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Immunogenetics of Disease-Causing Inflammation in Sarcoidosis

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Abstract

Sarcoidosis is a systemic inflammatory disorder characterised by tissue infiltration by mononuclear phagocytes and lymphocytes with associated non-caseating granuloma formation. Originally described as a disorder of the skin, sarcoidosis can involve any organ with wide-ranging clinical manifestations and disease course. Recent studies have provided new insights into the mechanisms involved in disease pathobiology, and we now know that sarcoidosis has a clear genetic basis largely involving human leukocyte antigen (HLA) genes. In contrast to Mendelian-monogenic disorders—which are generally due to specific and relatively rare mutations often leading to a single amino acid change in an encoded protein—sarcoidosis results from genetic variations relatively common in the general population and involving multiple genes, each contributing an effect of varying magnitude. However, an individual may have the necessary genetic profile and yet the disease will not develop unless an environmental or infectious factor is encountered. Genetics appears also to contribute to the huge variability in clinical phenotype and disease behaviour. Moreover, it has been established that sarcoidosis granulomatous inflammation is a highly polarized T helper 1 immune response that starts with an antigenic stimulus followed by T cell activation via a classic HLA class II-mediated pathway. A complex network of lymphocytes, macrophages, and cytokines is pivotal in the orchestration and evolution of the granulomatous process. Despite these advances, the aetiology of sarcoidosis remains elusive and its pathogenesis incompletely understood. As such, there is an urgent need for a better understanding of disease pathogenesis, which hopefully will translate into the development of truly effective therapies.

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References

  1. Familial associations in sarcoidosis (1973) A report to the Research Committee of the British Thoracic and Tuberculosis Association. Tubercle 54:87–98

    Google Scholar 

  2. Sverrild A, Backer V, Kyvik KO et al (2008) Heredity in sarcoidosis: a registry-based twin study. Thorax 63:894–896

    CAS  PubMed  Google Scholar 

  3. Rybicki BA, Kirkey KL, Major M et al (2001) Familial risk ratio of sarcoidosis in African-American sibs and parents. Am J Epidemiol 153:188–193

    CAS  PubMed  Google Scholar 

  4. Hosoda Y, Yamaguchi M, Hiraga Y (1997) Global epidemiology of sarcoidosis. What story do prevalence and incidence tell us? Clin Chest Med 18:681–694

    CAS  PubMed  Google Scholar 

  5. Fischer A, Grunewald J, Spagnolo P, Nebel A, Schreiber S, Müller-Quernheim J (2014) Genetics of sarcoidosis. Semin Respir Crit Care Med 35:296–306

    PubMed  Google Scholar 

  6. Spagnolo P, Richeldi L, du Bois RM (2008) Environmental triggers and susceptibility factors in idiopathic granulomatous diseases. Semin Respir Crit Care Med 29:610–619

    PubMed  Google Scholar 

  7. Spagnolo P, Grunewald J (2013) Recent advances in the genetics of sarcoidosis. J Med Genet 50:290–297

    CAS  PubMed  Google Scholar 

  8. Foley PJ, McGrath DS, Puscinska E et al (2001) Human leukocyte antigen-DRB1 position 11 residues are a common protective marker for sarcoidosis. Am J Respir Cell Mol Biol 25:272–277

    CAS  PubMed  Google Scholar 

  9. Moller DR, Chen ES (2002) Genetic basis of remitting sarcoidosis: triumph of the trimolecular complex? Am J Respir Cell Mol Biol 27:391–395

    CAS  PubMed  Google Scholar 

  10. Iannuzzi MC, Maliarik MJ, Poisson LM, Rybicki BA (2003) Sarcoidosis susceptibility and resistance HLA-DQB1 alleles in African Americans. Am J Respir Crit Care Med 167:1225–1231

    PubMed  Google Scholar 

  11. Wang JH, Reinherz EL (2002) Structural basis of T cell recognition of peptides bound to MHC molecules. Mol Immunol 38:1039–1049

    CAS  PubMed  Google Scholar 

  12. Appella E, Padlan EA, Hunt DF (1995) Analysis of the structure of naturally processed peptides bound by Class I and Class II major histocompatibility complex molecules. EXS 73:105–119

    CAS  PubMed  Google Scholar 

  13. Norment AM, Salter RD, Parham P, Engelhard VH, Littman DR (1988) Cell-cell adhesion mediated by CD8 and MHC class I molecules. Nature 336:79–81

    CAS  PubMed  Google Scholar 

  14. Doyle C, Strominger JL (1987) Interaction between CD4 and class II MHC molecules mediates cell adhesion. Nature 330:256–259

    CAS  PubMed  Google Scholar 

  15. Brachet V, Pehau-Arnaudet G, Desaymard C, Raposo G, Amigorena S (1999) Early endosomes are required for major histocompatibility complex Class II transport to peptide-loading compartments. Mol Biol Cell 10:2891–2904

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Lich JD, Elliott JF, Blum JS (2000) Cytoplasmic processing is a prerequisite for presentation of an endogenous antigen by major histocompatibility complex Class II proteins. J Exp Med 191:1513–1524

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Ramachandra L, Harding CV (2000) Phagosomes acquire nascent and recycling Class II MHC molecules but primarily use nascent molecules in phagocytic antigen processing. J Immunol 164:5103–5112

    CAS  PubMed  Google Scholar 

  18. Schwartz JC, Zhang X, Nathenson SG, Almo SC (2002) Structural mechanisms of costimulation. Nat Immunol 3:427–434

    CAS  PubMed  Google Scholar 

  19. du Bois RM, Kirby M, Balbi B, Saltini C, Crystal RG (1992) T-lymphocytes that accumulate in the lung in sarcoidosis have evidence of recent stimulation of the T-cell antigen receptor. Am Rev Respir Dis 145:1205–1211

