Amyloid Precursor Proteins in Sarcoidosis

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that involves the lungs in over 90% of affected individuals and may cause end-stage pulmonary fibrosis and death. The pathologic hallmark of sarcoidosis is non-caseating granulomatous inflammation. A major step in understanding sarcoidosis would be the identification of specific host proteins that regulate granuloma formation in this disease. Recently, using a limited proteomic approach with matrix-associated laser desorption/ionization-time of flight (MALDI-TOF) mass spectroscopy, we identified Mycobacterium tuberculosis catalase- eroxidase as a tissue antigen and target of the immune response in sarcoidosis, supporting a microbial, etiologyof sarcoidosis. Using this same proteomic approach, our preliminary studies have identified the amyloid precursor protein, serum amyloid A (SAA), as a potentially critical host protein regulating granuloma formation in sarcoidosis. SAA is expressed in a well-defined, often intense pattern of staining in epithelioid granulomas in sarcoidosis not typified by several other granulomatous disorders. SAA is highly inducible in mononuclear cells by mycobacterial organisms and has both pro- and anti-inflammatory properties. Our preliminary data suggests SAA promotes Th1 immune responses in sarcoidosis by stimulating expression of TNF, IL18, and possibly, IL12. Our hypothesis is that SAA, as part of an innate immune response, critically regulates granuloma formation in sarcoidosis. The goal of this application is to examine the roles of SAA in regulating granuloma formation in sarcoidosis--as a contributor to protein aggregation at sites of granuloma formation, as a promoter of Th1 immune responses, and as a critical regulator of Th1 mediated granulomatous inflammation in a rodent model of sarcoidosis. These studies have the potential to provide evidence for a critical host protein and pathway, linked to etiologic antigens, that regulates the origin and fate of sarcoidosis granulemas, thus becoming a potential target of therapeutic intervention.