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 determined that mice deficient in the IgG receptor FcgammaRIIB develop spontaneous anti-nuclear antibodies and fatal glomerulonephritis. Characterization of other genetic modifiers of lupus in the FcgammaRIIB-deficient mouse model allowed us to determine that a mere duplication of the Tlr7 gene is sufficient to aggravate autoimmune disease. We showed, using transgenic overexpression of TLR7, that TLR7 is essential to regulate autoimmunity and dendritic cell homeostasis. These mice provide a prime example of how important it is to control the expression of innate receptors. These studies provide a theoretical framework in which anti-viral innate responses, when not properly regulated, can result in autoreactivity and lethal inflammatory disease. During the past year we utilized the well-established murine model for SLE, FcRIIB/ mice, 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 have investigated the protective effect of a single infection with a malaria parasite on lethal autoimmune glomerulonephritis. SLE is characterized by high levels of serum autoantibodies and systemic immune activation. A common cause of lethality is the immune mediated destruction of kidney glomeruli. We have determined that a single malaria infection early in life can protect from kidney involvement while increasing overall levels of autoantibodies and systemic inflammation. Our results indicate a possible route for lupus protection that specifically targets renal function, which remains a cause of the substantial morbidity and mortality in SLE patients. Our work linking malaria infection with SLE suppression has also provided insight into pathogenic factors that trigger nephritic damage. We have discovered that infection with malaria parasites can reduce kidney pathology by averting the tissue infiltration of type 2 dendritic cells. The results of bone marrow chimaera studies suggest that Plasmodium infection directly alters bone marrow cells in such a way as to prevent DCs from migrating to the kidneys. We observed that the chemokine CCL17, mainly produced by dendritic cells, was specifically reduced in the kidney post infection with Plasmodium and that this chemokine was essential in the transition to end stage kidney disease. Importantly from a translational perspective, CCL17 blocking antibodies could reduce glomerulonephritis in lupus-prone mice without the need for parasitic infection, suggesting that CCL17 could be a future therapeutic target for lupus nephritis.