Autoimmune diseases afflict a significant portion of the US population, with the most common age of onset being during young adulthood leading to increased morbidity, early mortality and accrual of damage with associated disability, oftentimes early in life. Many of the systemic autoimmune diseases are characterized by a waxing and waning, or relapsing/remitting, course. These periods of increased disease activity, oftentimes with permanent organ-damage, are interspersed on a background of clinical suppression or quiescence. Although shared across many of the systemic autoimmune diseases, the mechanisms or predictors of disease flares are very poorly understood or not understood at all. This application will focus on understanding mechanisms of disease flare in SLE and then collaborating with other ACE centers, to expand these studies and evaluate which of these mechanisms are common across a number of autoimmune diseases or are disease specific. Over the past funding cycle, our Oklahoma ACE has established and expanded a number of patient collections which have provided insights or samples which will be relevant to understanding mechanisms of SLE disease flare. In preliminary studies of European American SLE patients who exhibited a disease flare within 6 or 12 weeks of baseline assessment compared to patients who did not flare, alterations in 27 soluble mediators {p<0.01) were found at baseline compared to non-flare patients, with significantly higher levels of pro-inflammatory mediators several weeks before clinical flare. Regulatory cytokines were increased at baseline in non-flare SLE patients. Nearly all of these abnormalities were also found in the SLE patients during their flare year compared to samples from these individuals in a non-flare year. Based upon these and other presented preliminary data, we hypothesize that critical alterations in cellular activation, TNF receptor shedding, innate and adaptive mediators of inflammation, and regulatory immune cell pathways are present immediately preceding SLE disease flare. We will test these hypotheses through the following specific aims: 1) determine alterations in innate and adaptive immune cell populations, functional responses and serologic biomarkers in SLE patients immediately before flare compared to matched SLE patients who do not flare, as well as in longitudinal samples;2) evaluate parent cellular populations, levels, locations and functional consequences of shed TNF and other immune receptors in SLE patients temporally preceding a clinical disease flare;and 3) assess the frequency and function of regulatory B and T cells temporally preceding SLE disease flare.
Autoimmune diseases affect 5-7% of the population and often have has periods of disease flares interspersed with disease suppression. This project aims to identify mechanisms responsible for disease flare and predictors of disease flare that are currently unknown or poorly understood to help aid earlier diagnosis, design appropriate clinical trials, develop new directed therapeutic agents and help guide therapy selection to improve the lives of patients with autoimmune diseases.
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