, Volume 19, Issue 2, pp 55–68

The potential of the immunological markers of sarcoidosis in exhaled breath and peripheral blood as future diagnostic and monitoring techniques



Sarcoidosis is characterised by non-caseating granulomatous inflammation, with exaggerated immune responses at sites of disease and derangements of normal tissue architecture. The lungs are most commonly involved and progressive inflammation may result in pulmonary fibrosis. The immunopathogenesis and aetiology remain uncertain, which has made it difficult to identify a single sufficiently sensitive or specific diagnostic marker. Further investigation is needed to identify sensitive and specific markers of disease, such as in peripheral blood and exhaled breath condensate (EBC). Identification of disease markers may also be useful for investigating disease activity and predicting progression to fibrosis. This review explores the literature on the cytokine profiles of blood and bronchoalveolar lavage lymphocytes following ex vivo stimulation, as well as disease markers measured using the medium of EBC.


Sarcoidosis TH1/TH2 balance TH17 cytokine measurement Flow cytometry Exhaled breath condensate Inflammatory markers Kveim–Siltzbach test 


  1. Agostini C, Adami F, Semenzato G (2000) New pathogenetic insights into the sarcoid granuloma. Curr Opin Rheumatol 12:71–76PubMedGoogle Scholar
  2. Agostini C, Meneghin A, Semenzato G (2002) T-lymphocytes and cytokines in sarcoidosis. Curr Opin Pulm Med 8(5):435–440PubMedGoogle Scholar
  3. Akahoshi M, Ishihara M, Remus N, Uno K, Miyake K, Hirota T, Nakashima K, Matsuda A, Kanda M, Enomoto T, Ohno S, Nakashima H, Casanova J, Hopkin JM, Tamari M, Mao X, Shirakawa T (2004) Association between IFNA genotype and the risk of sarcoidosis. Hum Genet 114:503–509PubMedGoogle Scholar
  4. Allen RK, Pierce RJ, Barter CE (1992) Angiotensin-converting enzyme in bronchoalveolar lavage fluid in sarcoidosis. Sarcoidosis 9(1):54–59PubMedGoogle Scholar
  5. Allen SS, Evans W, Carlisle J, Hajizadeh R, Nadaf M, Shepherd BE, Pride DT, Johnson JE, Drake WP (2008) Superoxide dismutase A antigens derived from molecular analysis of sarcoidosis granulomas elicit systemic Th-1 immune responses. Respir Res 9:36–47PubMedGoogle Scholar
  6. Antoniou KM, Soufla G, Proklou A, Margaritopoulos G, Choulaki C, Lymbouridou R, Samara KD, Spandidos DA, Siafakas NM (2009) Different activity of the biological axis VEGF-Flt-1 (fms-like tyrosine kinase 1) and CXC chemokines between pulmonary sarcoidosis and idiopathic pulmonary fibrosis: a bronchoalveolar lavage study. Clin Dev Immunol 537929 (Epub 2010 Feb 14)Google Scholar
  7. Bargagli E, Mazzi A, Rottoli P (2008) Markers of inflammation in sarcoidosis: blood, urine, BAL, sputum, and exhaled gas. Clin Chest Med 29(3):445–458PubMedGoogle Scholar
  8. Baughman RP, Lower EE, du Bois RM (2003) Sarcoidosis. Lancet 361:1111–1118PubMedGoogle Scholar
  9. Beirne P, Pantelidis P, Charles P, Wells AU, Abraham DJ, Denton CP, Welsh KI, Shah PL, du Bois RM, Kelleher P (2009) Multiplex immune serum biomarker profiling in sarcoidosis and systemic sclerosis. Eur Respir J 34(6):1376–1382PubMedGoogle Scholar
  10. Berge BT, Paats MS, Bergen IM, van den Blink B, Hoogsteden HC, Lambrecht BN, Hendriks RW, KleinJan A (2010) IL-17 and IL-22 expressing cells are involved in granuloma pathogenesis in pulmonary sarcoidosis. Am J Respir Crit Care Med 181(1):A3983Google Scholar
  11. Betelli E, Kom T, Oukka M, Kuchroo VK (2008) Induction and effector functions of TH17 cells. Nature 453:1051–1057Google Scholar
  12. Biller H, Ruprecht B, Gaede KI, Müller-Quernheim J, Zissel G (2009) Gene polymorphisms of ACE and the angiotensin receptor AT2R1 influence serum ACE levels in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 26(2):139–146PubMedGoogle Scholar
  13. Bolukbas C, Bolukbas FF, Kebdir T, Canayaz L, Dalay AR, Kilic G, Ovunc O (2005) Development of sarcoidosis during interferon alpha 2b and ribavirin combination therapy for chronic hepatitis C—a case report and review of the literature. Acta gastroenterel Belg 68(4):432–434Google Scholar
  14. Brice EA, Friedlander W, Bateman ED, Kirsch RE (1995) Serum angiotensin-converting enzyme activity, concentration, and specific activity in granulomatous interstitial lung disease, tuberculosis, and COPD. Chest 107(3):706–710PubMedGoogle Scholar