    PubMed  Google Scholar 

  20. Muller-Quernheim J, Saltini C, Sondermeyer P, Crystal RG (1986) Compartmentalized activation of the interleukin 2 gene by lung T lymphocytes in active pulmonary sarcoidosis. J Immunol 137:3475–3483

    CAS  PubMed  Google Scholar 

  21. Pinkston P, Bitterman PB, Crystal RG (1983) Spontaneous release of interleukin-2 by lung T lymphocytes in active pulmonary sarcoidosis. N Engl J Med 308:793–800

    CAS  PubMed  Google Scholar 

  22. 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 Invest 75:1488–1495

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Hunninghake GW, Crystal RG (1981) Pulmonary sarcoidosis: a disorder mediated by excess helper T-lymphocyte activity at sites of disease activity. N Engl J Med 305:429–434

    CAS  PubMed  Google Scholar 

  24. Forman JD, Klein JT, Silver RF, Liu MC, Greenlee BM, Moller DR (1994) Selective activation and accumulation of oligoclonal V beta-specific T cells in active pulmonary sarcoidosis. J Clin Invest 94:1533–1542

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Grunewald J, Janson CH, Eklund A et al (1992) Restricted V alpha 2.3 gene usage by CD4+ T lymphocytes in bronchoalveolar lavage fluid from sarcoidosis patients correlates with HLA-DR3. Eur J Immunol 22:129–135

    CAS  PubMed  Google Scholar 

  26. Moller DR, Konishi K, Kirby M, Balbi B, Crystal RG (1988) Bias toward use of a specific T cell receptor beta-chain variable region in a subgroup of individuals with sarcoidosis. J Clin Invest 82:1183–1191

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Grunewald J, Olerup O, Persson U, Ohrn MB, Wigzell H, Eklund A (1994) T-cell receptor variable region gene usage by CD4+ and CD8+ T cells in bronchoalveolar lavage fluid and peripheral blood of sarcoidosis patients. Proc Natl Acad Sci U S A 91:4965–4969

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Jones CM, Lake RA, Wijeyekoon JB, Mitchell DM, du Bois RM, O’Hehir RE (1996) Oligoclonal V gene usage by T lymphocytes in bronchoalveolar lavage fluid from sarcoidosis patients. Am J Respir Cell Mol Biol 14:470–477

    CAS  PubMed  Google Scholar 

  29. Forrester JM, Newman LS, Wang Y, King TE Jr, Kotzin BL (1993) Clonal expansion of lung V delta 1+ T cells in pulmonary sarcoidosis. J Clin Invest 91:292–300

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Grunewald J, Wahlstrom 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-DR beta chain conformation. Thorax 57:348–352

    CAS  PubMed Central  PubMed  Google Scholar 

  31. 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 163:1540–1545

    CAS  PubMed  Google Scholar 

  32. Wikén M, Ostadkarampour M, Eklund A et al (2012) Antigen-specific multifunctional T-cells in sarcoidosis patients with Lofgren’s syndrome. Eur Respir J 40:110–121

    PubMed  Google Scholar 

  33. Wikén M, Grunewald J, Eklund A, Wahlström J (2012) Multiparameter phenotyping of T-cell subsets in distinct subgroups of patients with pulmonary sarcoidosis. J Intern Med 271:90–103

    PubMed  Google Scholar 

  34. Grunewald J, Berlin M, Olerup O et al (2000) Lung T-helper cells expressing T-cell receptor AV2S3 associate with clinical features of pulmonary sarcoidosis. Am J Respir Crit Care Med 161:814–818

    CAS  PubMed  Google Scholar 

  35. Idali F, Wahlström J, Müller-Suur C, Eklund A, Grunewald J (2008) Analysis of regulatory T cell associated forkhead box P3 expression in the lungs of patients with sarcoidosis. Clin Exp Immunol 152:127–137

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Planck A, Eklund A, Grunewald J (2003) Markers of activity in clinically recovered human leukocyte antigen-DR17-positive sarcoidosis patients. Eur Respir J 21:52–57

    CAS  PubMed  Google Scholar 

  37. Spagnolo P, du Bois RM (2007) Genetics of sarcoidosis. Clin Dermatol 25:242–249

    PubMed  Google Scholar 

  38. Balbi B, Moller DR, Kirby M, Holroyd KJ, Crystal RG (1990) Increased numbers of T-lymphocytes with gamma delta1 antigen receptors in a subgroup of individuals with pulmonary sarcoidosis. J Clin Invest 85:1353–1361

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Brownell I, Ramírez-Valle F, Sanchez M, Prystowsky S (2011) Evidence for mycobacteria in sarcoidosis. Am J Respir Cell Mol Biol 45:899–905

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Hedfors E, Möller E (1973) HL-A antigens in sarcoidosis. Tissue Antigens 3:95–98

    CAS  PubMed  Google Scholar 

  41. Kueppers F, Brackertz D, Mueller-Eckhardt C (1972) HL-A antigens in sarcoidosis and rheumatoid arthritis. Lancet 2:1425

    CAS  PubMed  Google Scholar 

  42. McIntyre JA, McKee KT, Loadholt CB, Mercurio S, Lin I (1977) Increased HLA-B7 antigen frequency in South Carolina blacks in association with sarcoidosis. Transplant Proc 9:173–176

    CAS  PubMed  Google Scholar 

  43. Grunewald J, Eklund A, Olerup O (2004) Human leukocyte antigen class I alleles and the disease course in sarcoidosis patients. Am J Respir Crit Care Med 169:696–702

    PubMed  Google Scholar 

  44. Smith MJ, Turton CW, Mitchell DN, Turner-Warwick M, Morris LM, Lawler SD (1981) Association of HLA B8 with spontaneous resolution in sarcoidosis. Thorax 36:296–298

