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Serum Amyloid A Regulates Granulomatous Inflammation in Sarcoidosis through Toll-like Receptor-2

¹ Division of Pulmonary and Critical Care Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland; ² Section of Pathology, Department of Medicine, National Jewish Health and ³ Program of Translational Lung Research, University of Colorado Denver, School of Medicine, Denver, Colorado; and ⁴ Department of Molecular Microbiology and Immunology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to David R. Moller, M.D., 5501 Hopkins Bayview Circle, Baltimore, MD 21224. E-mail: dmoller{at}jhmi.edu

Rationale: The critical innate immune mechanisms that regulate granulomatous inflammation in sarcoidosis are unknown. Because the granuloma-inducing component of sarcoidosis tissues has physicochemical properties similar to those of amyloid fibrils, we hypothesized that host proteins capable of forming poorly soluble aggregates or amyloid regulate inflammation in sarcoidosis.

Objectives: To determine the role of the amyloid precursor protein, serum amyloid A, as an innate regulator of granulomatous inflammation in sarcoidosis.

Methods: Serum amyloid A expression was determined by immunohistochemistry in sarcoidosis and control tissues and by ELISA. The effect of serum amyloid A on nuclear factor (NF)-B induction, cytokine expression, and Toll-like receptor-2 stimulation was determined with transformed human cell lines and bronchoalveolar lavage cells from patients with sarcoidosis. The effects of serum amyloid A on regulating helper T cell type 1 (Th1) granulomatous inflammation were determined in experimental models of sarcoidosis, using Mycobacterium tuberculosis catalase–peroxidase.

Measurements and Main Results: We found that the intensity of expression and distribution of serum amyloid A within sarcoidosis granulomas was unlike that in many other granulomatous diseases. Serum amyloid A localized to macrophages and giant cells within sarcoidosis granulomas but correlated with CD3⁺ lymphocytes, linking expression to local Th1 responses. Serum amyloid A activated NF-B in Toll-like receptor-2–expressing human cell lines; regulated experimental Th1-mediated granulomatous inflammation through IFN-, tumor necrosis factor, IL-10, and Toll-like receptor-2; and stimulated production of tumor necrosis factor, IL-10, and IL-18 in lung cells from patients with sarcoidosis, effects inhibited by blocking Toll-like receptor-2.

Conclusions: Serum amyloid A is a constituent and innate regulator of granulomatous inflammation in sarcoidosis through Toll-like receptor-2, providing a mechanism for chronic disease and new therapeutic targets.

Key Words: sarcoidosis • serum amyloid A • innate immunity • granuloma • cytokines

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Studies support a mycobacterial etiology for sarcoidosis. The critical innate immune mechanisms that regulate chronic granulomatous inflammation in sarcoidosis in the absence of active infection remain unknown. What This Study Adds to the Field Serum amyloid A is an innate receptor ligand that aggregates and regulates granulomatous inflammation in sarcoidosis, providing a novel mechanism for chronic disease.