Significance Circulating Semaphorin 7a+ve Cells in Pulmonary Sarcoidosis

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DESCRIPTION (provided by applicant): Sarcoidosis is a chronic inflammatory disease that often results in progressive, untreatable pathology. It likely results from complex interactions between unidentified genetic, infectious, and/or environmental factors that combine to induce ongoing granuloma formation in affected tissues. These granulomas contain increased numbers of monocytes and CD4+ T cells and are accompanied by increased proinflammatory cytokines and chemokines, as well as by abnormalities in regulatory T cells (Tregs) which normally function to control inflammation. Little is known about how these factors lead to phenotypic differences in disease activity. Thus, while many patients with sarcoidosis will stabilize and in some cases even remit, approximately 20% of patients will develop progressive disease that in some cases results in death. Until we understand this disease better, there is little hope for predicting the clinical course and finding new therapies. We have recently found that the blood of patients with sarcoidosis contains several unique cell populations with potential import in disease pathogenesis. We have found that sarcoid patients show increased numbers of circulating fibrocytes, and that (unlike normal controls) these cells secrete increased quantities of proinflammatory cytokines. We have also found that the blood of sarcoid patients contains a unique Treg population that expresses Semaphorin 7a, and that these cells appear to stimulate exaggerated fibrocyte outgrowth and cytokine secretion. Curiously, both fibrocytes and Sema 7a+ Tregs are most elevated in those sarcoid patients with severe or progressive disease and as such may be related to disease phenotype. This grant tests the hypothesis that fibrocytes and/or Sema 7a+ Tregs function as biomarkers of disease progression in patients with newly diagnosed pulmonary sarcoidosis. In aim 1 we will recruit and characterize a cohort of sarcoid patients (and controls) to create a biorepository for the proposed studies. In aims 2 and 3 we will quantify circulating fibrocytes and Sema 7a+ Tregs and assess their ability to predict disease progression in the subjects recruited in aim 1. Mechanistic studies will be performed to determine the nature of the fibrocyte-Treg interactions. It is hoped that these studies will deepen our understanding of disease progression in patients with sarcoidosis and lead to new insight that could lead to novel therapeutic options.