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Hedfors E, Lindström F (1983) HLA-B8/DR3 in sarcoidosis. Correlation to acute onset disease with arthritis. Tissue Antigens 22:200–203

    CAS  PubMed  Google Scholar 

  46. Gardner J, Kennedy HG, Hamblin A, Jones E (1984) HLA associations in sarcoidosis: a study of two ethnic groups. Thorax 39:19–22

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Krause A, Goebel KM (1987) Class II MHC antigen (HLA-DR3) predisposes to sarcoid arthritis. J Clin Lab Immunol 24:25–27

    CAS  PubMed  Google Scholar 

  48. Lofgren S, Lundback H (1952) The bilateral hilar lymphoma syndrome; a study of the relation to tuberculosis and sarcoidosis in 212 cases. Acta Med Scand 142:265–273

    CAS  PubMed  Google Scholar 

  49. Grunewald J, Eklund A (2009) Löfgren’s syndrome. Human Leukocyte Antigen strongly influences the disease course. Am J Respir Crit Care Med 179:307–312

    PubMed  Google Scholar 

  50. Idali F, Wikén M, Wahlström J et al (2006) Reduced Th1 response in the lungs of HLA-DRB1*0301 patients with pulmonary sarcoidosis. Eur Respir J 27:451–459

    CAS  PubMed  Google Scholar 

  51. Grubić Z, Zunec R, Peros-Golubicić T et al (2007) HLA class I and class II frequencies in patients with sarcoidosis from Croatia: role of HLA-B8, -DRB1*0301, and -DQB1*0201 haplotype in clinical variations of the disease. Tissue Antigens 70:301–306

    PubMed  Google Scholar 

  52. Rybicki BA, Maliarik MJ, Poisson LM et al (2003) The major histocompatibility complex gene region and sarcoidosis susceptibility in African Americans. Am J Respir Crit Care Med 167:444–449

    PubMed  Google Scholar 

  53. Richeldi L, Sorrentino R, Saltini C (1993) HLA-DPB1 glutamate 69: a genetic marker of beryllium disease. Science 262:242–244

    CAS  PubMed  Google Scholar 

  54. Silveira LJ, McCanlies EC, Fingerlin TE et al (2012) Chronic beryllium disease, HLA-DPB1, and the DP peptide binding groove. J Immunol 189:4014–4023

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Falta MT, Pinilla C, Mack DG et al (2013) Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease. J Exp Med 210:1403–1418

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Petukh M, Wu B, Stefl S et al (2014) Chronic Beryllium Disease: revealing the role of beryllium ion and small peptides binding to HLA-DP2. PLoS One 9:e111604

    PubMed Central  PubMed  Google Scholar 

  57. Voorter CE, Amicosante M, Berretta F, Groeneveld L, Drent M, van den Berg-Loonen EM (2007) HLA class II amino acid epitopes as susceptibility markers of sarcoidosis. Tissue Antigens 70:18–27

    CAS  PubMed  Google Scholar 

  58. Grunewald J, Brynedal B, Darlington P et al (2010) Different HLA-DRB1 allele distributions in distinct clinical subgroups of sarcoidosis patients. Respir Res 11:25

    PubMed Central  PubMed  Google Scholar 

  59. Rossman MD, Thompson B, Frederick M et al (2003) HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites. Am J Hum Genet 73:720–735

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Wennerström A, Pietinalho A, Vauhkonen H et al (2012) HLA-DRB1 allele frequencies and C4 copy number variation in Finnish sarcoidosis patients and associations with disease prognosis. Hum Immunol 73:93–100

    PubMed  Google Scholar 

  61. Sato H, Woodhead FA, Ahmad T et al (2010) Sarcoidosis HLA class II genotyping distinguishes differences of clinical phenotype across ethnic groups. Hum Mol Genet 19:4100–4111

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Suzuki H, Ota M, Meguro A et al (2012) Genetic characterization and susceptibility for sarcoidosis in Japanese patients: risk factors of BTNL2 gene polymorphisms and HLA class II alleles. Invest Ophthalmol Vis Sci 53:7109–7115

    CAS  PubMed  Google Scholar 

  63. Zhou Y, Shen L, Zhang Y, Jiang D, Li H (2011) Human leukocyte antigen-A, -B, and -DRB1 alleles and sarcoidosis in Chinese Han subjects. Hum Immunol 72:571–575

    CAS  PubMed  Google Scholar 

  64. Sharma SK, Balamurugan A, Pandey RM, Saha PK, Mehra NK (2003) Human leukocyte antigen-DR alleles influence the clinical course of pulmonary sarcoidosis in Asian Indians. Am J Respir Cell Mol Biol 29:225–231

    CAS  PubMed  Google Scholar 

  65. Ishihara M, Ohno S, Ishida T et al (1994) Molecular genetic studies of HLA class II alleles in sarcoidosis. Tissue Antigens 43:238–241

    CAS  PubMed  Google Scholar 

  66. Oswald-Richter KA, Culver DA, Hawkins C et al (2009) Cellular responses to mycobacterial antigens are present in bronchoalveolar lavage fluid used in the diagnosis of sarcoidosis. Infect Immun 77:3740–3748

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Song Z, Marzilli L, Greenlee M et al (2005) Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis. J Exp Med 201:755–767

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Grunewald J (2012) HLA associations and Löfgren’s syndrome. Expert Rev Clin Immunol 8:55–62

    CAS  PubMed  Google Scholar 

  69. Berlin M, Fogdell-Hahn A, Olerup O, Eklund A, Grunewald J (1997) HLA-DR predicts the prognosis in Scandinavian patients with pulmonary sarcoidosis. Am J Respir Crit Care Med 156:1601–1605

