Role of serum amyloid A in interferon-3 expression and T helper 1 cell differentiation Summary: The goal of this study is to determine the role of serum amyloid A (SAA) in the cell mediated adaptive immunity. Achievement of this goal will expand the current understanding of adaptive immunity and lead to exploration new therapeutic targets of autoimmune diseases. The potential breakthrough of our proposed study can be significant because autoimmune diseases are a major cause of morbidity and mortality in the industrialized world, affecting 5-8% of the population. Autoimmunity develops after breaking self-tolerance of the immune system, a process that involves many different molecules and is currently a poorly understood series of processes. Autoreactive effector CD4+ T cells are associated with the pathogenesis of autoimmune disorders. Many studies indicated that the IFN3-producing T helper (Th) 1 subset of CD4+ cells and the IL-17-producing CD4+ (Th17) cells have the capacity to cause inflammation and autoimmune diseases. The elevation of SAA in acute-phase plasma and inflamed tissues has long been associated with inflammatory and autoimmune diseases including rheumatoid arthritis, atherosclerosis, and Crohn's disease. In the past, we and others have reported that SAA possesses cytokine-like activities and stimulates the secretion of pro-inflammatory factors such as IL-8, TNF1, IL-12, IL-6, matrix metalloproteinases and tissue factors, which, in turn, established SAA as a key inflammatory mediator in the innate immune system. Our recently published results also indicated that SAA induces immunoregulatory cytokine IL-23 expression in monocytes, suggesting the potential mechanism for SAA to regulate T cell differentiation. In our preliminary experiments, we showed that SAA stimulates T cells to secrete IFN3, a key cytokine directing the differentiation of naove CD4+ T cells into Th1 cells. Based on these compelling preliminary data, we propose to test the central hypothesis that SAA plays an important role in Th1 cell differentiation and therefore is potentially a causal agent in the pathogenesis of autoimmunity. We will test this hypothesis in three specific aims.
Aim 1 is to investigate SAA-induced IFN3 secretion.
Aim 2 is to determine the role of SAA in Th1 cell differentiation.
Aim 3 is to study the receptor-mediated signaling mechanisms involved in SAA-stimulated IFN3 expression and Th1 cell differentiation. A broad, long-ranging goal of this application is to understand the relationship of leukocyte activation and progression of inflammatory diseases. The overall goal of the experiments in this proposal is to understand better the function of acute-phase protein SAA in adaptive immunity - especially cell-mediated immunity - and establish a role of SAA in inflammatory diseases. In addition to the scientific aims, funding of this research will provide critical resources for my professional development insofar as it will support the continuation of my research and thereby lead to both my promotion within the institution and my ability to attract future mainstream funding.

Public Health Relevance

The experiments proposed in this application will establish a role of SAA in cell-mediated immunity. Moreover, our findings have the potential to provide novel mechanistic insights into signaling events in autoimmune diseases that can lead to the identification of new therapeutic targets for autoimmune diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Continuance Award (SC3)
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Special Emphasis Panel (ZGM1)
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Krasnewich, Donna M
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Chicago State University
Schools of Arts and Sciences
United States
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