  15. Brown ST, Brett I, Almenoff PL, Lesser M, Terrin M, Teirstein AS (2003) Recovery of cell wall-deficient organisms does not distinguish between patients with sarcoidosis and control subjects. Chest 123:413–417PubMedGoogle Scholar
  16. Cannone M, Vago L, Porini G, Bonetto S, Cassi C, Bramerio M, Rizzato G, Barberis MC (1997) Detection of Mycobacterium tuberculosis DNA using nested polymerase chain reaction in lymph nodes with sarcoidosis, fixed in formalin and embedded in paraffin. Pathologica 89(5):512–516PubMedGoogle Scholar
  17. Carlisle J, Evans W, Hajizadeh R, Nadaf M, Shepherd B, Ott RD, Richter K, Drake WP (2007) Multiple Mycobacterium antigens induce interferon-γ production for sarcoidosis peripheral blood mononuclear cells. Clin Exp Immunol 150:460–468PubMedGoogle Scholar
  18. Celik G, Sen E, Ulger AF, Kumbasar OO, Bozkaya H, Alper D, Karayalcin S (2005) Sarcoidosis caused by interferon therapy. Respirology 10(4):535–540PubMedGoogle Scholar
  19. Chan HP, Lewis C, Thomas PS (2008) Exhaled breath analysis: novel approach for early detection of lung cancer. Lung Cancer 63:164–168PubMedGoogle Scholar
  20. Chase MW (1961) The preparation and standardization of Kveim testing antigen. Am Rev Respir Dis 84(5):Pt. 2:86–88Google Scholar
  21. Chase MW, Siltzbach LE (1967) Concentration of the active principle responsible for the Kveim reaction. In: Proceedings of the 4th international conference on sarcoidosis, Mason, ParisGoogle Scholar
  22. Chen ES, Moller DR (2006) Cytokines and chemokines in sarcoidosis. Lung biology in health and disease—sarcoidosis, vol 210. Taylor and Francis Group, New YorkGoogle Scholar
  23. Chen ES, Moller DR (2008) Etiology of sarcoidosis. Clin Chest Med 29:365–377PubMedGoogle Scholar
  24. Chen ES, Wahlström J, Song Z, Willett MH, Wikén M, Yung RC, West EE, McDyer JF, Zhang Y, Eklund A, Grunewald J, Moller DR (2008) T cell responses to mycobacterial catalase-peroxidase profile a pathogenic antigen in systemic sarcoidosis. J Immunol 181:8784–8796PubMedGoogle Scholar
  25. Chen ES, Song Z, Willett MH, Heine S, Yung RC, Liu MC, Groshong SD, Zhang Y, Tuder RM, Moller DR (2010) Serum amyloid A regulates granulomatous inflammation in sarcoidosis through Toll-like receptor-2. Am J Respir Crit Care Med 181:360–373PubMedGoogle Scholar
  26. Chow S (2009) Non-invasive measurement of markers of oxidative stress in asbestos-related lung diseases and pulmonary fibrosis. PhD thesis, Department of Pathology, University of New South Wales, SydneyGoogle Scholar
  27. Cowling DC, Quaglino D, Barrett PKM (1964) Effect of Kveim antigen and old tuberculin on lymphocytes in culture from sarcoid patients. Br Med J 1(5396):1481–1482PubMedGoogle Scholar
  28. Crystal R (2005) Sarcoidosis. Harrison’s principles of internal medicine. McGraw-Hill, New YorkGoogle Scholar
  29. Cummings MM (1964) An evaluation of the possible relationship of pine pollen to sarcoidosis (a critical summary). Acta Medica Scand 425(Supp):48–50Google Scholar
  30. de Silva RN, Will RG (1993) Moratorium on Kveim test. Lancet 342(8864):173PubMedGoogle Scholar
  31. Drake WP, Pei Z, Pride DT, Collins RD, Cover TL, Blaser MJ (2002) Molecular analysis of sarcoidosis tissues for Mycobacterium species DNA. Emerg Infect Dis 8(11):1334–1341PubMedGoogle Scholar
  32. Drake WP, Dhason MS, Nadaf M, Shepherd BE, Vadivelu S, Hajizadeh R, Newman LS, Kalams SA (2007) Cellular recognition of Mycobacterium tuberculosis ESAT-6 and KatG peptides in systemic sarcoidosis. Infect Immun 75(1):527–530PubMedGoogle Scholar
  33. Dubaniewicz A (2010) Mycobacterium tuberculosis heat shock proteins and autoimmunity in sarcoidosis. Autoimmun Rev 9(6):419–424PubMedGoogle Scholar
  34. Dubaniewicz A, Trzonkowski P, Dubaniewicz-Wybieralska M, Dubaniewicz A, Singh M, Mýsliwski A (2007) Mycobacterial heat shock protein-induced blood T lymphocytes subsets and cytokine pattern: comparison of sarcoidosis with tuberculosis and healthy controls. Respirology 12:346–354PubMedGoogle Scholar
  35. Edmé JL, Tellart AS, Launay D, Neviere R, Grutzmacher C, Boulenguez C, Labalette M, Hachulla E, Hatron PY, Dessaint JP, Matran R, Sobaszek A (2008) Cytokine concentrations in exhaled breath condensates in systemic sclerosis. Inflamm Res 57(4):151–156PubMedGoogle Scholar
  36. Eishi Y, Suga M, Ishige I, Kobayashi D, Yamada T, Takemura T, Takizawa T, Koike M, Kudoh S, Costabel U, Guzman J, Rizzato G, Gambacorta M, du Bois R, Nicholson AG, Sharma OP, Ando M (2002) Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis. J Clin Microbiol 40(1):198–204PubMedGoogle Scholar
