Browsing by Subject "autoimmunity"
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Item Should Renal Inflammation Be Targeted While Treating Hypertension?(Frontiers Media S.A., 2022-06-13) Chaudhari, Sarika; Pham, Grace S.; Brooks, Calvin D.; Dinh, Viet Q.; Young-Stubbs, Cassandra M.; Shimoura, Caroline G.; Mathis, Keisa W.Despite extensive research and a plethora of therapeutic options, hypertension continues to be a global burden. Understanding of the pathological roles of known and underexplored cellular and molecular pathways in the development and maintenance of hypertension is critical to advance the field. Immune system overactivation and inflammation in the kidneys are proposed alternative mechanisms of hypertension, and resistant hypertension. Consideration of the pathophysiology of hypertension in chronic inflammatory conditions such as autoimmune diseases, in which patients present with autoimmune-mediated kidney inflammation as well as hypertension, may reveal possible contributors and novel therapeutic targets. In this review, we 1) summarize current therapies used to control blood pressure and their known effects on inflammation; 2) provide evidence on the need to target renal inflammation, specifically, and especially when first-line and combinatory treatment efforts fail; and 3) discuss the efficacy of therapies used to treat autoimmune diseases with a hypertension/renal component. We aim to elucidate the potential of targeting renal inflammation in certain subsets of patients resistant to current therapies.Item Thymic involution perturbs negative selection and leads to chronic inflammation(2015-08-01) Coder, Brandon D.; Dong-Ming Su; Rance E. Berg; Hriday K. DasThe ubiquitous presence of chronic low-level pro-inflammatory factors in elderly individuals (termed inflammaging) is a significant risk factor for morbidity and mortality. The etiology of inflammaging is largely unknown. Recent evidence has identified the persistent activation of immune cells, thought to arise from latent viral infections, as key contributors towards the development of a chronic inflammatory environment. However, the contribution of autoreactive T cells towards the development of inflammaging has yet to be investigated. Another pervasive feature of the aging process is the age-related involution of the thymus gland, which has been linked with a predisposition toward developing autoimmunity. In the present study, we determined how age-related thymic involution leads to the persistent release and activation of autoreactive T cells capable of inducing inflammaging. We utilized a FoxN1 conditional knock-out (FoxN1-cKO) mouse model that mimics thymic involution while maintaining a young periphery and naturally aged C57Bl/6 mice. We found that thymic involution leads to T cell activation shortly after thymic egress, which is accompanied by cellular infiltration into non-lymphoid tissues, elevated serum IL-6, and enhanced production of TNFα. Additionally, activated autoreactive T cell clones were detected in the periphery of FoxN1-cKO mice. We determined that a failure of negative selection, facilitated by decreased AIRE expression rather than impaired regulatory T cell (Treg) generation, and led to autoreactive T cell activation in the periphery. Furthermore, we have demonstrated that the young environment can reverse the age-related accumulation of Tregs but not inflammatory infiltration. Together, these findings identify thymic involution and the persistent activation of autoreactive T cells as a source of chronic age-related inflammation (inflammaging).