Immunologic Response of Sarcoidosis

ABSTRACT

Sarcoidosis is a chronic granulomatous disorder characterized by an accumulation of T lymphocytes, macrophages, and immune-effector cells within affected organs. The pathogenesis of sarcoidosis involves a complex interplay between immune and nonimmune cells, with myriad cytokines and chemokines involved in the orchestration and evolution of the granulomatous/fibrotic process. The etiology of sarcoidosis is not known, but a granulomatous response to antigen(s) is likely. Genetic polymorphisms influence the susceptibility to sarcoidosis as well as the evolution/prognosis of the disease among patients with sarcoidosis. This article discusses the complex immunological events and immune effector cells that are critical to the induction, evolution, and resolution of the sarcoid granulomatous response.

Sarcoidosis - granulomatous - innate immunity - macrophages - lymphocytes - dendritic cells

REFERENCES

• 1 Schürmann M. Genetics of sarcoidosis.  Semin Respir Crit Care Med. 2003;  24 213-222
• 2 Rybicki B A, Hirst K, Iyengar S K et al.. A sarcoidosis genetic linkage consortium: the sarcoidosis genetic analysis (SAGA) study.  Sarcoidosis Vasc Diffuse Lung Dis. 2005;  22 115-122
• 3 Müller-Quernheim J, Schürmann M, Hofmann S et al.. Genetics of sarcoidosis.  Clin Chest Med. 2008;  29 391-414, viii , 
• 4 Bianchi M E. DAMPs, PAMPs and alarmins: all we need to know about danger.  J Leukoc Biol. 2007;  81 1-5
• 5 Manfredi A A, Capobianco A, Bianchi M E, Rovere-Querini P. Regulation of dendritic- and T-cell fate by injury-associated endogenous signals.  Crit Rev Immunol. 2009;  29 69-86
• 6 Pechkovsky D V, Zalutskaya O M, Ivanov G I, Misuno N I. Calprotectin (MRP8/14 protein complex) release during mycobacterial infection in vitro and in vivo.  FEMS Immunol Med Microbiol. 2000;  29 27-33
• 7 Bargagli E, Olivieri C, Prasse A et al.. Calgranulin B (S100A9) levels in bronchoalveolar lavage fluid of patients with interstitial lung diseases.  Inflammation. 2008;  31 351-354
• 8 Veress B, Malmsköld K. The distribution of S100 and lysozyme immunoreactive cells in the various phases of granuloma development in sarcoidosis.  Sarcoidosis. 1987;  4 33-37
• 9 Ashitani J, Matsumoto N, Nakazato M. Elevated alpha-defensin levels in plasma of patients with pulmonary sarcoidosis.  Respirology. 2007;  12 339-345
• 10 Paone G, Lucantoni G, Leone A et al.. Human neutrophil peptides stimulate tumor necrosis factor-alpha release by alveolar macrophages from patients with sarcoidosis.  Chest. 2009;  135 586-587
• 11 Chen E S, Song Z, Willett M H et al.. Serum amyloid A regulates granulomatous inflammation in sarcoidosis through Toll-like receptor-2.  Am J Respir Crit Care Med. 2010;  181 360-373 , [Epub ahead of print]
• 12 Pechkovsky D V, Zissel G, Ziegenhagen M W et al.. Effect of proinflammatory cytokines on interleukin-8 mRNA expression and protein production by isolated human alveolar epithelial cells type II in primary culture.  Eur Cytokine Netw. 2000;  11 618-625
• 13 Larsen C G, Anderson A O, Oppenheim J J, Matsushima K. Production of interleukin-8 by human dermal fibroblasts and keratinocytes in response to interleukin-1 or tumour necrosis factor.  Immunology. 1989;  68 31-36
