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Semin Respir Crit Care Med 2010; 31(4): 375-379
DOI: 10.1055/s-0030-1262205
© Thieme Medical Publishers

The Etiologic Role of Infectious Antigens in Sarcoidosis Pathogenesis

Kyra A. Oswald-Richter1 , Wonder P. Drake1 , 2 , 3
  • 1Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee
  • 2Division of Infectious Diseases, Vanderbilt University Medical School, Nashville, Tennessee
  • 3Department of Medicine, Vanderbilt University Medical School, Nashville, Tennessee
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Publication History

Publication Date:
27 July 2010 (online)

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ABSTRACT

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.

KEYWORDS

Sarcoidosis - etiology - pathogenesis - microbial antigens - mycobacteria

REFERENCES

  • 1 Baughman R P. Sarcoidosis.  Clin Dermatol. 2007;  25 231
    CrossrefPubMedGoogle Scholar
  • 2 Newman L S, Rose C S, Bresnitz E A ACCESS Research Group et al. A case control etiologic study of sarcoidosis: environmental and occupational risk factors.  Am J Respir Crit Care Med. 2004;  170 1324-1330
    CrossrefPubMedGoogle Scholar
  • 3 Kajdasz D K, Judson M A, Mohr Jr L C, Lackland D T. Geographic variation in sarcoidosis in South Carolina: its relation to socioeconomic status and health care indicators.  Am J Epidemiol. 1999;  150 271-278
    PubMedGoogle Scholar
  • 4 Falkinham III J O. Nontuberculous mycobacteria in the environment.  Clin Chest Med. 2002;  23 529-551
    CrossrefPubMedGoogle Scholar
  • 5 Hanak V, Kalra S, Aksamit T R, Hartman T E, Tazelaar H D, Ryu J H. Hot tub lung: presenting features and clinical course of 21 patients.  Respir Med. 2006;  100 610-615
    CrossrefPubMedGoogle Scholar
  • 6 DiGiulio D B, Romero R, Amogan H P et al.. Microbial prevalence, diversity and abundance in amniotic fluid during preterm labor: a molecular and culture-based investigation.  PLoS One. 2008;  3 e3056
    CrossrefPubMedGoogle Scholar
  • 7 Bik E M, Eckburg P B, Gill S R et al.. Molecular analysis of the bacterial microbiota in the human stomach.  Proc Natl Acad Sci U S A. 2006;  103 732-737
    CrossrefPubMedGoogle Scholar
  • 8 Relman D A, Schmidt T M, MacDermott R P, Falkow S. Identification of the uncultured bacillus of Whipple’s disease.  N Engl J Med. 1992;  327 293-301
    CrossrefPubMedGoogle Scholar
  • 9 Ksiazek T G, Erdman D, Goldsmith C S SARS Working Group et al. A novel coronavirus associated with severe acute respiratory syndrome.  N Engl J Med. 2003;  348 1953-1966
    CrossrefPubMedGoogle Scholar
  • 10 Whitley R. The new age of molecular diagnostics for microbial agents.  N Engl J Med. 2008;  358 988-989
    CrossrefPubMedGoogle Scholar
  • 11 Palacios G, Druce J, Du L et al.. A new arenavirus in a cluster of fatal transplant-associated diseases.  N Engl J Med. 2008;  358 991-998
    CrossrefPubMedGoogle Scholar
  • 12 Ishige I, Eishi Y, Takemura T et al.. Propionibacterium acnes is the most common bacterium commensal in peripheral lung tissue and mediastinal lymph nodes from subjects without sarcoidosis.  Sarcoidosis Vasc Diffuse Lung Dis. 2005;  22 33-42
    PubMedGoogle Scholar
  • 13 Ichikawa H, Kataoka M, Hiramatsu J et al.. Quantitative analysis of propionibacterial DNA in bronchoalveolar lavage cells from patients with sarcoidosis.  Sarcoidosis Vasc Diffuse Lung Dis. 2008;  25 15-20
    PubMedGoogle Scholar