  37. Eklund A, Blaschke E (1986) Elevated serum neopterin levels in sarcoidosis. Lung 164(6):325–332PubMedGoogle Scholar
  38. Facco M, Cabrelle A, Teramo A, Olivieri V, Gnoato M, Teolato S, Ave E, Gattazzo C, Fadini GP, Calabrese F, Semenzato G, Agostini C (2010) Sarcoidosis is a Th1/Th17 multisystem disorder. Thorax December 7 2010 (Epub ahead of print)Google Scholar
  39. Faehling M, Anders D, Hetzel M, Hombach V, Bachem M (2008) HGF and IL-6 in BAL fluid of interstitial lung diseases: effect on human lung fibroblasts. Eur Respir J Suppl 32(Supp 52):316SGoogle Scholar
  40. Foulon G, Wislez M, Naccache JM, Blanc FX, Rabbat A, Israël-Biet D, Valeyre D, Mayaud C, Cadranel J (2004) Sarcoidosis in HIV-infected patients in the era of highly active antiretroviral therapy. Clin Infect Dis 38(3):418–425PubMedGoogle Scholar
  41. Gazouli M, Ikonomopoulos J, Trigidou R, Foteinou M, Kittas C, Gorgoulis V (2002) Assessment of mycobacterial, propionibacterial, and human herpesvirus 8 DNA in tissues of Greek patients with sarcoidosis. J Clin Microbiol 40:3060–3063PubMedGoogle Scholar
  42. Gerke AK, Hunninghake G (2008) The immunology of sarcoidosis. Clin Chest Med 29(3):379–390PubMedGoogle Scholar
  43. Gronhagen-Riska C, Kurppa K, Fyhrquist F, Selroos O (1978) Angiotensin-converting enzyme and lysozyme in silicosis and asbestosis. Scand J Respir Dis 59(4):228–231PubMedGoogle Scholar
  44. Grosser M, Luther T, Muller J, Schuppler M, Brickhardt J, Matthiessen W, Muller M (1999) Detection of M. tuberculosis DNA in sarcoidosis: correlation with T-cell response. Lab Investig J Tech Methods Pathol 79(7):775–784Google Scholar
  45. Grunewald J, Eklund A (2007) Role of CD4+ T cells in sarcoidosis. Proc Am Thorac Soc 4(5):461–464PubMedGoogle Scholar
  46. Grunewald J, Wahlström J, Berlin M, Wigzell H, Eklund A, Olerup O (2002) Lung restricted T cell receptor AV2S3+ CD4+ T cell expansions in sarcoidosis patients with a shared HLA-DRbeta chain conformation. Thorax 57:348–352PubMedGoogle Scholar
  47. Grunewald J, Brynedal B, Darlington P, Nisell M, Cederlund K, Hillert J, Eklund A (2010) Different HLA-DRB1 allele distributions in distinct clinical subgroups of sarcoidosis patients. Respir Res 11:25–31PubMedGoogle Scholar
  48. Gupta SK, Chakraborty M, Mitra K (1992) Serum angiotensin converting enzyme in respiratory diseases. Indian J Chest Dis Allied Sci 34(1):19–24PubMedGoogle Scholar
  49. Gupta D, Agarwal R, Agarwal AN, Jindal SK (2007) Molecular evidence for the role of mycobacteria in sarcoidosis: a meta-analysis. Eur Respir J 30(3):508–516PubMedGoogle Scholar
  50. Gurrieri C, Bortoli M, Brunetta E, Piazza F, Agostini C (2005) Cytokines, chemokines and other biomolecular markers in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 22(Supp 1):S9–S14PubMedGoogle Scholar
  51. Hajizadeh R, Sato H, Carlisle J, Nadaf MT, Evans W, Shepherd BE, Miller RF, Kalams SA, Drake WP (2007) Mycobacterium tuberculosis antigen 85A induces Th-1 immune responses in systemic sarcoidosis. J Clin Immunol 27(4):445–454PubMedGoogle Scholar
  52. Hauber H, Gholami D, Meyer A, Pforte A (2003) Increased interleukin-13 expression in patients with sarcoidosis. Thorax 58(6):519–524PubMedGoogle Scholar
  53. Hill TA, Lightman S, Pantelidis P, Abdallah A, Spagnolo P, du Bois RM (2008) Intracellular cytokine profiles and T cell activation in pulmonary sarcoidosis. Cytokine 42:289–292PubMedGoogle Scholar
  54. Homolka J, Lorenz J, Zuchold HD, Müller-Quernheim J (1992) Evaluation of soluble CD 14 and neopterin as serum parameters of the inflammatory activity of pulmonary sarcoidosis. Clin Investig 70(10):909–916PubMedGoogle Scholar
  55. Hörster R, Kirsten D, Gaede KI, Jafari C, Strassburg A, Greinert U, Kalsdorf B, Ernst M, Lange C (2009) Antimycobacterial immune responses in patients with pulmonary sarcoidosis. Clin Respir J 3(4):229–238PubMedGoogle Scholar
  56. Horváth I, Hunt J, Barnes PJ (2005) Exhaled breath condensate: methodological recommendations and unresolved questions. Eur Respir J 26(3):523–548PubMedGoogle Scholar
  57. Horváth I, Lázár Z, Gyulai N, Kollai M, Losonczy G (2009) Exhaled biomarkers in lung cancer. Eur Respir J 34(1):261–275PubMedGoogle Scholar
