Cellular Recognition of Mycobacterium Tuberculosis ESAT-6 and KatG Peptides in Systemic Sarcoidosis

Infection and Immunity. Jan, 2007  |  Pubmed ID: 17088357

Sarcoidosis is an enigmatic disease with a pathology similar to that of tuberculosis. We detected Th-1 immune responses to Mycobacterium tuberculosis ESAT-6 and KatG peptides from peripheral blood mononuclear cells from 15/26 sarcoidosis, 1/24 purified-protein-derivative-negative (PPD-) (P < 0.0001, Fisher's exact test), and 7/8 PPD-positive (PPD+) subjects (P = 0.21). This finding provides immunologic links between mycobacteria and systemic sarcoidosis.

Superoxide Dismutase A Antigens Derived from Molecular Analysis of Sarcoidosis Granulomas Elicit Systemic Th-1 Immune Responses

Respiratory Research. 2008  |  Pubmed ID: 18439270

Sarcoidosis is an idiopathic granulomatous disease with pathologic and immunologic features similar to tuberculosis. Routine histologic staining and culture fail to identify infectious agents. An alternative means for investigating a role of infectious agents in human pathogenesis involves molecular analysis of pathologic tissues for microbial nucleic acids, as well as recognition of microbial antigens by the host immune system. Molecular analysis for superoxide dismutase A (sodA) allows speciation of mycobacteria. SodA is an abundantly secreted virulence factor that generates cellular immune responses in infected hosts. The purpose of this study is to investigate if target antigens of the sarcoidosis immune response can be identified by molecular analysis of sarcoidosis granulomas.

Cellular Responses to Mycobacterial Antigens Are Present in Bronchoalveolar Lavage Fluid Used in the Diagnosis of Sarcoidosis

Infection and Immunity. Sep, 2009  |  Pubmed ID: 19596780

Considerable evidence supports the concept that CD4(+) T cells are important in sarcoidosis pathogenesis, but the antigens responsible for the observed Th1 immunophenotype remain elusive. The epidemiologic association with bioaerosols and the presence of granulomatous inflammation support consideration of mycobacterial antigens. To explore the role of mycobacterial antigens in sarcoidosis immunopathogenesis, we assessed the immune recognition of mycobacterial antigens, the 6-kDa early secreted antigenic protein (ESAT-6) and catalase-peroxidase (KatG), by T cells derived from bronchoalveolar lavage (BAL) fluid obtained during diagnostic bronchoscopy. We report the presence of antigen-specific recognition of ESAT-6 and KatG in T cells from BAL fluid of 32/44 sarcoidosis subjects, compared to 1/27 controls (P < 0.0001). CD4(+) T cells were primarily responsible for immune recognition (32/44 sarcoidosis subjects), although CD8(+) T-cell responses were observed (25/41 sarcoidosis subjects). Recognition was significantly absent from BAL fluid cells of patients with other lung diseases, including infectious granulomatous diseases. Blocking of Toll-like receptor 2 reduced the strength of the observed immune response. The presence of immune responses to mycobacterial antigens in cells from BAL fluid used for sarcoidosis diagnosis suggests a strong association between mycobacteria and sarcoidosis pathogenesis. Inhibition of immune recognition with monoclonal antibody against Toll-like receptor 2 suggests that induction of innate immunity by mycobacteria contributes to the polarized Th1 immune response.

Vitamin D, Innate Immunity, and Sarcoidosis Granulomatous Inflammation: Insights from Mycobacterial Research

Current Opinion in Pulmonary Medicine. Sep, 2010  |  Pubmed ID: 20473167

Recent discoveries cast doubt on granuloma formation solely as a protective mechanism, and highlight the importance of innate immunity of the host response to pathogenic mycobacteria. Here, we briefly review evidence that mycobacterial antigens are involved in sarcoidosis pathogenesis, and explore how defects in innate immunity might contribute to the disease.

The Etiologic Role of Infectious Antigens in Sarcoidosis Pathogenesis

Seminars in Respiratory and Critical Care Medicine. Aug, 2010  |  Pubmed ID: 20665387

Sarcoidosis is a disease of unknown etiology, characterized pathologically by noncaseating granulomas that most commonly involve the lung, skin, lymph nodes, and eyes. Syndromes with similar pathological and immunologic features to sarcoidosis such as chronic beryllium disease, hypersensitivity pneumonitis, and tuberculosis illustrate that granulomatous diseases may or may not have an infectious etiology. Although the etiology of sarcoidosis remains unknown, recent molecular, genetic, and immunologic studies strengthen the association of sarcoidosis with infectious antigens. Currently, the strongest agents considered include PROPIONIBACTERIUM and MYCOBACTERIUM species. Independent studies report the presence of microbial nucleic acids and proteins within sarcoidosis specimens. Th-1 immune responses to mycobacterial proteins have been detected within sarcoidosis diagnostic bronchoalveolar lavage (BAL). These proteins are actively secreted by the mycobacterial SecA 2 secretion system and are important to evade the host immune system. Recent discoveries regarding MHC class II alleles provide additional insight regarding the role of microbial antigens in sarcoidosis pathogenesis. Although further investigation is warranted, the recent progress of independent laboratories, using complementary techniques, strengthens the role of microbial antigens in sarcoidosis pathogenesis. These studies lay a strong foundation toward identifying therapeutic targets.

Where Next for Gene Expression Profiling? So Much Promise

American Journal of Respiratory and Critical Care Medicine. Nov, 2011  |  Pubmed ID: 22086986

Development of a Sarcoidosis Murine Lung Granuloma Model Using Mycobacterium Superoxide Dismutase A Peptide

American Journal of Respiratory Cell and Molecular Biology. Feb, 2011  |  Pubmed ID: 20348207

Sarcoidosis is characterized by noncaseating granulomas containing CD4(+) T cells with a Th1 immunophenotype. Although the causative antigens remain unknown, independent studies noted molecular and immunologic evidence of mycobacterial virulence factors in sarcoidosis specimens. A major limiting factor in discovering new insights into the pathogenesis of sarcoidosis is the lack of an animal model. Using a distinct superoxide dismutase A peptide (sodA) associated with sarcoidosis granulomas, we developed a pulmonary model of sarcoidosis granulomatous inflammation. Mice were sensitized by a subcutaneous injection of sodA, incorporated in incomplete Freund's adjuvant (IFA). Control subjects consisted of mice with no sensitization (ConNS), sensitized with IFA only (ConIFA), or with Schistosoma mansoni eggs. Fourteen days later, sensitized mice were challenged by tail-vein injection of naked beads, covalently coupled to sodA peptides or to schistosome egg antigens (SEA). Histologic analysis revealed hilar lymphadenopathy and noncaseating granulomas in the lungs of sodA-treated or SEA-treated mice. Flow cytometry of bronchoalveolar lavage (BAL) demonstrated CD4(+) T-cell responses against sodA peptide in the sodA-sensitized mice only. Cytometric bead analysis revealed significant differences in IL-2 and IFN-γ secretion in the BAL fluid of sodA-treated mice, compared with mice that received SEA or naked beads (P = 0.008, Wilcoxon rank sum test). ConNS and ConIFA mice demonstrated no significant formation of granuloma, and no Th1 immunophenotype. The use of microbial peptides distinct for sarcoidosis reveals a histologic and immunologic profile in the murine model that correlates well with those profiles noted in human sarcoidosis, providing the framework to investigate the molecular basis for the progression or resolution of sarcoidosis.