    CAS  PubMed  Google Scholar 

  70. Sato H, Grutters JC, Pantelidis P et al (2002) HLA-DQB1*0201: a marker for good prognosis in British and Dutch patients with sarcoidosis. Am J Respir Cell Mol Biol 27:406–412

    CAS  PubMed  Google Scholar 

  71. 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 66:826–835

    CAS  PubMed  Google Scholar 

  72. Darlington P, Haugom-Olsen H, von Sivers K et al (2012) T-cell phenotypes in bronchoalveolar lavage fluid, blood and lymph nodes in pulmonary sarcoidosis—indication for an airborne antigen as the triggering factor in sarcoidosis. J Intern Med 272:465–471

    CAS  PubMed  Google Scholar 

  73. Naruse TK, Matsuzawa Y, Ota M et al (2000) HLA-DQB1*0601 is primarily associated with the susceptibility to cardiac sarcoidosis. Tissue Antigens 56:52–57

    CAS  PubMed  Google Scholar 

  74. Sato H, Nagai S, du Bois RM et al (2007) HLA-DQB1 0602 allele is associated with splenomegaly in Japanese sarcoidosis. J Intern Med 262:449–457

    CAS  PubMed  Google Scholar 

  75. Voorter CE, Drent M, Hoitsma E, Faber KG, van den Berg-Loonen EM (2005) Association of HLA DQB1 0602 in sarcoidosis patients with small fiber neuropathy. Sarcoidosis Vasc Diffuse Lung Dis 22:129–32

    PubMed  Google Scholar 

  76. Martinetti M, Tinelli C, Kolek V et al (1995) “The sarcoidosis map”: a joint survey of clinical and immunogenetic findings in two European countries. Am J Respir Crit Care Med 152:557–564

    CAS  PubMed  Google Scholar 

  77. Bogunia-Kubik K, Tomeczko J, Suchnicki K, Lange A (2001) HLA-DRB1*03, DRB1*11 or DRB1*12 and their respective DRB3 specificities in clinical variants of sarcoidosis. Tissue Antigens 57:87–90

    CAS  PubMed  Google Scholar 

  78. Grunewald J, Eklund A (2001) Human leukocyte antigen genes may outweigh racial background when generating a specific immune response in sarcoidosis. Eur Respir J 17:1046–1048

    CAS  PubMed  Google Scholar 

  79. Darlington P, Tallstedt L, Padyukov L et al (2011) HLA-DRB1* alleles and symptoms associated with Heerfordt’s syndrome in Sarcoidosis. Eur Respir J 38:1151–1157

    CAS  PubMed  Google Scholar 

  80. Adrianto I, Lin CP, Hale JJ et al (2012) Genome-wide association study of African and European Americans implicates multiple shared and ethnic specific loci in sarcoidosis susceptibility. PLoS ONE 7:e43907

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Hofmann S, Franke A, Fischer A et al (2008) Genome-wide association study identifies ANXA11 as a new susceptibility locus for sarcoidosis. Nat Genet 40:1103–1106

    CAS  PubMed  Google Scholar 

  82. Li Y, Pabst S, Kubisch C, Grohé C, Wollnik B (2010) First independent replication study confirms the strong genetic association of ANXA11 with sarcoidosis. Thorax 65:939–940

    PubMed  Google Scholar 

  83. Mrazek F, Stahelova A, Kriegova E et al (2011) Functional variant ANXA11 R230C: true marker of protection and candidate disease modifier in sarcoidosis. Genes Immun 12:490–494

    CAS  PubMed  Google Scholar 

  84. Levin AM, Iannuzzi MC, Montgomery CG et al (2013) Association of ANXA11 genetic variation with sarcoidosis in African Americans and European Americans. Genes Immun 14:13–18

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Valentonyte R, Hampe J, Huse K et al (2005) Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat Genet 37:357–364

    CAS  PubMed  Google Scholar 

  86. Rybicki BA, Walewski JL, Maliarik MJ et al (2005) The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites. Am J Hum Genet 77:491–499

    CAS  PubMed Central  PubMed  Google Scholar 

  87. Li Y, Wollnik B, Pabst S et al (2006) BTNL2 gene variant and sarcoidosis. Thorax 61:273–274

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Spagnolo P, Sato H, Grutters JC et al (2007) Analysis of BTNL2 genetic polymorphisms in British and Dutch patients with sarcoidosis. Tissue Antigens 70:219–227

    CAS  PubMed  Google Scholar 

  89. Morais A, Lima B, Peixoto MJ, Alves H, Marques A, Delgado L (2012) BTNL2 gene polymorphism associations with susceptibility and phenotype expression in sarcoidosis. Respir Med 106:1771–1777

    PubMed  Google Scholar 

  90. Milman N, Svendsen CB, Nielsen FC, van Overeem Hansen T (2011) The BTNL2 A allele variant is frequent in Danish patients with sarcoidosis. Clin Respir J 5:105–111

    CAS  PubMed  Google Scholar 

  91. Wijnen PA, Voorter CE, Nelemans PJ, Verschakelen JA, Bekers O, Drent M (2011) Butyrophilin-like 2 in pulmonary sarcoidosis: a factor for susceptibility and progression? Hum Immunol 72:342–347

    CAS  PubMed  Google Scholar 

  92. Wennerström A, Pietinalho A, Lasota J et al (2013) Major histocompatibility complex class II and BTNL2 associations in sarcoidosis. Eur Respir J 42:550–553

    PubMed  Google Scholar 

  93. Fischer A, Schmid B, Ellinghaus D et al (2012) A novel sarcoidosis risk locus for Europeans on chromosome 11q13.1. Am J Respir Crit Care Med 186:877–885