  58. Husain AN (2010) The lung. In: Kumar V, Abbas AK, Fausto N, Aster JC (eds) Robbins and Cotran Pathologic basis of disease, 8th edn. Elsevier Saunders, PhiladelphiaGoogle Scholar
  59. Iannuzzi MC, Maliarik M, Poisson LM, Rybicki BA (2003) Sarcoidosis susceptibility and resistance HLA-DQB1 alleles in African Americans. Am J Respir Crit Care Med 167:1225–1231PubMedGoogle Scholar
  60. Iannuzzi MC, Maliarik M, Rybicki BA (2006) Genetics of sarcoidosis. lung biology in health and disease—sarcoidosis, vol 210. Taylor and Francis Group, New YorkGoogle Scholar
  61. Iannuzzi MC, Rybicki BA, Teirstein AS (2007) Sarcoidosis. N Engl J Med 357(21):2153–2165PubMedGoogle Scholar
  62. Idali F, Wikén M, Wahlstrom J, Mellstedt H, Eklund A, Rabbani H, Grunewald J (2006) Reduced Th1 response in the lungs of HLA-DRB1*0301 patients with pulmonary sarcoidosis. Eur Respir J 27:451–459PubMedGoogle Scholar
  63. Iida KKJ, Kawakami K, Matsubara Y, Shirai R, Kohno S (1997) Analysis of T cell subsets and β chemokines in patients with pulmonary sarcoidosis. Thorax 52:431–437PubMedGoogle Scholar
  64. Inui N, Chida K, Suda T, Nakamura H (2001) TH1/TH2 and TC1/TC2 profiles in peripheral blood and bronchoalveolar lavage fluid cells in pulmonary sarcoidosis. J Allergy Clin Immunol 107(2):337–344PubMedGoogle Scholar
  65. Ishige I, Eishi Y, Takemura T, Kobayashi I, Nakata K, Tanaka I, Nagaoka S, Iwai K, Watanabe K, Takizawa T, Koike M (2005) 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 22(1):33–42PubMedGoogle Scholar
  66. Izumi T, Nilsson BS, Ripe E (1973) In vitro lymphocyte reactivity to different Kveim preparations in patients with sarcoidosis. Scand J Respir Dis 54(2):123–127PubMedGoogle Scholar
  67. Jackson AS, Sandrini A, Campbell C, Chow S, Thomas PS, Yates DH (2007) Comparison of biomarkers in exhaled breath condensate and bronchoalveolar lavage. Am J Respir Crit Care Med 175:222–227PubMedGoogle Scholar
  68. Jamaati H, Mansoori S, Najafizadeh K, Mohammadi F, Masjedi M, Entezami Z, Shahgasempour S (2003) T-lymphocyte subsets in bronchoalveolar lavage: a flow cytometric analysis and its importance in the differential diagnosis of sarcoidosis. Arch Iran Med 6(3):204–207Google Scholar
  69. James GD, Williams WJ (1991) Kveim–Siltzbach test revisited. Sarcoidosis 8(1):6–9PubMedGoogle Scholar
  70. Kataria YP (2006) 8. The Kveim–Siltzbach skin test. Lung biology in health and disease—sarcoidosis, vol 210. Taylor and Francis Group, New YorkGoogle Scholar
  71. Katchar K, Wahlström J, Eklund A, Grunewald J (2001) Highly activated T-cell receptor AV2S3(+) CD4(+) lung T-cell expansions in pulmonary sarcoidosis. Am J Respir Crit Care Med 163(7):1540–1545PubMedGoogle Scholar
  72. Katchar K, Eklund A, Grunewald J (2003) Expression of Th1 markers by lung accumulated T cells in pulmonary sarcoidosis. J Intern Med 254:564–571PubMedGoogle Scholar
  73. Kharitonov SA, Barnes PJ (2001) Exhaled markers of pulmonary disease. Am J Respir Crit Care Med 163:1693–1722PubMedGoogle Scholar
  74. Klein JT, Horn TD, Forman JD, Silver RF, Teirstein AS, Moller DR (1995) Selection of oligoclonal Vβ-specific T cells in the intradermal response to Kveim–Siltzbach reagent in individuals with sarcoidosis. J Immunol 154:1450–1460PubMedGoogle Scholar
  75. Klemen H, Husain AN, Cagle PT, Garrity ER, Popper HH (2000) Mycobacterial DNA in recurrent sarcoidosis in the transplanted lung—a PCR-based study on four cases. Virchows Arch 436(4):365–369PubMedGoogle Scholar
  76. Kon OM, du Bois RM (1997) Mycobacteria and sarcoidosis. Thorax 52(Suppl 3):S47–S51PubMedGoogle Scholar
  77. Kowalska A, Puścińska E, Czerniawska J, Goljan-Geremek A, Czystowska M, Roży A, Chorostowska-Wynimko J, Górecka D (2010) Markers of fibrosis and inflammation in exhaled breathcondensate (EBC) and bronchoalveolar lavage fluid (BALF) of patients with pulmonary sarcoidosis- a pilot study. Pneumonol Alergol Pol 78(5):356–362 (Polish)PubMedGoogle Scholar
  78. Krawczyk A (2006) Immunopathogenesis of sarcoidosis. Int Rev Allergol Clin Immunol 12(2):80–84Google Scholar
  79. Kreiss K, Newman LS, Mroz MM, Campbell PA (1989) Screening blood test identifies subclinical beryllium disease. J Occup Med 31(7):603–608PubMedGoogle Scholar
  80. Kruit A, Grutters JC, Ruven HJT, van Moorsel CHM, Weiskirchen R, Mengsteab S, van den Bosch JMM (2006) Transforming growth factor-β gene polymorphisms in sarcoidosis patients with and without fibrosis. Chest 129:1584–1591PubMedGoogle Scholar