• 14 Sugiyama K, Mukae H, Ishii H et al.. Elevated levels of interferon gamma-inducible protein-10 and epithelial neutrophil-activating peptide-78 in patients with pulmonary sarcoidosis.  Respirology. 2006;  11 708-714
• 15 Ziegenhagen M W, Schrum S, Zissel G, Zipfel P F, Schlaak M, Müller-Quernheim J. Increased expression of proinflammatory chemokines in bronchoalveolar lavage cells of patients with progressing idiopathic pulmonary fibrosis and sarcoidosis.  J Investig Med. 1998;  46 223-231
• 16 Car B D, Meloni F, Luisetti M, Semenzato G, Gialdroni-Grassi G, Walz A. Elevated IL-8 and MCP-1 in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis.  Am J Respir Crit Care Med. 1994;  149(3 Pt 1) 655-659
• 17 Tutor-Ureta P, Citores M J, Castejón R et al.. Prognostic value of neutrophils and NK cells in bronchoalveolar lavage of sarcoidosis.  Cytometry B Clin Cytom. 2006;  70 416-422
• 18 Ziegenhagen M W, Rothe M E, Schlaak M, Müller-Quernheim J. Bronchoalveolar and serological parameters reflecting the severity of sarcoidosis.  Eur Respir J. 2003;  21 407-413
• 19 Borzì R M, Grigolo B, Meliconi R et al.. Elevated serum superoxide dismutase levels correlate with disease severity and neutrophil degranulation in idiopathic pulmonary fibrosis.  Clin Sci (Lond). 1993;  85 353-359
• 20 Rottoli P, Magi B, Cianti R et al.. Carbonylated proteins in bronchoalveolar lavage of patients with sarcoidosis, pulmonary fibrosis associated with systemic sclerosis and idiopathic pulmonary fibrosis.  Proteomics. 2005;  5 2612-2618
• 21 Lenz A G, Costabel U, Maier K L. Oxidized BAL fluid proteins in patients with interstitial lung diseases.  Eur Respir J. 1996;  9 307-312
• 22 Müller-Quernheim J, Pfeifer S, Männel D, Strausz J, Ferlinz R. Lung-restricted activation of the alveolar macrophage/monocyte system in pulmonary sarcoidosis.  Am Rev Respir Dis. 1992;  145 187-192
• 23 Ziegenhagen M W, Müller-Quernheim J. The cytokine network in sarcoidosis and its clinical relevance.  J Intern Med. 2003;  253 18-30
• 24 Wahlström J, Berlin M, Sköld C M, Wigzell H, Eklund A, Grunewald J. Phenotypic analysis of lymphocytes and monocytes/macrophages in peripheral blood and bronchoalveolar lavage fluid from patients with pulmonary sarcoidosis.  Thorax. 1999;  54 339-346
• 25 Bachwich P R, Lynch III J P, Larrick J W, Spengler M, Kunkel S L. Tumor necrosis factor production by human sarcoid alveolar macrophages.  Am J Pathol. 1986;  125 421-425
• 26 Wikén M, Grunewald J, Eklund A, Wahlström J. Higher monocyte expression of TLR2 and TLR4, and enhanced pro-inflammatory synergy of TLR2 with NOD2 stimulation in sarcoidosis.  J Clin Immunol. 2009;  29 78-89
• 27 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
• 28 Pathak S K, Basu S, Basu K K et al.. Direct extracellular interaction between the early secreted antigen ESAT-6 of Mycobacterium tuberculosis and TLR2 inhibits TLR signaling in macrophages.  Nat Immunol. 2007;  8 610-618
• 29 Murphy E E, Terres G, Macatonia S E et al.. B7 and interleukin 12 cooperate for proliferation and interferon γ production by mouse T helper clones that are unresponsive to B7 costimulation.  J Exp Med. 1994;  180 223-231