    CAS  PubMed  Google Scholar 

  94. Takada T, Suzuki E, Ishida T et al (2001) Polymorphism in RANTES chemokine promoter affects extent of sarcoidosis in a Japanese population. Tissue Antigens 58:293–298

    CAS  PubMed  Google Scholar 

  95. Fischer A, Valentonyte R, Nebel A et al (2008) Female-specific association of C-C chemokine receptor 5 gene polymorphisms with Löfgren’s syndrome. J Mol Med (Berl) 86:553–561

    CAS  Google Scholar 

  96. Fridlender ZG, Schwartz A, Kohan M, Amir G, Glazer M, Berkman N (2010) Association between CD14 gene polymorphisms and disease phenotype in sarcoidosis. Respir Med 104:1336–1343

    PubMed  Google Scholar 

  97. Franke A, Fischer A, Nothnagel M et al (2008) Genome-wide association analysis in sarcoidosis and Crohn’s disease unravels a common susceptibility locus on 10p12.2. Gastroenterology 135:1207–1215

    CAS  PubMed  Google Scholar 

  98. Heron M, van Moorsel CHM, Grutters JC et al (2011) Genetic variation in GREM1 is a risk factor for fibrosis in pulmonary sarcoidosis. Tissue Antigens 77:112–117

    CAS  PubMed  Google Scholar 

  99. Heron M, Grutters JC, van Moorsel CH et al (2009) Variation in IL7R predisposes to sarcoid inflammation. Genes Immun 10:647–653

    CAS  PubMed  Google Scholar 

  100. Fischer A, Nothnagel M, Franke A et al (2011) Association of inflammatory bowel disease risk loci with sarcoidosis, and its acute and chronic subphenotypes. Eur Respir J 37:610–616

    CAS  PubMed  Google Scholar 

  101. Kim HS, Choi D, Lim LL et al (2011) Association of interleukin 23 receptor gene with sarcoidosis. Dis Markers 31:17–24

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Heron M, Grutters JC, Van Moorsel CHM et al (2009) Effect of variation in ITGAE on risk of sarcoidosis, CD103 expression, and chest radiography. Clin Immunol 133:117–125

    CAS  PubMed  Google Scholar 

  103. Piotrowski WJ, Górski P, Pietras T, Fendler W, Szemraj J (2011) The selected genetic polymorphisms of metalloproteinases MMP2, 7, 9 and MMP inhibitor TIMP2 in sarcoidosis. Med Sci Monit 17:CR598–CR607

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Hattori T, Konno S, Takahashi A et al (2010) Genetic variants in mannose receptor gene (MRC1) confer susceptibility to increased risk of sarcoidosis. BMC Med Genet 11:151

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Daniil Z, Mollaki V, Malli F et al (2013) Polymorphisms and haplotypes in MyD88 are associated with the development of sarcoidosis: a candidate-gene association study. Mol Biol Rep 40:4281–4286

    CAS  PubMed  Google Scholar 

  106. Hofmann S, Fischer A, Till A, GenPhenReSa Consortium et al (2011) A genome-wide association study reveals evidence of association with sarcoidosis at 6p12.1. Eur Respir J 38:1127–1135

    CAS  PubMed  Google Scholar 

  107. Hill MR, Papafili A, Booth H et al (2006) Functional prostaglandin-endoperoxide synthase 2 polymorphism predicts poor outcome in sarcoidosis. Am J Respir Crit Care Med 174:915–922

    CAS  PubMed  Google Scholar 

  108. Lopez-Campos JL, Rodriguez-Rodriguez D, Rodriguez-Becerra E et al (2009) Cyclooxygenase-2 polymorphisms confer susceptibility to sarcoidosis but are not related to prognosis. Respir Med 103:427–433

    PubMed  Google Scholar 

  109. Hofmann S, Fischer A, Nothnagel M et al (2013) A genome-wide association analysis reveals chromosome 12q13.3-q14.1 as a new risk locus for sarcoidosis. Eur Respir J 41:888–900

    CAS  PubMed  Google Scholar 

  110. Jonth AC, Silveira L, Fingerlin TE et al (2007) ACCESS Group. TGF-beta 1variants in chronic beryllium disease and sarcoidosis. J Immunol 179:4255–4262

    CAS  PubMed  Google Scholar 

  111. Pabst S, Fränken T, Schönau J et al (2011) Transforming growth factor beta gene polymorphisms in different phenotypes of sarcoidosis. Eur Respir J 38:169–175

    CAS  PubMed  Google Scholar 

  112. Kruit A, Grutters JC, Ruven HJ et al (2006) Transforming growth factor-β gene polymorphisms in sarcoidosis patients with and without fibrosis. Chest 129:1584–1591

    CAS  PubMed  Google Scholar 

  113. Veltkamp M, van Moorsel CH, Rijkers GT, Ruven HJ, Grutters JC (2012) Genetic variation in the Toll-like receptor gene cluster (TLR10-TLR1-TLR6) influences disease course in sarcoidosis. Tissue Antigens 79:25–32

    CAS  PubMed  Google Scholar 

  114. Pabst S, Bradler O, Gillissen A, Nickenig G, Skowasch D, Grohe C (2013) Toll-like receptor-9 polymorphisms in sarcoidosis and chronic obstructive pulmonary disease. Adv Exp Med Biol 756:239–245

    CAS  PubMed  Google Scholar 

  115. Seitzer U, Swider C, Stüber F et al (1997) Tumour necrosis factor alpha promoter gene polymorphism in sarcoidosis. Cytokine 9:787–790

    CAS  PubMed  Google Scholar 

  116. McDougal KE, Fallin MD, Moller DR, ACCESS Research Group et al (2009) Variation in the lymphotoxin-alpha/tumor necrosis factor locus modifies risk of erythema nodosum in sarcoidosis. J Invest Dermatol 129:1921–1926

