The effect of age on xenobiotic-induced autoimmunity

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Aging is associated with dysregulation of immune function manifested by increased susceptibility to infections and an increase in chronic inflammation. Such chronic inflammation, especially the presence of proinflammatory cytokines (IL-6, TNF-α), are predictors of failing immune status and mortality in the elderly. Associated with these changes is an increase in autoantibody responses and some autoimmune diseases. Environmental factors play a significant role in the development of human autoimmunity, however age has not figured significantly in studies on environmentally- induced autoimmunity other than the observation that occupational exposure is a significant factor. Mercury exposure has been implicated in the expression of autoimmunity in humans and experimental animal models. The human populations at risk are sizable and diverse. We have extensive experience in the use of murine mercury-induced autoimmunity (mHgIA) as an experimental model to study the initiation and development of systemic autoimmunity. The animal age at exposure in these studies have ranged from 4-12 weeks with the length of exposure usually being 4 weeks. Disease severity is dependent upon the presence of IFN-γ and IL-6, and localized inflammatory response associated with increased proinflammatory cytokines including IL-1β, IFN- γ and TNF-α. It remains unknown if induction of autoimmunity by mercury is exacerbated by the age-related chronic inflammation and proinflammatory cytokine expression found in both humans and mice. The importance of proinflammatory cytokines such as IL-6, TNF-α and IFN-γ in aging and in mHgIA and idiopathic autoimmunity suggests that aging will lead to exacerbation of mHgIA compared to younger animals. This application will test the hypothesis that "advanced age impacts the experimental outcomes of mHgIA used to study environmentally-induced autoimmunity in adult human populations." The proposed research will proceed in two phases as outlined in the FOA (RFA-AG-16-020). The UH2 phase will focus on breeding cohorts of animals up to the 75% survival level of B10.S, B10.S/Ifng-/- and B10.S/Il6-/- mice and includes a cohort to be used for a preliminary test of the feasibility of using aged animals to induce mHgIA. The UH3 phase will compare the central hypothesis that “older ages of animals impact experimental outcomes” by comparing and contrasting mHgIA in old versus young male and female B10.S mice. We will also use B10.S/Ifng-/- and B10.S/Il6-/- mice to examine the contribution of IL-6 and IFN-γ to age associated proinflammatory responses and whether they are requited for development of age-related autoimmunity, and whether exposure to HgCl2 exacerbates autoimmunity in aged animals deficient in either IL-6 or IFN-γ.