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. We have also investigated the effect of malaria infection in the progression of lupus disease. In particular we have: 1) made considerable progress in understanding the functional state and clonal selection of CD8 cells in lupus 2) investigated the role of type I interferon and the anti-viral sensor MAVS in B cell responses 3) studied a possible suppresor role of CD8 cells primed by a virus in systemic autoimmunity, 4) determined that a single infection with a malaria parasite provides a long lasting protective effect in lupus that is targeting end organ disease and does not alter tolerance mechanisms. 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. Studying the protective effect of various infections provides new views of possible effect of infection with pathogens over the course of disease in human patients. 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.

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17
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2018
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Morawski, Peter A; Qi, Chen-Feng; Bolland, Silvia (2017) Non-pathogenic tissue-resident CD8(+) T cells uniquely accumulate in the brains of lupus-prone mice. Sci Rep 7:40838
Morawski, Peter A; Bolland, Silvia (2017) Expanding the B Cell-Centric View of Systemic Lupus Erythematosus. Trends Immunol 38:373-382
Akkaya, Munir; Akkaya, Billur; Miozzo, Pietro et al. (2017) B Cells Produce Type 1 IFNs in Response to the TLR9 Agonist CpG-A Conjugated to Cationic Lipids. J Immunol 199:931-940
Davidson, Dominique; Zhong, Ming-Chao; Pandolfi, Pier Paolo et al. (2016) The Csk-Associated Adaptor PAG Inhibits Effector T Cell Activation in Cooperation with Phosphatase PTPN22 and Dok Adaptors. Cell Rep 17:2776-2788
Yao, Xiangyu; Wu, Jian; Lin, Meng et al. (2016) Increased CD40 Expression Enhances Early STING-Mediated Type I Interferon Response and Host Survival in a Rodent Malaria Model. PLoS Pathog 12:e1005930
Bolland, Silvia; Pierce, Susan K (2015) Ups and downs in the search for a Herpes simplex virus vaccine. Elife 4:
Voynova, Elisaveta N; Skinner, Jeffrey; Bolland, Silvia (2015) Expansion of an atypical NK cell subset in mouse models of systemic lupus erythematosus. J Immunol 194:1503-13
Voynova, Elisaveta; Qi, Chen-Feng; Scott, Bethany et al. (2015) Cutting Edge: Induction of Inflammatory Disease by Adoptive Transfer of an Atypical NK Cell Subset. J Immunol 195:806-9
Wu, Jian; Cai, Baowei; Sun, Wenxiang et al. (2015) Genome-wide Analysis of Host-Plasmodium yoelii Interactions Reveals Regulators of the Type I Interferon Response. Cell Rep 12:661-72
Chen, Zhengshan; Shojaee, Seyedmehdi; Buchner, Maike et al. (2015) Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia. Nature 521:357-61

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