  • 14 McCaskill J G, Chason K D, Hua X et al.. Pulmonary immune responses to Propionibacterium acnes in C57BL/6 and BALB/c mice.  Am J Respir Cell Mol Biol. 2006;  35 347-356
    CrossrefPubMedGoogle Scholar
  • 15 Drake W P, Pei Z, Pride D T, Collins R D, Cover T L, Blaser M J. Molecular analysis of sarcoidosis tissues for mycobacterium species DNA.  Emerg Infect Dis. 2002;  8 1334-1341
    PubMedGoogle Scholar
  • 16 Song Z, Marzilli L, Greenlee B M et al.. Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis.  J Exp Med. 2005;  201 755-767
    CrossrefPubMedGoogle Scholar
  • 17 Dubaniewicz A, Dubaniewicz-Wybieralska M, Sternau A et al.. Mycobacterium tuberculosis complex and mycobacterial heat shock proteins in lymph node tissue from patients with pulmonary sarcoidosis.  J Clin Microbiol. 2006;  44 3448-3451
    CrossrefPubMedGoogle Scholar
  • 18 Allen S S, Evans W, Carlisle J et al.. Superoxide dismutase A antigens derived from molecular analysis of sarcoidosis granulomas elicit systemic Th-1 immune responses.  Respir Res. 2008;  9 36
    CrossrefPubMedGoogle Scholar
  • 19 Ding X L, Cai L, Zhang J Z. Detection and identification of mycobacterial gene in skin lesions and lymph nodes in patients with sarcoidosis [in Chinese].  Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2009;  31 20-23
    PubMedGoogle Scholar
  • 20 Zhou Y, Li H P, Li Q H et al.. Differentiation of sarcoidosis from tuberculosis using real-time PCR assay for the detection and quantification of Mycobacterium tuberculosis .  Sarcoidosis Vasc Diffuse Lung Dis. 2008;  25 93-99
    PubMedGoogle Scholar
  • 21 Nakata Y, Ejiri T, Kishi T et al.. Alveolar lymphocyte proliferation induced by Propionibacterium acnes in sarcoidosis patients.  Acta Med Okayama. 1986;  40 257-264
    PubMedGoogle Scholar
  • 22 Nakata Y, Ejiri T, Kishi T et al.. Alveolar lymphocyte proliferation in sarcoidosis patients induced by Propionibacterium acnes [in Japanese].  Nihon Kyobu Shikkan Gakkai Zasshi. 1985;  23 413-419
    PubMedGoogle Scholar
  • 23 Drake W P, Dhason M S, Nadaf M et al.. Cellular recognition of Mycobacterium tuberculosis ESAT-6 and KatG peptides in systemic sarcoidosis.  Infect Immun. 2007;  75 527-530
    CrossrefPubMedGoogle Scholar
  • 24 Launois P, DeLeys R, Niang M N et al.. T-cell-epitope mapping of the major secreted mycobacterial antigen Ag85A in tuberculosis and leprosy.  Infect Immun. 1994;  62 3679-3687
    PubMedGoogle Scholar
  • 25 Hajizadeh R, Sato H, Carlisle J et al.. Mycobacterium tuberculosis antigen 85A induces Th-1 immune responses in systemic sarcoidosis.  J Clin Immunol. 2007;  27 445-454
    CrossrefPubMedGoogle Scholar
  • 26 Carlisle J, Evans W, Hajizadeh R et al.. Multiple Mycobacterium antigens induce interferon-gamma production from sarcoidosis peripheral blood mononuclear cells.  Clin Exp Immunol. 2007;  150 460-468
    CrossrefPubMedGoogle Scholar
  • 27 Edwards K M, Cynamon M H, Voladri R K et al.. Iron-cofactored superoxide dismutase inhibits host responses to Mycobacterium tuberculosis .  Am J Respir Crit Care Med. 2001;  164 2213-2219
    PubMedGoogle Scholar
  • 28 Rigel N W, Gibbons H S, McCann J R, McDonough J A, Kurtz S, Braunstein M. The accessory SecA2 system of mycobacteria requires ATP binding and the canonical SecA1.  J Biol Chem. 2009;  284 9927-9936
    CrossrefPubMedGoogle Scholar
  • 29 Braunstein M, Espinosa B J, Chan J, Belisle J T, Jacobs Jr W R. SecA2 functions in the secretion of superoxide dismutase A and in the virulence of Mycobacterium tuberculosis .  Mol Microbiol. 2003;  48 453-464