  81. Kunisawa A, Kawanishi Y, Tago H, Nagate A, Kasuga I, Ohyashiki K (2002) Direct demonstration of the productive capability of cytokines at the single cell level in lung sarcoidosis using multicolour cytometry. Respiration 69:155–164PubMedGoogle Scholar
  82. Kurti V, Mankiewicz E (1972) In vitro study of macrophages from patients with sarcoidosis. Can Med Assoc J 107(6):509–515PubMedGoogle Scholar
  83. Kveim A (1941) En ny og spesifikk kutan-reaksjon ved Boeck’s sarcoid. Nordisk Medicin 9:169–172Google Scholar
  84. Kwiatkowska S, Luczynska M, Grzelewska-Rzymowska I, Nowak D, Zieba M (2005) Comparison of oxidative stress markers in exhaled breath condensate and in serum of patients with tuberculosis and sarcoidosis. Polski Merkuriusz Lekarski 19(109):37–40 (Polish)PubMedGoogle Scholar
  85. Lazarus A (2009) Sarcoidosis: epidemiology, etiology, pathogenesis, and genetics. Dis Month 55:649–660Google Scholar
  86. Lebbe C, Agbalika F, Flageul B, Pellet C, Rybojad M, Cordoliani F, Farge D, Vignon-Pennamen MD, Sheldon J, Morel P, Calvo F, Schulz TF (1999) No evidence for the role of human herpesvirus type 8 in sarcoidosis: molecular and serological analysis. Br J Dermatol 141:492–496PubMedGoogle Scholar
  87. Lenner R, Bregman Z, Teirstein AS, DePalo L (2001) Recurrent pulmonary sarcoidosis in HIV-infected patients receiving highly active antiretroviral therapy. Chest 119(3):978–981PubMedGoogle Scholar
  88. Li N, Bajoghli A, Kubba A, Bhawan J (1999) Identification of mycobacterial DNA in cutaneous lesions in sarcoidosis. J Cutan Pathol 26:271–278PubMedGoogle Scholar
  89. Li Y, Wollnik B, Pabst S, Lennarz M, Rohmann E, Gillissen A, Vetter H, Grohé C (2006) BTNL2 gene variant and sarcoidosis. Thorax 61:273–274PubMedGoogle Scholar
  90. Lieberman J, Beutler E (1976) Elevation of serum angiotensin-converting enzyme in Gaucher’s disease. N Engl J Med 294(26):1442–1444PubMedGoogle Scholar
  91. Lien E, Ingalls R (2002) Toll-like receptors. Crit Care Med 30(1 Supp):S1–S11Google Scholar
  92. Lindahl M, Andersson O, Ripe E, Holm G (1988) Stimulation of bronchoalveolar (BAL) and blood lymphocytes by Kveim antigen, tuberculin, and concanavalin A in sarcoidosis. Br Dis Chest 82(4):386–393Google Scholar
  93. Lisby G, Milman N, Jacobsen GK (1993) Search for Mycobacterium paratuberculosis DNA in tissue from patients with sarcoidosis by enzymatic gene amplification. Acta Pathol Microbiol Immunol Scand 101(11):876–878Google Scholar
  94. Lyons DJ, Mitchell EB, Mitchell DN (1991) Sarcoidosis: in search of Kveim reactivity in vitro. Biomed Pharmacother 45(4–5):187–192PubMedGoogle Scholar
  95. Lyons DJ, Donald S, Mitchell DN, Asherson GL (1992) Chemical inactivation of the Kveim reagent. Respiration 59:22–26PubMedGoogle Scholar
  96. Martinetti M, Luisetti M, Cuccia M (2002) HLA and sarcoidosis: new pathogenetic insights. Sarcoidosis Vasc Diffuse Lung Dis 19(2):83–95PubMedGoogle Scholar
  97. Mathew S, Bauer KL, Fischoeder A, Bhardwaj N, Oliver SJ (2008) The anergic state in sarcoidosis is associated with diminished dendritic cell function. J Immunol 181:746–755PubMedGoogle Scholar
  98. McGuire-Gray C, Sinha R, Iyengar S, Millard C, Rybicki BA, Elston RC, Iannuzzi MC (2006) Genetic characterization and fine mapping of susceptibility loci for sarcoidosis in African Americans on chromosome 5. Hum Genet 120(3):420–430Google Scholar
  99. Medica I, Kastrin A, Maver A, Peterlin B (2007) Role of genetic polymorphisms in ACE and TNF-α gene in sarcoidosis: a meta-analysis. J Hum Genet 52(10):836–847PubMedGoogle Scholar
  100. Meloni F, Solari N, Cavagna L, Morosini M, Montecucco CM, Fietta AM (2009) Frequency of Th1, Th2 and Th17 producing T lymphocytes in bronchoalveolar lavage of patients with systemic sclerosis. Clin Exp Rheumatol 27(5):765–772PubMedGoogle Scholar
  101. Milman N (2006) From mycobacteria to sarcoidosis—is the gate still open? Respiration 73:14–15PubMedGoogle Scholar
  102. Miyara M, Amoura Z, Parizot C, Badoual C, Dorgham K, Trad S, Kambouchner M, Valeyre D, Chapelon-Abric C, Piette Debré J, Gorochov G (2006) The immune paradox of sarcoidosis and regulatory T cells. J Exp Med 203(2):359–370PubMedGoogle Scholar
  103. Moller DR (1999) Cells and cytokines involved in the pathogenesis of sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 16(1):24–31PubMedGoogle Scholar
  104. Moller DR (2003) Pulmonary fibrosis of sarcoidosis: new approaches, old ideas. Am J Respir Cell Mol Biol 29:S37–S41PubMedGoogle Scholar