• 30 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
• 31 Grosser M, Dittert D D, Luther T. Re: Molecular detection of M. tuberculosis DNA in tuberculosis and sarcoidosis.  Diagn Mol Pathol. 2001;  10 66-68
• 32 Eishi Y, Suga M, Ishige I et al.. Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis.  J Clin Microbiol. 2002;  40 198-204
• 33 Hiramatsu J, Kataoka M, Nakata Y et al.. Propionibacterium acnes DNA detected in bronchoalveolar lavage cells from patients with sarcoidosis.  Sarcoidosis Vasc Diffuse Lung Dis. 2003;  20 197-203
• 34 Tanabe T, Ishige I, Suzuki Y et al.. Sarcoidosis and NOD1 variation with impaired recognition of intracellular Propionibacterium acnes.  Biochim Biophys Acta. 2006;  1762(9) 794-801
• 35 de Rochemonteix-Galve B, Dayer J M, Junod A F. Fibroblast-alveolar cell interactions in sarcoidosis and idiopathic pulmonary fibrosis: evidence for stimulatory and inhibitory cytokine production by alveolar cells.  Eur Respir J. 1990;  3(6) 653-664
• 36 Baughman R P, Strohofer S A, Buchsbaum J, Lower E E. Release of tumor necrosis factor by alveolar macrophages of patients with sarcoidosis.  J Lab Clin Med. 1990;  115 36-42
• 37 Zheng L, Teschler H, Guzman J, Hübner K, Striz I, Costabel U. Alveolar macrophage TNF-α release and BAL cell phenotypes in sarcoidosis.  Am J Respir Crit Care Med. 1995;  152 1061-1066
• 38 Fehrenbach H, Zissel G, Goldmann T et al.. Alveolar macrophages are the main source for tumour necrosis factor-alpha in patients with sarcoidosis.  Eur Respir J. 2003;  21 421-428
• 39 Hänsch H C, Smith D A, Mielke M E, Hahn H, Bancroft G J, Ehlers S. Mechanisms of granuloma formation in murine Mycobacterium avium infection: the contribution of CD4+ T cells.  Int Immunol. 1996;  8 1299-1310
• 40 Smith D, Hänsch H, Bancroft G, Ehlers S. T-cell-independent granuloma formation in response to Mycobacterium avium: role of tumour necrosis factor-alpha and interferon-gamma.  Immunology. 1997;  92 413-421
• 41 Lammas D A, De Heer E, Edgar J D et al.. Heterogeneity in the granulomatous response to mycobacterial infection in patients with defined genetic mutations in the interleukin 12-dependent interferon-gamma production pathway.  Int J Exp Pathol. 2002;  83 1-20
• 42 Pechkovsky D V, Goldmann T, Vollmer E, Müller-Quernheim J, Zissel G. Interleukin-18 expression by alveolar epithelial cells type II in tuberculosis and sarcoidosis.  FEMS Immunol Med Microbiol. 2006;  46 30-38
• 43 Shigehara K, Shijubo N, Ohmichi M et al.. IL-12 and IL-18 are increased and stimulate IFN-gamma production in sarcoid lungs.  J Immunol. 2001;  166 642-649
• 44 Moller D R, Forman J D, Liu M C et al.. Enhanced expression of IL-12 associated with Th1 cytokine profiles in active pulmonary sarcoidosis.  J Immunol. 1996;  156 4952-4960
• 45 Zissel G, Prasse A, Müller-Quernheim J. Sarcoidosis—immunopathogenetic concepts.  Semin Respir Crit Care Med. 2007;  28 3-14
• 46 Dustin M L. Coordination of T cell activation and migration through formation of the immunological synapse.  Ann N Y Acad Sci. 2003;  987 51-59