    CAS  PubMed Central  PubMed  Google Scholar 

  117. Labunski S, Posern G, Ludwig S, Kundt G, Bröcker EB, Kunz M (2001) Tumour necrosis factor-alpha promoter polymorphism in erythema nodosum. Acta Derm Venereol 81:18–21

    CAS  PubMed  Google Scholar 

  118. Medica I, Kastrin A, Maver A, Peterlin B (2007) Role of genetic polymorphisms in ACE and TNF-alpha gene in sarcoidosis: a metaanalysis. J Hum Genet 52:836–847

    CAS  PubMed  Google Scholar 

  119. Grutters JC, Sato H, Pantelidis P et al (2002) Increased frequency of the uncommon tumor necrosis factor -857 T allele in British and Dutch patients with sarcoidosis. Am J Respir Crit Care Med 165:1119–1124

    PubMed  Google Scholar 

  120. Niimi T, Tomita H, Sato S et al (1999) Vitamin D receptor gene polymorphism in patients with sarcoidosis. Am J Respir Crit Care Med 160:1107–1109

    CAS  PubMed  Google Scholar 

  121. Morohashi K, Takada T, Omori K, Suzuki E, Gejyo F (2003) Vascular endothelial growth factor gene polymorphisms in Japanese patients with sarcoidosis. Chest 123:1520–1526

    CAS  PubMed  Google Scholar 

  122. Seyhan EC, Cetinkaya E, Altin S et al (2008) Vascular endothelial growth factor gene polymorphisms in Turkish patients with sarcoidosis. Tissue Antigens 72:162–165

    CAS  PubMed  Google Scholar 

  123. Pabst S, Karpushova A, Dìaz-Lacava A et al (2010) VEGF gene haplotypes are associated with sarcoidosis. Chest 137:156–163

    CAS  PubMed  Google Scholar 

  124. Williams GT, Williams WJ (1983) Granulomatous inflammation - a review. J Clin Pathol 36:723–733

    CAS  PubMed Central  PubMed  Google Scholar 

  125. Romagnani S (2006) Regulation of the T cell response. Clin Exp Allergy 36:1357–1366

    CAS  PubMed  Google Scholar 

  126. Chen ES, Moller DR (2011) Sarcoidosis - scientific progress and clinical challenges. Nat Rev Rheumatol 7:457–467

    CAS  PubMed  Google Scholar 

  127. Zissel G (2014) Cellular activation in the immune response of sarcoidosis. Semin Respir Crit Care Med 35:307–315

    PubMed  Google Scholar 

  128. Orme IM, Cooper AM (1999) Cytokine/chemokine cascades in immunity to tuberculosis. Immunol Today 20:307–312

    CAS  PubMed  Google Scholar 

  129. Boros DL (1978) Granulomatous inflammations. Prog Allergy 24:183–267

    CAS  PubMed  Google Scholar 

  130. Chen ES, Song Z, Willett MH et al (2010) Serum amyloid A regulates granulomatous inflammation in sarcoidosis through Toll-like receptor-2. Am J Respir Crit Care Med 181:360–373

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Wikén M, Grunewald J, Eklund A, Wahlström J (2009) Higher monocyte expression of TLR2 and TLR4, and enhanced pro-inflammatory synergy of TLR2 with NOD2 stimulation in sarcoidosis. J Clin Immunol 29:78–89

    PubMed  Google Scholar 

  132. Gabrilovich MI, Walrath J, van Lunteren J et al (2013) Disordered Toll-like receptor 2 responses in the pathogenesis of pulmonary sarcoidosis. Clin Exp Immunol 173:512–522

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Puissegur MP, Lay G, Gilleron M et al (2007) Mycobacterial lipomannan induces granuloma macrophage fusion via a TLR2-dependent, ADAM9- and beta1 integrin-mediated pathway. J Immunol 178:3161–3169

    CAS  PubMed  Google Scholar 

  134. Gerke AK, Hunninghake G (2008) The immunology of sarcoidosis. Clin Chest Med 29:379–390

    PubMed  Google Scholar 

  135. Agostini C, Semenzato G (1998) Cytokines in sarcoidosis. Semin Respir Infect 13:184–196

    CAS  PubMed  Google Scholar 

  136. Bachwich PR, Lynch JP 3rd, Larrick J, Spengler M, Kunkel SL (1986) Tumor necrosis factor production by human sarcoid alveolar macrophages. Am J Pathol 125:421–425

    CAS  PubMed Central  PubMed  Google Scholar 

  137. Strausz J, Männel DN, Pfeifer S, Borkowski A, Ferlinz R, Müller-Quernheim J (1991) Spontaneous monokine release by alveolar macrophages in chronic sarcoidosis. Int Arch Allergy Appl Immunol 96:68–75

    CAS  PubMed  Google Scholar 

  138. Gupta D, Agarwal R, Aggarwal AN, Jindal SK (2007) Molecular evidence for the role of mycobacteria in sarcoidosis: a meta-analysis. Eur Respir J 30:508–516

    CAS  PubMed  Google Scholar 

  139. Dubaniewicz A, Dubaniewicz-Wybieralska M, Sternau A et al (2006) Mycobacterium tuberculosis complex and mycobacterial heat shock proteins in lymph node tissue from patients with pulmonary sarcoidosis. J Clin Microbiol 44:3448–3451

    PubMed Central  PubMed  Google Scholar 

  140. Oswald-Richter KA, Beachboard DC, Seeley EH et al (2012) Dual analysis for mycobacteria and propionibacteria in sarcoidosis BAL. J Clin Immunol 32:1129–1140

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Chen ES, Wahlström J, Song Z et al (2008) T cell responses to mycobacterial catalase-peroxidase profile a pathogenic antigen in systemic sarcoidosis. J Immunol 181:8784–8796

