While heredity is a primary predisposing factor for autoimmunity, cumulative exposures to environmental factors such as toxic stressors and diet greatly impact the latency and severity of autoimmune diseases such as lupus. The chapters within this dissertation test the hypothesis that dietary DHA prevents activation of autoreactive lymphocytes that establish the lung as a platform to exacerbate systemic autoimmunity after cSiO2 exposure in lupus-prone NZBWF1 mice. Herein, it is demonstrated... Show moreWhile heredity is a primary predisposing factor for autoimmunity, cumulative exposures to environmental factors such as toxic stressors and diet greatly impact the latency and severity of autoimmune diseases such as lupus. The chapters within this dissertation test the hypothesis that dietary DHA prevents activation of autoreactive lymphocytes that establish the lung as a platform to exacerbate systemic autoimmunity after cSiO2 exposure in lupus-prone NZBWF1 mice. Herein, it is demonstrated that airway exposure to crystalline silica (cSiO2) triggers early loss of self-tolerance in the lung characterized by prolonged elevations in pro-inflammatory cytokines, and strikingly, early infiltration of autoreactive B and T cells into the lung which collectively drive production of autoantibodies that exacerbate systemic autoimmunity and glomerulonephritis in the lupus-prone female NZBWF1 mouse. Supplementing NZBWF1 mouse diets with docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid (PUFA), dose-dependently blocks this triggering in the lung, kidney, and systemic circulation. The anti-inflammatory effects of DHA were evident through ablation of lymphocytic infiltration and reduction of pro-inflammatory cytokines in the lungs that corresponded to reduced serum autoantibodies and cytokine concentrations and accordingly, reduced severity of cSiO2-triggered glomerulonephritis in the kidneys of NZBWF1 mice. To elaborate on these findings, we utilized an integrative approach with quantitative immunohistochemistry, transcriptomics, and targeted proteomics to identify relevant cell populations and putative molecular pathways responsible for cSiO2-driven autoimmunity and targets for the ameliorative effects of DHA. Taken together, the findings in this dissertation establish a model that permits dissection of the countervailing roles of cSiO2 (potentiation) and DHA (attenuation) in initiation and progression of autoimmunity. The results from these studies demonstrate how modification of cellular lipids with the ω-3 fatty acid, DHA, could be harnessed to attenuate lupus and related autoimmune diseases triggered by toxic environmental stressors. Show less