• 47 Yarbrough Jr W C, Wilkes D S, Weissler J C. Human alveolar macrophages inhibit receptor-mediated increases in intracellular calcium concentration in lymphocytes.  Am J Respir Cell Mol Biol. 1991;  5 411-415
• 48 Ettensohn D B, Lalor P A, Roberts Jr N J. Human alveolar macrophage regulation of lymphocyte proliferation.  Am Rev Respir Dis. 1986;  133 1091-1096
• 49 Lem V M, Lipscomb M F, Weissler J C et al.. Bronchoalveolar cells from sarcoid patients demonstrate enhanced antigen presentation.  J Immunol. 1985;  135 1766-1771
• 50 Venet A, Hance A J, Saltini C, Robinson B WS, Crystal R G. Enhanced alveolar macrophage-mediated antigen-induced T-lymphocyte proliferation in sarcoidosis.  J Clin Invest. 1985;  75 293-301
• 51 Ina Y, Takada K, Yamamoto M, Morishita M, Miyachi A. Antigen-presenting capacity in patients with sarcoidosis.  Chest. 1990;  98 911-916
• 52 Zissel G, Ernst M, Schlaak M, Müller-Quernheim J. Accessory function of alveolar macrophages from patients with sarcoidosis and other granulomatous and nongranulomatous lung diseases.  J Investig Med. 1997;  45 75-86
• 53 Poulter L W. Changes in lung macrophages during disease.  FEMS Microbiol Immunol. 1990;  2 327-331
• 54 Rossi G A, Zocchi E, Sacco O, Balbi B, Ravazzoni C, Damiani G. Alveolar macrophage stimulation of T-cell proliferation in autologous mixed lymphocyte reactions. Role of HLA-DR antigens.  Am Rev Respir Dis. 1986;  133 78-82
• 55 Berlin M, Fogdell-Hahn A, Olerup O, Eklund A, Grunewald J. HLA-DR predicts the prognosis in Scandinavian patients with pulmonary sarcoidosis.  Am J Respir Crit Care Med. 1997;  156 1601-1605
• 56 Martinetti M, Luisetti M, Cuccia M. HLA and sarcoidosis: new pathogenetic insights.  Sarcoidosis Vasc Diffuse Lung Dis. 2002;  19 83-95
• 57 Schürmann M, Bein G, Kirsten D, Schlaak M, Müller-Quernheim J, Schwinger E. HLA-DQB1 and HLA-DPB1 genotypes in familial sarcoidosis.  Respir Med. 1998;  92 649-652
• 58 Hoshino T, Itoh K, Gouhara R et al.. Spontaneous production of various cytokines except IL-4 from CD4+ T cells in the affected organs of sarcoidosis patients.  Clin Exp Immunol. 1995;  102 399-405
• 59 Nicod L P, Isler P, Isler P. Alveolar macrophages in sarcoidosis coexpress high levels of CD86 (B7.2), CD40, and CD30L.  Am J Respir Cell Mol Biol. 1997;  17 91-96
• 60 Kaneko Y, Kuwano K, Kunitake R et al.. Immunohistochemical localization of B7 costimulating molecules and major histocompatibility complex class II antigen in pulmonary sarcoidosis.  Respiration. 1999;  66 343-348
• 61 Agostini C, Trentin L, Perin A et al.. Regulation of alveolar macrophage-T cell interactions during Th1-type sarcoid inflammatory process.  Am J Physiol. 1999;  277(2 Pt 1) L240-L250
• 62 Zissel G, Ernst M, Schlaak M, Müller-Quernheim J. Pharmacological modulation of the IFNgamma-induced accessory function of alveolar macrophages and peripheral blood monocytes.  Inflamm Res. 1999;  48 662-668
• 63 Nicod L P, el Habre F. Adhesion molecules on human lung dendritic cells and their role for T-cell activation.  Am J Respir Cell Mol Biol. 1992;  7 207-213
• 64 Nguyen T, Liu X K, Zhang Y, Dong C. BTNL2, a butyrophilin-like molecule that functions to inhibit T cell activation.  J Immunol. 2006;  176 7354-7360