    CrossrefPubMedGoogle Scholar
  • 30 Chen E S, Wahlström J, Song Z et al.. T cell responses to mycobacterial catalase-peroxidase profile a pathogenic antigen in systemic sarcoidosis.  J Immunol. 2008;  181 8784-8796
    CrossrefPubMedGoogle Scholar
  • 31 Pathan A A, Wilkinson K A, Klenerman P et al.. Direct ex vivo analysis of antigen-specific IFN-gamma-secreting CD4 T cells in Mycobacterium tuberculosis-infected individuals: associations with clinical disease state and effect of treatment.  J Immunol. 2001;  167 5217-5225
    PubMedGoogle Scholar
  • 32 Oswald-Richter K A, Culver D A, Hawkins C et al.. Cellular responses to mycobacterial antigens are present in bronchoalveolar lavage fluid used in the diagnosis of sarcoidosis.  Infect Immun. 2009;  77 3740-3748
    CrossrefPubMedGoogle Scholar
  • 33 Andersen P. The T cell response to secreted antigens of Mycobacterium tuberculosis .  Immunobiology. 1994;  191 537-547
    PubMedGoogle Scholar
  • 34 Andersen P, Askgaard D, Ljungqvist L, Bentzon M W, Heron I. T-cell proliferative response to antigens secreted by Mycobacterium tuberculosis .  Infect Immun. 1991;  59 1558-1563
    PubMedGoogle Scholar
  • 35 Iannuzzi M C, Iyengar S K, Gray-McGuire C et al.. Genome-wide search for sarcoidosis susceptibility genes in African Americans.  Genes Immun. 2005;  6 509-518
    CrossrefPubMedGoogle Scholar
  • 36 Rossman M D, Thompson B, Frederick M ACCESS Group et al. HLA and environmental interactions in sarcoidosis.  Sarcoidosis Vasc Diffuse Lung Dis. 2008;  25 125-132
    PubMedGoogle Scholar
  • 37 Rossman M D, Thompson B, Frederick M ACCESS Group et al. HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites.  Am J Hum Genet. 2003;  73 720-735
    CrossrefPubMedGoogle Scholar
  • 38 Grunewald J, Eklund A. Löfgren’s syndrome: human leukocyte antigen strongly influences the disease course.  Am J Respir Crit Care Med. 2009;  179 307-312
    CrossrefPubMedGoogle Scholar
  • 39 Ishihara M, Ishida T, Inoko H et al.. HLA serological and class II genotyping in sarcoidosis patients in Japan.  Jpn J Ophthalmol. 1996;  40 86-94
    PubMedGoogle Scholar
  • 40 Oswald-Richter K, Sato H, Hajizadeh R et al.. 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. 2010;  30 157-166
    CrossrefPubMedGoogle Scholar
  • 41 Zhang F R, Huang W, Chen S M et al.. Genomewide association study of leprosy.  N Engl J Med. 2009;  361 2609-2618
    CrossrefPubMedGoogle Scholar
  • 42 Zhang F, Liu H, Chen S et al.. Evidence for an association of HLA-DRB1*15 and DRB1*09 with leprosy and the impact of DRB1*09 on disease onset in a Chinese Han population.  BMC Med Genet. 2009;  10 133
    CrossrefPubMedGoogle Scholar
  • 43 Saltini C, Pallante M, Puxeddu E et al.. M. avium binding to HLA-DR expressed alleles in silico: a model of phenotypic susceptibility to sarcoidosis.  Sarcoidosis Vasc Diffuse Lung Dis. 2008;  25 100-116
    PubMedGoogle Scholar
  • 44 Amicosante M, Puxeddu E, Saltini C. Reactivity to mycobacterial antigens by patients with Lofgren’s syndrome as a model of phenotypic susceptibility to disease and disease progression.  Am J Respir Crit Care Med. 2009;  180 685-686, author reply 685–686
    PubMedGoogle Scholar

Kyra A Oswald-RichterPh.D. 

Division of Infectious Diseases, Vanderbilt University Medical School, 1161 21st Avenue South, Medical Center North

Rm. A-3314, Nashville, TN 37232-2363

Email: Kyra.Richter@vanderbilt.edu