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Drake WP, Dhason MS, Nadaf M et al (2007) Cellular recognition of Mycobacterium tuberculosis ESAT-6 and KatG peptides in systemic sarcoidosis. Infect Immun 75:527–530

    CAS  PubMed Central  PubMed  Google Scholar 

  143. Dubaniewicz A, Trzonkowski P, Dubaniewicz-Wybieralska M, Dubaniewicz A, Singh M, Myśliwski A (2007) Mycobacterial heat shock protein-induced blood T lymphocytes subsets and cytokine pattern: comparison of sarcoidosis with tuberculosis and healthy controls. Respirology 12:346–354

    PubMed  Google Scholar 

  144. Oswald-Richter KA, Beachboard DC, Zhan X et al (2010) Multiple mycobacterial antigens are targets of the adaptive immune response in pulmonary sarcoidosis. Respir Res 11:161

    CAS  PubMed Central  PubMed  Google Scholar 

  145. Eishi Y, Suga M, Ishige I et al (2002) Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis. J Clin Microbiol 40:198–204

    CAS  PubMed Central  PubMed  Google Scholar 

  146. Ebe Y, Ikushima S, Yamaguchi T et al (2000) 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 17:256–265

    CAS  PubMed  Google Scholar 

  147. Chen ES, Moller DR (2014) Etiologic role of infectious agents. Semin Respir Crit Care Med 35:285–295

    PubMed  Google Scholar 

  148. Wahlström J, Dengjel J, Persson B et al (2007) Identification of HLA-DR-bound peptides presented by human bronchoalveolar lavage cells in sarcoidosis. J Clin Invest 117:3576–3582

    PubMed Central  PubMed  Google Scholar 

  149. Wahlström J, Dengjel J, Winqvist O et al (2009) Autoimmune T cell responses to antigenic peptides presented by bronchoalveolar lavage cell HLA-DR molecules in sarcoidosis. Clin Immunol 133:353–363

    PubMed  Google Scholar 

  150. Zissel G, Prasse A, Muller-Quernheim J (2007) Sarcoidosis—immunopathogenetic concepts. Semin Respir Crit Care Med 28:3–14

    PubMed  Google Scholar 

  151. Agostini C, Trentin L, Facco M et al (1996) Role of IL-15, IL-2, and their receptors in the development of T cell alveolitis in pulmonary sarcoidosis. J Immunol 157:910–918

    CAS  PubMed  Google Scholar 

  152. Greene CM, Meachery G, Taggart CC et al (2000) Role of IL-18 in CD4+ T lymphocyte activation in sarcoidosis. J Immunol 165:4718–4724

    CAS  PubMed  Google Scholar 

  153. Larousserie F, Pflanz S, Coulomb-L’Herminé A, Brousse N, Kastelein R, Devergne O (2004) Expression of IL-27 in human TH1-associated granulomatous diseases. J Pathol 202:164–171

    CAS  PubMed  Google Scholar 

  154. Devergne O, Emilie D, Peuchmaur M, Crevon MC, D’Agay MF, Galanaud P (1992) Production of cytokines in sarcoid lymph nodes: preferential expression of interleukin-1 beta and interferon-gamma genes. Hum Pathol 23:317–323

    CAS  PubMed  Google Scholar 

  155. Moller DR, Forman JD, Liu MC et al (1996) Enhanced expression of IL-12 associated with TH1 cytokine profiles in active pulmonary sarcoidosis. J Immunol 156:4952–4960

    CAS  PubMed  Google Scholar 

  156. Shigehara K, Shijubo N, Ohmichi M et al (2000) Enhanced mRNA expression of Th1 cytokines and IL-12 in active pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 17:151–157

    CAS  PubMed  Google Scholar 

  157. Kim DS, Jeon YG, Shim TS et al (2000) The value of interleukin-12 as an activity marker of pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 17:271–276

    CAS  PubMed  Google Scholar 

  158. Minshall EM, Tsicopoulos A, Yasruel Z et al (1997) Cytokine mRNA gene expression in active and nonactive pulmonary sarcoidosis. Eur Respir J 10:2034–2039

    CAS  PubMed  Google Scholar 

  159. Zissel G, Bäumer I, Schlaak M, Müller-Quernheim J (2000) 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 11:105–112

    CAS  PubMed  Google Scholar 

  160. Shigehara K, Shijubo N, Ohmichi M et al (2000) Increased levels of interleukin-18 in patients with pulmonary sarcoidosis. Am J Respir Crit Care Med 162:1979–1982

    CAS  PubMed  Google Scholar 

  161. Agostini C, Meneghin A, Semenzato G (2002) T-lymphocytes and cytokines in sarcoidosis. Curr Opin Pulm Med 8:435–440

    PubMed  Google Scholar 

  162. Agostini C, Trentin L, Perin A et al (1999) Regulation of alveolar macrophage-T cell interactions during Th1-type sarcoid inflammatory process. Am J Physiol 277:L240–L250

    CAS  PubMed  Google Scholar 

  163. Gudmundsson G, Hunninghake GW (1997) Interferon-gamma is necessary for the expression of hypersensitivity pneumonitis. J Clin Invest 99:2386–2390

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Leclerc S, Myers RP, Moussalli J, Herson S, Poynard T, Benveniste O (2003) Sarcoidosis and interferon therapy: report of five cases and review of the literature. Eur J Intern Med 14:237–243

    CAS  PubMed  Google Scholar 

  165. Spagnolo P, Zeuzem S, Richeldi L, du Bois RM (2010) The complex interrelationships between chronic lung and liver disease: a review. J Viral Hepat 17:381–390