• 65 Valentonyte R, Hampe J, Huse K et al.. Sarcoidosis is associated with a truncating splice site mutation in BTNL2.  Nat Genet. 2005;  37 357-364
• 66 Li Y, Wollnik B, Pabst S et al.. BTNL2 gene variant and sarcoidosis.  Thorax. 2006;  61 273-274
• 67 Rybicki B A, Walewski J L, Maliarik M J, Kian H, Iannuzzi M C. ACCESS Research Group . The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites.  Am J Hum Genet. 2005;  77 491-499
• 68 Gordon S. Alternative activation of macrophages.  Nat Rev Immunol. 2003;  3 23-35
• 69 Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization.  Trends Immunol. 2004;  25 677-686
• 70 Prasse A, Pechkovsky D V, Toews G B et al.. A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18.  Am J Respir Crit Care Med. 2006;  173 781-792
• 71 Bargagli E, Margollicci M, Luddi A et al.. Chitotriosidase activity in patients with interstitial lung diseases.  Respir Med. 2007;  101 2176-2181
• 72 Bargagli E, Bianchi N, Margollicci M et al.. Chitotriosidase and soluble IL-2 receptor: comparison of two markers of sarcoidosis severity.  Scand J Clin Lab Invest. 2008;  68 479-483
• 73 Lommatzsch M, Bratke K, Bier A et al.. Airway dendritic cell phenotypes in inflammatory diseases of the human lung.  Eur Respir J. 2007;  30 878-886
• 74 Munro C S, Campbell D A, Du Bois R M, Mitchell D N, Cole P J, Poulter L W. Dendritic cells in cutaneous, lymph node and pulmonary lesions of sarcoidosis.  Scand J Immunol. 1987;  25 461-467
• 75 van Haarst J M, Verhoeven G T, de Wit H J, Hoogsteden H C, Debets R, Drexhage H A. CD1a+ and CD1a− accessory cells from human bronchoalveolar lavage differ in allostimulatory potential and cytokine production.  Am J Respir Cell Mol Biol. 1996;  15 752-759
• 76 Mathew S, Bauer K L, Fischoeder A, Bhardwaj N, Oliver S J. The anergic state in sarcoidosis is associated with diminished dendritic cell function.  J Immunol. 2008;  181 746-755
• 77 Kulakova N, Urban B, McMichael A J, Ho L P. Functional analysis of dendritic cell-T cell interaction in sarcoidosis.  Clin Exp Immunol. 2010;  159 82-86
• 78 Gibejova A, Mrazek F, Subrtova D et al.. Expression of macrophage inflammatory protein-3 beta/CCL19 in pulmonary sarcoidosis.  Am J Respir Crit Care Med. 2003;  167 1695-1703
• 79 Facco M, Baesso I, Miorin M et al.. Expression and role of CCR6/CCL20 chemokine axis in pulmonary sarcoidosis.  J Leukoc Biol. 2007;  82 946-955
• 80 Holter J F, Park H K, Sjoerdsma K W, Kataria Y P. Nonviable autologous bronchoalveolar lavage cell preparations induce intradermal epithelioid cell granulomas in sarcoidosis patients.  Am Rev Respir Dis. 1992;  145(4 Pt 1) 864-871
• 81 Katchar K, Söderström K, Wahlstrom J, Eklund A, Grunewald J. Characterisation of natural killer cells and CD56+ T-cells in sarcoidosis patients.  Eur Respir J. 2005;  26 77-85
• 82 Robinson B W, Pinkston P, Crystal R G. Natural killer cells are present in the normal human lung but are functionally impotent.  J Clin Invest. 1984;  74 942-950
• 83 Du Bois R M, Kirby M, Balbi B, Saltini C, Crystal R G. T-lymphocytes that accumulate in the lung in sarcoidosis have evidence of recent stimulation of the T-cell antigen receptor.  Am Rev Respir Dis. 1992;  145 1205-1211
