Xenobiotics such as silica and mercury are associated with systemic autoimmunity in humans and mice. While mechanistic studies have addressed the immune dysfunction resulting from exposure to these xenobiotics little has been done to examine the role of immune regulation in suppressing development of xenobiotic-induced systemic autoimmunity. Decay accelerating factor (DAF, CD55), a complement regulatory protein, functions as a negative regulator of adaptive immune responses. Recent studies have shown that deficiency of CD55 exacerbates TH1-driven organ specific and systemic autoimmunity. Additionally, CD55 is reduced on T and B cells in idiopathic murine lupus and is specifically reduced on CD4+ T cells in murine mercury- induced autoimmunity (mHgIA). CD55 has also been shown to be reduced on lymphocytes of patients with SLE. Stimulation of CD4+ T cells with a soluble form of the CD55 receptor, CD97, results in IL-2 dependent expression of IL-10 and reduction of the autoimmunity promoting cytokines IFN-? and IL-17 suggesting that the interaction of soluble CD97 (sCD97) with CD55 drives CD4+ T cells away from a proinflammatory response towards immunosuppression. This is reminiscent of the IL-2 dependent induction of regulatory IL-10+CD4+ T cells by another complement regulatory protein CD46. Engagement of CD46 switches proinflammatory TH1 cells toward the IL-10+ immunoregulatory phenotype. Based on the similarities between CD46 engagement and CD97 mediated stimulation of CD55 we hypothesize that autoimmunity induced by mercury and silica may arise because of a defect in TH1 to Treg differentiation due to ineffective CD97-CD55 interaction. (Note: The mechanism of IL-10 production via CD46 and CD55 activation is likely different as one (CD46) requires complement and the other (CD55) does not.) If this hypothesis is correct then sCD97, in the presence of IL-2, should mediate increases in the Treg phenotype and reduction of the TH1 phenotype of CD4+ T cells. This should lead to reduced proinflammatory cytokine expression and amelioration of autoimmunity. The role of sCD97 in regulating xenobiotic-induced autoimmunity will be examined in the following two aims: 1) Does sCD97 stimulation result in CD4+ T cells with the cytokine profile and phenotype of T regulatory cells? and 2) Does CD97 influence expression of xenobiotic - induced autoimmunity? Experimental confirmation that CD97 regulates lymphoid cell activity and development of systemic autoimmunity will contribute significantly to our understanding of the autoimmune disease process and aid in the development of novel therapeutic interventions.
Studies have shown that stimulation of CD4+ T cells with soluble CD97 can alter the profile of proteins (called cytokines) they secrete from autoimmunity promoting to immuneregulatory. In this application we propose to determine the mechanism by which soluble CD97 modulates T cell activity to suppress development of autoimmunity induced by environmental factors.
|Pollard, Kenneth Michael; Kono, Dwight H (2013) Requirements for innate immune pathways in environmentally induced autoimmunity. BMC Med 11:100|
|Pollard, Kenneth M; Cauvi, David M; Toomey, Christopher B et al. (2013) Interferon-Î³ and systemic autoimmunity. Discov Med 16:123-31|