  105. Möllers M, Aries SP, Drömann D, Mascher B, Braun J, Dalhoff K (2001) Intracellular cytokine repertoire in different T cell subsets from patients with sarcoidosis. Thorax 56:487–493PubMedGoogle Scholar
  106. Montuschi P, Barnes PJ (2002) Analysis of exhaled breath condensate for monitoring airway inflammation. Trends Pharmacol Sci 23(5):232–237PubMedGoogle Scholar
  107. Müller-Quernheim J (1998) Sarcoidosis: immunopathogenetic concepts and their clinical application. Eur Respir J 12:716–738PubMedGoogle Scholar
  108. Mutlu GM, Garey KW, Robbins RA, Danziger LH, Rubinstein I (2001) Collection and analysis of exhaled breath condensate in humans. Am J Respir Crit Care Med 164:731–737PubMedGoogle Scholar
  109. Nayeri F, Millinger E, Nilsson I, Zetterström Brudin L, Forsberg P (2002) Exhaled breath condensate and serum levels of hepatocyte growth factor in pneumonia. Respir Med 96(2):115–119PubMedGoogle Scholar
  110. Newman LS, Orton R, Kreiss K (1992) Serum angiotensin converting enzyme activity in chronic beryllium disease. Am Rev Respir Dis 146(1):39–42PubMedGoogle Scholar
  111. Newman LS, Rose CS, Bresnitz EA, Rossman MD, Barnard J, Frederick M, Terrin ML, Weinberger SE, Moller DR, McLennan G, Hunninghake G, DePalo L, Baughman RP, Iannuzzi MC, Judson MA, Knatterud GL, Thompson BW, Teirstein AS, Yeager H Jr, Johns CJ, Rabin DL, Rybicki BA, Cherniack R, ACCESS Research Group (2004) A case control etiologic study of sarcoidosis—environmental and occupational risk factors. Am J Respir Crit Care Med 170:1324–1330PubMedGoogle Scholar
  112. Noor A, Knox KS (2007) Immunopathogenesis of sarcoidosis. Clin Dermatol 25:250–258PubMedGoogle Scholar
  113. Nureki S, Miyazaki E, Ando M, Ueno T, Fukami T, Kumamoto T, Sugisaki K, Tsuda T (2008) Circulating levels of both Th1 and Th2 chemokines are elevated in patients with sarcoidosis. Respir Med 102:239–247PubMedGoogle Scholar
  114. Oswald-Richter K, Culver DA, Hawkins C, Hajizadeh R, Abraham S, Shepherd BE, Jenkins CA, Judson MA, Drake WP (2009) Cellular responses to mycobacterial antigens are present in bronchoalveolar lavage fluid used in the diagnosis of sarcoidosis. Infect Immun 77(9):3740–3748PubMedGoogle Scholar
  115. Oswald-Richter K, Sato H, Hajizadeh R, Shepherd BE, Sidney J, Sette A, Newman LS, Drake WP (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 30:157–166PubMedGoogle Scholar
  116. Ota M, Amakawa R, Uehira K, Ito T, Yagi Y, Oshiro A, Date Y, Oyaizu H, Shigeki T, Ozaki Y, Yamaguchi K, Uemura Y, Yonezu S, Fukuhara S (2004) Involvement of dendritic cells in sarcoidosis. Thorax 59:408–413PubMedGoogle Scholar
  117. Parrish S, Turner JF (2009) Diagnosis of sarcoidosis. Dis Month 55(11):693–703Google Scholar
  118. Petrek M, Gibejova A, Drabek J, Mrazek F, Kolek V, Weigl E, du Bois RM (2002) CC chemokine receptor 5 (CCR5) mRNA expression in pulmonary sarcoidosis. Immunol Lett 80(3):189–193PubMedGoogle Scholar
  119. Petrek M, Kriegova E, Fillerova R, Arakelyan A, Mrazek F, Hutyrova B, Kolek V, du Bois RM (2009) Chemokine network in pulmonary sarcoidosis. Am J Respir Crit Care Med 179(1):A3186Google Scholar
  120. Piotrowski WJ, Antczak A, Marczak J, Nawrocka A, Kurmanowska Z, Górski P (2007) Eicosanoids in exhaled breath condensate and BAL fluid of patients with sarcoidosis. Chest 132:589–596PubMedGoogle Scholar
  121. Piotrowski WJ, Kurmanowska Z, Antczak A, Marczak J, Górski P (2010a) Exhaled 8-isoprostane as a prognostic marker in sarcoidois. A short-term follow-up. BMC Pulm Med 10:23–29PubMedGoogle Scholar
  122. Piotrowski WJ, Kurmanowska Z, Antczak A, Marczak J, Górski P (2010b) Hepatocyte growth factor in exhaled breath and BAL fluid in sarcoidosis. Pneumonol Alergol Pol 78(3):187–191PubMedGoogle Scholar
  123. Planck A, Katchar K, Eklund A, Gripenback S, Grunenwald J (2003) T-lymphocyte activity in HLA-DR17 positive patients with active and clinically recovered sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 20:110–117PubMedGoogle Scholar
  124. Prasse A, Georges CG, Biller H, Hamm H, Matthys H, Luttmann W, Virchow JC Jr (2000) Th1 cytokine pattern in sarcoidosis is expressed by bronchoalveolar CD4+ and CD8+ T cells. Clin Exp Immunol 122:241–248PubMedGoogle Scholar