• 84 Müller-Quernheim J, Saltini C, Sondermeyer P, Crystal R G. Compartmentalized activation of the interleukin 2 gene by lung T lymphocytes in active pulmonary sarcoidosis.  J Immunol. 1986;  137 3475-3483
• 85 Devergne O, Emilie D, Peuchmaur M, Crevon M C, D’Agay M F, Galanaud P. Production of cytokines in sarcoid lymph nodes: preferential expression of interleukin-1 beta and interferon-gamma genes.  Hum Pathol. 1992;  23 317-323
• 86 Zhu J, Paul W E. CD4 T cells: fates, functions, and faults.  Blood. 2008;  112 1557-1569
• 87 Agostini C, Cabrelle A, Calabrese F et al.. Role for CXCR6 and its ligand CXCL16 in the pathogenesis of T-cell alveolitis in sarcoidosis.  Am J Respir Crit Care Med. 2005;  172 1290-1298
• 88 Takeuchi M, Oh-I K, Suzuki J et al.. Elevated serum levels of CXCL9/monokine induced by interferon-gamma and CXCL10/interferon-gamma-inducible protein-10 in ocular sarcoidosis.  Invest Ophthalmol Vis Sci. 2006;  47 1063-1068
• 89 Morgan A J, Guillen C, Symon F A et al.. Expression of CXCR6 and its ligand CXCL16 in the lung in health and disease.  Clin Exp Allergy. 2005;  35 1572-1580
• 90 Capelli A, Di Stefano A, Lusuardi M, Gnemmi I, Donner C F. Increased macrophage inflammatory protein-1alpha and macrophage inflammatory protein-1beta levels in bronchoalveolar lavage fluid of patients affected by different stages of pulmonary sarcoidosis.  Am J Respir Crit Care Med. 2002;  165 236-241
• 91 Müller-Quernheim J, Krönke M, Strausz J, Schykowski M, Ferlinz R. Interleukin-2 receptor gene expression by bronchoalveolar lavage lymphocytes in pulmonary sarcoidosis.  Am Rev Respir Dis. 1989;  140 82-88
• 92 Paine III R, Mody C H, Chavis A, Spahr M A, Turka L A, Toews G B. Alveolar epithelial cells block lymphocyte proliferation in vitro without inhibiting activation.  Am J Respir Cell Mol Biol. 1991;  5 221-229
• 93 Prasse A, Katic C, Germann M, Buchwald A, Zissel G, Müller-Quernheim J. Phenotyping sarcoidosis from a pulmonary perspective.  Am J Respir Crit Care Med. 2008;  177 330-336
• 94 Grutters J C, Fellrath J M, Mulder L, Janssen R, van den Bosch J M, van Velzen-Blad H. Serum soluble interleukin-2 receptor measurement in patients with sarcoidosis: a clinical evaluation.  Chest. 2003;  124 186-195
• 95 Rothkrantz-Kos S, van Dieijen-Visser M P, Mulder P G, Drent M. Potential usefulness of inflammatory markers to monitor respiratory functional impairment in sarcoidosis.  Clin Chem. 2003;  49 1510-1517
• 96 Müller-Quernheim J, Pfeifer S, Strausz J, Ferlinz R. Correlation of clinical and immunologic parameters of the inflammatory activity of pulmonary sarcoidosis.  Am Rev Respir Dis. 1991;  144 1322-1329
• 97 Richter E, Kataria Y P, Zissel G, Homolka J, Schlaak M, Müller-Quernheim J. Analysis of the Kveim-Siltzbach test reagent for bacterial DNA.  Am J Respir Crit Care Med. 1999;  159 1981-1984
• 98 Klein J T, Horn T D, Forman J D, Silver R F, Teirstein A S, Moller D R. Selection of oligoclonal V β-specific T cells in the intradermal response to Kveim-Siltzbach reagent in individuals with sarcoidosis.  J Immunol. 1995;  154 1450-1460
