The prevalence of hypertension is markedly increased in women with systemic lupus erythematosus (SLE) for reasons that are not clear. Hypertension is an independent predictor of mortality and a major cardiovascular risk factor for this patient population. Renal injury and inflammation is common in patients with SLE which is significant to the risk of hypertension because of the kidney's central role in the long term blood pressure control. Growing evidence suggests that autoimmunity may underlie both human and experimental hypertension. Therefore, autoimmune induced renal inflammation may promote the development of hypertension in women with SLE. In support of this, preliminary data show that renal hemodynamic function is impaired in a hypertensive mouse model with SLE. In addition, our data show that hypertension in female SLE mice is mediated in part by B and T cells of the adaptive immune system. For example, the hypertension associates with autoantibody production and B cell depletion prevents the hypertension and renal injury. Renal and circulating levels of T cell associated cytokines (TNF-, IL-17) are increased in mice with SLE, as well. IL- 17 is widely implicated in autoimmune mediated tissue injury and renal TNF- promotes SLE associated hypertension. When T cells are depleted in SLE mice, autoantibodies are reduced and the progression of hypertension is attenuated. The lower blood pressure in T cell depleted SLE mice is associated with preservation of renal microvascular structure. The major focus of this proposal will be to determine the relative contribution of different immune cell subsets and their impact on renal hemodynamic function during SLE. The overall hypothesis is that the Th2 cell mediated B cell production of autoantibodies associated with SLE impairs renal hemodynamic function. In addition, Th1 and Th17 cells contribute to the hypertension by secreting cytokines (TNF- IL-17) that directly impair renal cortical or medullary vascular flow. The result of these changes is to shift the set point of the chronic pressure natriuresis relationship resulting in the development of hypertension.
This specific aims will test whether (1) Th2/B cell interaction and the production of autoantibodies promotes the development of hypertension during SLE. (2) Th1 and Th17 cells contribute to the pathogenesis of hypertension and renal inflammation during SLE. (3) Adaptive immune system activation impairs renal hemodynamic function causing a hypertensive shift in the pressure natriuresis relationship during SLE. The proposed studies have significant clinical implications for veterans for whom hypertension remains a significant health concern. In addition, rheumatic diseases and their complications have been a major health concern for the U.S. military and their families for over 100 years. Therefore understanding mechanisms that promote SLE or its sequelae will improve the quality of clinical care for veterans with hypertension or SLE.
Despite decades of work, the mechanisms that cause high blood pressure (hypertension), a major health concern for veterans, continue to be elucidated. Recently, there has been considerable interest in the possibility that the immune system contributes to the development of hypertension. Interestingly, hypertension is also prevalent in rheumatic diseases like systemic lupus erythematosus (SLE) that predominantly affect women. Rheumatic disease and their consequences are a major health concern for the military and women represent an increasing demographic among veterans. This proposal will explore how the immune system activation associated with SLE leads to hypertension. Examining how the immune system impacts blood pressure during this disease will not only provide new insights for women with SLE, but also will add to the overall understanding of hypertension.
|Taylor, Erin B; Barati, Michelle T; Powell, David W et al. (2018) Plasma Cell Depletion Attenuates Hypertension in an Experimental Model of Autoimmune Disease. Hypertension 71:719-728|
|Taylor, Erin B; Ryan, Michael J (2017) Immunosuppression With Mycophenolate Mofetil Attenuates Hypertension in an Experimental Model of Autoimmune Disease. J Am Heart Assoc 6:|
|Mathis, Keisa W; Taylor, Erin B; Ryan, Michael J (2017) Anti-CD3 antibody therapy attenuates the progression of hypertension in female mice with systemic lupus erythematosus. Pharmacol Res 120:252-257|
|Taylor, Erin B; Ryan, Michael J (2016) Understanding mechanisms of hypertension in systemic lupus erythematosus. Ther Adv Cardiovasc Dis :|