  125. Psathakis K, Papatheodorou G, Plataki M, Panagou P, Loukides S, Siafakas NM, Bouros D (2004) 8-Isoprostane, a marker of oxidative stress, is increased in the expired breath condensate of patients with pulmonary sarcoidosis. Chest 125:1005–1011PubMedGoogle Scholar
  126. Robinson BW, McLemore TL, Crystal RG (1985) Gamma interferon is spontaneously released by alveolar macrophages and lung T lymphocytes in patients with pulmonary sarcoidosis. J Clin Investig 75(5):1488–1495PubMedGoogle Scholar
  127. Robroeks CM, Rijkers GT, Jöbsis Q, Hendriks HJ, Damoiseaux JG, Zimmermann LJ, van Schayck OP, Dompeling E (2010) Increased cytokines, chemokines and soluble adhesion molecules in exhaled breath condensate of asthmatic children. Clin Exp Allergy 40(1):77–84PubMedGoogle Scholar
  128. Rossman MD, Kreider ME (2003) Is chronic beryllium disease sarcoidosis of known etiology? Sarcoidosis Vasc Diffuse Lung Dis 20:104–109PubMedGoogle Scholar
  129. Rottoli P, Magi B, Perari MG, Liberatori S, Nikiforakis N, Bargagli E, Cianti R, Bini L, Pallini V (2005) Cytokine profile and proteome analysis in bronchoalveolar lavage of patients with sarcoidosis, pulmonary fibrosis associated with systemic sclerosis and idiopathic pulmonary fibrosis. Proteomics 5:1423–1430PubMedGoogle Scholar
  130. Rożyi ACJ, Stępniewska A, Woźbińska B, Goljan A, Puścińska E, Górecka D, Chorostowska-Wynimko J (2006) Inflammatory markers in the exhaled breath condensate of patients with pulmonary sarcoidosis. J Physiol Pharmacol 57(4):335–340Google Scholar
  131. Rybicki BA, Maliarik MJ, Major M, Popovich J Jr, Iannuzzi MC (1997) Genetics of sarcoidosis. Clin Chest Med 18:707–717PubMedGoogle Scholar
  132. Rybicki BA, Walewski JL, Maliarik MJ, Kian H, Iannuzzi MC (2005) The BTNL2 gene and sarcoidosis susceptibility in African Americans and whites. Am J Hum Genet 77(3):491–499PubMedGoogle Scholar
  133. Saboor SA, Johnson NM, McFadden J (1992) Detection of mycobacterial DNA in sarcoidosis and tuberculosis with polymerase chain reaction. Lancet 339:1012–1015PubMedGoogle Scholar
  134. Salez F, Gosset P, Copin MC, Degros CL, Tonnel AB, Wallaert B (1998) Transforming growth-factor β1 in sarcoidosis. Eur Respir J 12:913–919PubMedGoogle Scholar
  135. Sato H, Grutters JC, Pantelidis P, Mizzon AN, Ahmad T, Van Houte AJ, Lammers JW, Van Den Bosch JM, Welsh KI, Du Bois RM (2002) HLA-DQB1*0201: a marker for good prognosis in British and Dutch patients with sarcoidosis. Am J Respir Cell Mol Biol 27(4):406–412PubMedGoogle Scholar
  136. Schürmann M, Kwiatkowski R, Albrecht M, Fischer A, Hampe J, Müller-Quernheim J, Schwinger E, Schreiber S (2008) Study of Toll-like receptor gene loci in sarcoidosis. Clin Exp Immunol 152:413–431Google Scholar
  137. Semenzato G (2005) ACCESS: a case control etiologic study of sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 22(2):83–86PubMedGoogle Scholar
  138. Shahid SK, Kharitonov SA, Wilson NM, Bush A, Barnes PJ (2002) Increased interleukin-4 and decreased interferon-gamma in exhaled breath condensate of children with asthma. Am J Respir Crit Care Med 165(9):1290–1293PubMedGoogle Scholar
  139. Siltzbach LE (1961) The Kveim test in sarcoidosis: a study of 750 patients. J Am Med Assoc 178:476–482Google Scholar
  140. Siltzbach LE (1967) An international Kveim test study in sarcoidosis. In: Proceedings of the fourth international conference on sarcoidosis, Mason, ParisGoogle Scholar
  141. Smallridge RC, Rogers J, Verma PS (1983) Serum angiotensin-converting enzyme: alterations in hyperthyroidism, hypothyroidism and subacute thyroiditis. J Am Med Assoc 250:2489–2493Google Scholar
  142. Smith G, Brownell I, Sanchez M, Prystowski S (2008) Advances in the genetics of sarcoidosis. Clin Genet 73:401–412PubMedGoogle Scholar
  143. Song Z, Marzilli L, Greenlee BM, Chen ES, Silver RF, Askin FB, Teirstein AS, Zhang Y, Cotter RJ, Moller DR (2005) Mycobacterial catalase–peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis. J Exp Med 201(5):755–767PubMedGoogle Scholar
  144. Spagnalo P, Sato H, Grunewald J, Brynedal B, Hillert J, Mana J, Wells AU, Eklund A, Welsh KI, du Bois RM (2008) A common haplotype of the C-C chemokine receptor 2 gene and HLA-DRB1*-0301 are independent genetic risk factors for Löfgren’s syndrome. J Intern Med 264(5):433–441Google Scholar
  145. Takeuchi M, Oh-i K, Suzuki J, Hattori T, Takeuchi A, Okunuki Y, Usui Y, Usui M (2006) Elevated serum levels of CXCL9/monokine induced by interferon-γ and CXCL10/interferon-γ-inducible protein 10 in ocular sarcoidosis. Investig Ophthalmol Vis Sci 47(3):1063–1068Google Scholar