• 99 Silver R F, Crystal R G, Moller D R. Limited heterogeneity of biased T-cell receptor V beta gene usage in lung but not blood T cells in active pulmonary sarcoidosis.  Immunology. 1996;  88 516-523
• 100 Zissel G, Bäumer I, Fleischer B, Schlaak M, Müller-Quernheim J. TCR V β families in T cell clones from sarcoid lung parenchyma, BAL, and blood.  Am J Respir Crit Care Med. 1997;  156 1593-1600
• 101 Prasse A, Georges C G, Biller H et al.. Th1 cytokine pattern in sarcoidosis is expressed by bronchoalveolar CD4+ and CD8+ T cells.  Clin Exp Immunol. 2000;  122 241-248
• 102 Bäumer I, Zissel G, Schlaak M, Müller-Quernheim J. Th1/Th2 cell distribution in pulmonary sarcoidosis.  Am J Respir Cell Mol Biol. 1997;  16 171-177
• 103 Grunewald J, Wahlström J, Berlin M, Wigzell H, Eklund A, Olerup O. Lung restricted T cell receptor AV2S3+ CD4+ T cell expansions in sarcoidosis patients with a shared HLA-DRbeta chain conformation.  Thorax. 2002;  57 348-352
• 104 Katchar K, Wahlström J, Eklund A, Grunewald J. Highly activated T-cell receptor AV2S3(+) CD4(+) lung T-cell expansions in pulmonary sarcoidosis.  Am J Respir Crit Care Med. 2001;  163 1540-1545
• 105 Grunewald J, Berlin M, Olerup O, Eklund A. Lung T-helper cells expressing T-cell receptor AV2S3 associate with clinical features of pulmonary sarcoidosis.  Am J Respir Crit Care Med. 2000;  161(3 Pt 1) 814-818
• 106 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
• 107 Ishige I, Usui Y, Takemura T, Eishi Y. Quantitative PCR of mycobacterial and propionibacterial DNA in lymph nodes of Japanese patients with sarcoidosis.  Lancet. 1999;  354 120-123
• 108 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
• 109 Ebe Y, Ikushima S, Yamaguchi T et al.. Proliferative response of peripheral blood mononuclear cells and levels of antibody to recombinant protein from Propionibacterium acnes DNA expression library in Japanese patients with sarcoidosis.  Sarcoidosis Vasc Diffuse Lung Dis. 2000;  17 256-265
• 110 Kalis C, Gumenscheimer M, Freudenberg N et al.. Requirement for TLR9 in the immunomodulatory activity of Propionibacterium acnes .  J Immunol. 2005;  174 4295-4300
• 111 Wahlström J, Dengjel J, Persson B et al.. Identification of HLA-DR-bound peptides presented by human bronchoalveolar lavage cells in sarcoidosis.  J Clin Invest. 2007;  117 3576-3582
• 112 Wahlström J, Dengjel J, Winqvist O et al.. Autoimmune T cell responses to antigenic peptides presented by bronchoalveolar lavage cell HLA-DR molecules in sarcoidosis.  Clin Immunol. 2009;  133 353-363
• 113 Miyara M, Amoura Z, Parizot C et al.. The immune paradox of sarcoidosis and regulatory T cells.  J Exp Med. 2006;  203 359-370
• 114 Idali F, Wahlström J, Müller-Suur C, Eklund A, Grunewald J. Analysis of regulatory T cell associated forkhead box P3 expression in the lungs of patients with sarcoidosis.  Clin Exp Immunol. 2008;  152 127-137
• 115 Taflin C, Miyara M, Nochy D et al.. FoxP3+ regulatory T cells suppress early stages of granuloma formation but have little impact on sarcoidosis lesions.  Am J Pathol. 2009;  174 497-508
