cell activation. During the past year we utilized our murine models of SLE to investigate interactions between infections and autoimmune disease. Our work with malaria infections has provided a new model to investigate potential end organ therapeutic targets in SLE. We reported that a single infection with a murine malaria parasite has a protective effect on lethal autoimmune glomerulonephritis while maintaining general autoreactivity levels. From these studies we uncovered an important role for type 2 inflammatory dendritic cells in end-stage kidney disease. We then considered various parasite-mediated long-term alterations in the host that could explain the kidney-specific protection. These experiments led to our finding of a long-term skewing of bone marrow cell maturation after infection with Plasmodium. This type of skewing then prevents damaging leukocyte infiltration into the inflamed kidney so that autoimmune glomerulonephritis does not progress to lethal pathology.