  146. Teirstein AS (1986) The Kveim–Siltzbach test. Clin Dermatol 4(4):154–164PubMedGoogle Scholar
  147. Thomas KW, Hunninghake GW (2006) Sarcoidosis: the search for a potential pathogen. Lung biology in health and disease—sarcoidosis, vol 210. Taylor and Francis Group, New YorkGoogle Scholar
  148. Tsiligianni I, Antoniou KM, Kyriakou D, Tzanakis N, Chrysofakis G, Siafakas NM, Bouros D (2005) Th1/Th2 cytokine pattern in bronchoalveolar lavage fluid and induced sputum in pulmonary sarcoidosis. BMC Pulm Med 5:8–13PubMedGoogle Scholar
  149. Uhlar CM, Whitehead AS (1999) Serum amyloid A, the major vertebrate acute-phase reactant. Eur J Biochem 265:501–523PubMedGoogle Scholar
  150. Valentonyte R, Hampe J, Huse K, Rosenstiel P, Albrecht M, Stenzel A, Nagy M, Gaede KI, Franke A, Haesler R, Koch A, Lengauer T, Seegert D, Reiling N, Ehlers S, Schwinger E, Platzer M, Krawczak M, Müller-Quernheim J, Schürmann M, Schreiber S (2005) Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat Genet 37(4):357–364PubMedGoogle Scholar
  151. Vokurka M, Lecoissier D, du Bois RM, Wallaert B, Kambouchner M, Tazi A, Hance AJ (1997) Absence of DNA from mycobacteria of the M. tuberculosis complex in sarcoidosis. Am J Respir Crit Care Med 156:1000–1003PubMedGoogle Scholar
  152. Voorter CE, Drent M, van den Berg-Loonen EM (2005) Severe pulmonary sarcoidosis is strongly associated with the haplotype HLA-DQB1*0602-DRB1*150101. Hum Immunol 66:826–835PubMedGoogle Scholar
  153. Wahlström J, Berlin M, Sköld CM, Wigzell H, Eklund A, Grunewald J (1999) Phenotypic analysis of lymphocytes and monocytes/macrophages in peripheral blood and bronchoalveolar lavage fluid from patients with pulmonary sarcoidosis. Thorax 54:339–346PubMedGoogle Scholar
  154. Wahlström J, Katchar K, Wigzell H, Olerup O, Eklund A, Grunewald J (2001) Analysis of intracellular cytokines in CD4+ and CD8+ lung and blood T cells in sarcoidosis. Am J Respir Crit Care Med 163:115–121PubMedGoogle Scholar
  155. Wahlström J, Dengjel J, Persson B, Duyar H, Rammensee HG, Stevanović S, Eklund A, Weissert R, Grunewald J (2007) Identification of HLA-DR-bound peptides presented by human bronchoalveolar lavage cells in sarcoidosis. J Clin Invest 117(11):3576–3582PubMedGoogle Scholar
  156. Wahlström J, Dengjel J, Winqvist O, Targoff I, Persson B, Duyar H, Rammensee H, Eklund A, Weissert R, Grunewald J (2009) Autoimmune T cell responses to antigenic peptides presented to bronchoalveolar lavage HLA-DR molecules in sarcoidosis. J Clin Immunol 133:353–363Google Scholar
  157. Warren HS (2005) Toll-like receptors. Crit Care Med 33(12):S457–S459PubMedGoogle Scholar
  158. Wikén M, Idali F, Al Hayja MA, Grunewald J, Eklund A, Wahlström J (2010) No evidence of altered alveolar macrophage polarization, but reduced expression of TLR2 in bronchoalveolar lavage cells in sarcoidosis. Respir Res 11(1):121–133PubMedGoogle Scholar
  159. Williams WJ, Price CD, Pugh A, Dighero M (1977) In vitro (KMIF) Test. Zeitschrift für Erkrankungen der Atmungsorgane 149(2):226–230PubMedGoogle Scholar
  160. Wilsher ML, Hallowes M, Birchall NM (1996) Gamma/delta cells in tissue from patients with sarcoidosis. Thorax 51:1123–1126PubMedGoogle Scholar
  161. Winterbauer RH, Lammert J, Selland M, Wu R, Corley D, Springmeyer SC (1977) Bronchoalveolar lavage cell populations in the diagnosis of sarcoidosis. Chest 104:352–361Google Scholar
  162. Zaba LC, Smith GP, Sanchez M, Prystowsky SD (2010) Dendritic cells in the pathogenesis of sarcoidosis. Am J Respir Cell Mol Biol 42:32–39PubMedGoogle Scholar
  163. Ziegenhagen MW, Müller-Quernheim J (2003) The cytokine network in sarcoidosis and its clinical relevance. J Intern Med 253:18–30PubMedGoogle Scholar
  164. Zissel G, Prasse A, Müller-Quernheim J (2007) Sarcoidosis—immunopathogenetic concepts. Semins Respir Crit Care Med 28(1):3–14Google Scholar

Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  • Hasib Ahmadzai
    • 1
    • 2
  • Denis Wakefield
    • 1
    • 3
  • Paul S. Thomas
    • 1
    • 2
  1. 1.Inflammation and Infection Research Centre, Faculty of MedicineUniversity of New South WalesSydneyAustralia
  2. 2.Department of Respiratory MedicinePrince of Wales HospitalRandwickAustralia
  3. 3.Immunology of the Eye Clinic, St. Vincent’s ClinicDarlinghurstAustralia

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