Sarcoidosis is a disease of unknown etiology, characterized pathologically by noncaseating granulomas which most commonly involve the lung, skin, lymph node and eyes. Syndromes with similar pathologic and immunologic features to sarcoidosis such as chronic beryllium disease, hypersensitivity pneumonitis, and tuberculosis illustrate that granulomatous diseases may or may have an infectious etiology. We performed PCR analysis of paraffin-embedded sarcoidosis and control specimens for the presence of Mycobacterium 16S rRNA and rpoB. We found evidence of mycobacterial nucleic acids in 60% of the sarcoid granulomas and in none of the controls (p<0.00002, chi square). Sequence analysis of the 16S rRNA and rpoB amplicons revealed the presence of a novel Mycobacterium, genetically similar to M. tuberculosis (MTB) (99% positional identity). We expanded our work to include ten frozen sarcoidosis and ten control tissues from Vanderbilt University and from other regions of the United States. We identified mycobacterial nucleic acid in 50% of frozen sarcoidosis specimens and in none of controls (p<0.0325, two-tailed Fisher's test). Most recently, we performed ELISPOT assays on sarcoidosis '(n=10) and control (n=9) peripheral blood mononuclear cells (PBMC). We found immune recognition of MTB katG peptides in 70.0% of the sarcoidosis specimens compared to none of the negative control specimens (p=0.01, ANOVA analysis). The central hypothesis is that sarcoidosis is an immunologic response to a mycobacterial infection in a genetically susceptible host. We have formed a national collaboration involving National Jewish Medical and Research Center, Vanderbilt University School of Medicine, and University of Colorado, Boulder. The purpose of the collaboration is to determine if mycobacteria have a role in sarcoidosis immunopathogenesis. We will combine the sarcoidosis and control resources 1) to perform molecular characterization of sarcoidosis granulomas using genes which speciate pathogenic mycobacteria, 2) to compare T-cell specific interferon-y production to mycobacterial peptides in sarcoidosis patients to CBD patients, a PPD- control population, and patients with M. tuberculosis infection, 3) to use in situ hybridization to localize mycobacteria within sarcoidosis species in order to better understand host-pathogen interactions. These findings, which will assess in an independent and complementary fashion the role of mycobacteria in sarcoidosis immunopathogenesis, may have an impact on future therapeutic modalities for sarcoidosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI065744-04
Application #
7588881
Study Section
Special Emphasis Panel (ZRG1-CRFS-C (01))
Program Officer
Parker, Tina M
Project Start
2006-04-01
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2009
Total Cost
$364,415
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Oswald-Richter, Kyra A; Richmond, Bradley W; Braun, Nicole A et al. (2013) Reversal of global CD4+ subset dysfunction is associated with spontaneous clinical resolution of pulmonary sarcoidosis. J Immunol 190:5446-53
Oswald-Richter, Kyra A; Beachboard, Dia C; Seeley, Erin H et al. (2012) Dual analysis for mycobacteria and propionibacteria in sarcoidosis BAL. J Clin Immunol 32:1129-40
Chambers, Isfahan R; Cone, Tiffany R; Oswald-Richter, Kyra et al. (2010) Enzyme-linked immunospot assay (ELISPOT): Quantification of Th-1 cellular immune responses against microbial antigens. J Vis Exp :
Oswald-Richter, Kyra A; Drake, Wonder P (2010) The etiologic role of infectious antigens in sarcoidosis pathogenesis. Semin Respir Crit Care Med 31:375-9
Richmond, Bradley W; Drake, Wonder P (2010) Vitamin D, innate immunity, and sarcoidosis granulomatous inflammation: insights from mycobacterial research. Curr Opin Pulm Med 16:461-4
Oswald-Richter, Kyra A; Beachboard, Dia C; Zhan, Xiaoyan et al. (2010) Multiple mycobacterial antigens are targets of the adaptive immune response in pulmonary sarcoidosis. Respir Res 11:161
Oswald-Richter, Kyra; Sato, Hiroe; Hajizadeh, Rana et al. (2010) Mycobacterial ESAT-6 and katG are recognized by sarcoidosis CD4+ T cells when presented by the American sarcoidosis susceptibility allele, DRB1*1101. J Clin Immunol 30:157-66
Oswald-Richter, Kyra A; Culver, Daniel A; Hawkins, Charlene et al. (2009) Cellular responses to mycobacterial antigens are present in bronchoalveolar lavage fluid used in the diagnosis of sarcoidosis. Infect Immun 77:3740-8
Allen, Shannon S; Evans, Whitney; Carlisle, James et al. (2008) Superoxide dismutase A antigens derived from molecular analysis of sarcoidosis granulomas elicit systemic Th-1 immune responses. Respir Res 9:36
Carlisle, J; Evans, W; Hajizadeh, R et al. (2007) Multiple Mycobacterium antigens induce interferon-gamma production from sarcoidosis peripheral blood mononuclear cells. Clin Exp Immunol 150:460-8

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