• 116 Zissel G, Bäumer I, Schlaak M, Müller-Quernheim J. In vitro release of interleukin-15 by broncho-alveolar lavage cells and peripheral blood mononuclear cells from patients with different lung diseases.  Eur Cytokine Netw. 2000;  11 105-112
• 117 Stridh H, Planck A, Gigliotti D, Eklund A, Grunewald J. Apoptosis resistant bronchoalveolar lavage (BAL) fluid lymphocytes in sarcoidosis.  Thorax. 2002;  57 897-901
• 118 Zissel G, Homolka J, Schlaak J, Schlaak M, Müller-Quernheim J. Anti-inflammatory cytokine release by alveolar macrophages in pulmonary sarcoidosis.  Am J Respir Crit Care Med. 1996;  154(3 Pt 1) 713-719
• 119 Ziegenhagen M W, Benner U K, Zissel G, Zabel P, Schlaak M, Müller-Quernheim J. Sarcoidosis: TNF-alpha release from alveolar macrophages and serum level of sIL-2R are prognostic markers.  Am J Respir Crit Care Med. 1997;  156 1586-1592
• 120 Veltkamp M, Wijnen P A, van Moorsel C H et al.. Linkage between Toll-like receptor (TLR) 2 promotor and intron polymorphisms: functional effects and relevance to sarcoidosis.  Clin Exp Immunol. 2007;  149 453-462
• 121 Tsan M F, Gao B. Endogenous ligands of Toll-like receptors.  J Leukoc Biol. 2004;  76 514-519
• 122 Ota M, Amakawa R, Uehira K et al.. Involvement of dendritic cells in sarcoidosis.  Thorax. 2004;  59 408-413
• 123 Möllers M, Aries S P, Drömann D, Mascher B, Braun J, Dalhoff K. Intracellular cytokine repertoire in different T cell subsets from patients with sarcoidosis.  Thorax. 2001;  56 487-493
• 124 Strausz J, Männel D N, Pfeifer S, Borkowski A, Ferlinz R, Müller-Quernheim J. Spontaneous monokine release by alveolar macrophages in chronic sarcoidosis.  Int Arch Allergy Appl Immunol. 1991;  96 68-75
• 125 Pechkovsky D V, Goldmann T, Ludwig C et al.. CCR2 and CXCR3 agonistic chemokines are differently expressed and regulated in human alveolar epithelial cells type II.  Respir Res. 2005;  6 75
• 126 Petrek M, Kolek V, Szotkowská J, du Bois R M. CC and C chemokine expression in pulmonary sarcoidosis.  Eur Respir J. 2002;  20 1206-1212
• 127 Bergeron A, Bonay M, Kambouchner M et al.. Cytokine patterns in tuberculous and sarcoid granulomas: correlations with histopathologic features of the granulomatous response.  J Immunol. 1997;  159 3034-3043
• 128 Somoskövi A, Zissel G, Zipfel P F et al.. Different cytokine patterns correlate with the extension of disease in pulmonary tuberculosis.  Eur Cytokine Netw. 1999;  10 135-142
• 129 Zissel G, Schlaak J, Schlaak M, Müller-Quernheim J. Regulation of cytokine release by alveolar macrophages treated with interleukin-4, interleukin-10, or transforming growth factor beta.  Eur Cytokine Netw. 1996;  7 59-66
• 130 Limper A H, Colby T V, Sanders M S, Asakura S, Roche P C, DeRemee R A. Immunohistochemical localization of transforming growth factor-β 1 in the nonnecrotizing granulomas of pulmonary sarcoidosis.  Am J Respir Crit Care Med. 1994;  149 197-204
• 131 Marshall B G, Wangoo A, Cook H T, Shaw R J. Increased inflammatory cytokines and new collagen formation in cutaneous tuberculosis and sarcoidosis.  Thorax. 1996;  51 1253-1261
• 132 Baughman R P, Drent M, Kavuru M Sarcoidosis Investigators et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement.  Am J Respir Crit Care Med. 2006;  174 795-802