Genetic and Environmental Modifiers Of Autoimmune Disease

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

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 have analyzed the specific role of a variety of anti-viral pathways and their possible production of interferon in the development of autoimmune disease. In particular we have: 1) made considerable progress in understanding the cellular basis of the role of TLR7 in lupus 2) investigated the role of type I interferon in B cell responses, as well as in the host immune response to malaria infections, 3) studied a possible regulatory role of CD8 cells in systemic autoimmunity 4) studied the infiltration of CD8+ cells into brain in lupus-prone mice possibly contributing to brain pathology observed in SLE; 5) explored the role of additional endocytic TLRs, namely TLR9 and TLR3 in lupus and the interaction of these TLRs with TLR7 and 6) explored the possibility that various cytoplasmic sensors of viral RNA and DNA may also potentiate or modify the development of autoimmune disease. Studying the role of innate responses against pathogens in autoimmune-prone settings may shed light on gender bias, influence of infections, and the stochastic pathogenesis that is often seen in the development of autoimmunity In our study published in Sci. Reports, we have found a protective role of CD8 lymphocytes in preventing local tissue destruction associated with systemic autoimmune disease. This work provides the first comprehensive look at tissue resident lymphocytes in the brain of mouse models of lupus, which could shed light to mechanisms underlying neurological symptoms in human SLE. The main finding of this report is the fact that in the context of systemic inflammatory disease, lymphocyte accumulation in the brain shows a bias for CD8+ cells with characteristics of tissue resident cells that we dont observe in other tissues. Contrary to the general assumption that CD8 infiltrates are pathogenic, our data points to a regulatory role of this population that can extend to other systems where tissue resident CD8 cells are studied. We believe these results are exciting for the SLE community as well as those interested in understanding he role of immune cells within tissues. In collaboration with the laboratory of Susan Pierce, we have investigated B cells as a potential source of type I interferons. These cytokines play a critical role in the development of lupus autoimmune disease, as an interferon gene expression profile is specially high in lupus patients. Even though dendritic cells are known to be the immune cell population with higher yield of interferon production, studies by the Pierce laboratory show that certain innate ligands that trigger TLRs can induce type I interferon production by B cells. This effect is relevant in designing vaccines that use TLR ligands as adjuvants. In addition, we have collaborated with other members of the Malaria Research Program at NIAID to understand a possible link between resistance to malaria infection and autoimmunity. In collaboration with Dr. Sus group at LMVR, NIAID we are investigating innate pathways that are turned on in the context of murine malaria models. In a paper published in Cell Reports, we reported that the CD40 pathway is critical during malaria infection because of its interaction with the STING innate pathway. Separately and in collaboration with Dr. Crompton at LIG, NIAID, we are uncovering the presence of autoantibodies in samples recovered from malaria endemic areas. Overall these results point towards a possible role of autoreactive responses in developing long-term immunity to malaria.