    CAS  PubMed  Google Scholar 

  166. Walker C, Bauer W, Braun RK et al (1994) Activated T cells and cytokines in bronchoalveolar lavages from patients with various lung diseases associated with eosinophilia. Am J Respir Crit Care Med 150:1038–1048

    CAS  PubMed  Google Scholar 

  167. Chensue SW, Warmington K, Ruth JH, Lukacs N, Kunkel SL (1997) Mycobacteria and schistosomal antigen-elicited granuloma formation in IFN-γ and IL-4 knockout mice. J Immunol 159:3565–3573

    CAS  PubMed  Google Scholar 

  168. Umemura M, Yahagi A, Hamada S et al (2007) IL-17-mediated regulation of innate and acquired immune response against pulmonary Mycobacterium bovis bacille Calmette-Guerin infection. J Immunol 178:3786–3796

    CAS  PubMed  Google Scholar 

  169. Okamoto Yoshida Y, Umemura M, Yahagi A et al (2010) Essential role of IL-17A in the formation of a mycobacterial infection-induced granuloma in the lung. J Immunol 184:4414–4422

    CAS  PubMed  Google Scholar 

  170. Facco M, Cabrelle A, Teramo A et al (2011) Sarcoidosis is a Th1/Th17 multisystem disorder. Thorax 66:144–150

    PubMed  Google Scholar 

  171. Ten Berge B, Paats MS, Bergen IM et al (2012) Increased IL-17A expression in granulomas and in circulating memory T cells in sarcoidosis. Rheumatology (Oxford) 51:37–46

    Google Scholar 

  172. Richmond BW, Ploetze K, Isom J et al (2013) Sarcoidosis Th17 cells are ESAT-6 antigen specific but demonstrate reduced IFN-γ expression. J Clin Immunol 33:446–455

    CAS  PubMed  Google Scholar 

  173. Ostadkarampour M, Eklund A, Moller D et al (2014) Higher levels of interleukin IL-17 and antigen-specific IL-17 responses in pulmonary sarcoidosis patients with Löfgren’s syndrome. Clin Exp Immunol 178:342–352

    CAS  PubMed  Google Scholar 

  174. Tøndell A, Moen T, Børset M, Salvesen Ø, Rø AD, Sue-Chu M (2014) Bronchoalveolar lavage fluid IFN-γ + Th17 cells and regulatory T cells in pulmonary sarcoidosis. Mediators Inflamm 2014:438070

    PubMed Central  PubMed  Google Scholar 

  175. Sakaguchi S, Miyara M, Costantino CM, Hafler DA (2010) FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 10:490–500

    CAS  PubMed  Google Scholar 

  176. Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25 + CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352

    CAS  PubMed  Google Scholar 

  177. Miyara M, Amoura Z, Parizot C et al (2006) The immune paradox of sarcoidosis and regulatory T cells. J Exp Med 203:359–370

    PubMed Central  PubMed  Google Scholar 

  178. Taflin C, Miyara M, Nochy D et al (2009) FoxP3+ regulatory T cells suppress early stages of granuloma formation but have little impact on sarcoidosis lesions. Am J Pathol 174:497–508

    PubMed Central  PubMed  Google Scholar 

  179. 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 181:746–755

    CAS  PubMed Central  PubMed  Google Scholar 

  180. Ahmadzai H, Cameron B, Chui JJ, Lloyd A, Wakefield D, Thomas PS (2012) Peripheral blood responses to specific antigens and CD28 in sarcoidosis. Respir Med 106:701–709

    PubMed  Google Scholar 

  181. Rappl G, Pabst S, Riemann D et al (2011) Regulatory T cells with reduced repressor capacities are extensively amplified in pulmonary sarcoid lesions and sustain granuloma formation. Clin Immunol 140:71–83

    CAS  PubMed  Google Scholar 

  182. Prasse A, Zissel G, Lützen N et al (2010) Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis. Am J Respir Crit Care Med 182:540–548

    CAS  PubMed  Google Scholar 

  183. Ho LP, Urban BC, Thickett DR, Davies RJ, McMichael AJ (2005) Deficiency of a subset of T-cells with immunoregulatory properties in sarcoidosis. Lancet 365:1062–1072

    CAS  PubMed  Google Scholar 

  184. Crawshaw A, Kendrick YR, McMichael AJ, Ho LP (2014) Abnormalities in iNKT cells are associated with impaired ability of monocytes to produce IL-10 and suppress T-cell proliferation in sarcoidosis. Eur J Immunol 44:2165–2174

    CAS  PubMed  Google Scholar 

  185. Baughman RP, Nagai S, Balter M et al (2011) Defining the clinical outcome status (COS) in sarcoidosis: Results of WASOG task force. Sarcoidosis Vasc Diffuse Lung Dis 28:56–64

    CAS  PubMed  Google Scholar 

  186. Ziegenhagen MW, Schrum S, Zissel G et al (1998) Increased expression of proinflammatory chemokines in bronchoalveolar lavage cells of patients with progressing idiopathic pulmonary fibrosis and sarcoidosis. J Investig Med 46:223–231

    CAS  PubMed  Google Scholar 

  187. Salez F, Gosset P, Copin MC, Lamblin Degros C, Tonnel AB, Wallaert B (1998) Transforming growth factor-beta1 in sarcoidosis. Eur Respir J 12:913–919

    CAS  PubMed  Google Scholar 

  188. Homma S, Nagaoka I, Abe H et al (1995) Localization of platelet-derived growth factor and insulin-like growth factor I in the fibrotic lung. Am J Respir Crit Care Med 152:2084–2089

    CAS  PubMed  Google Scholar 

  189. Elias JA, Freundlich B, Kern JA, Rosenbloom J (1990) Cytokine networks in the regulation of inflammation and fibrosis in the lung. Chest 97:1439–1445

    CAS  PubMed  Google Scholar 

  190. Chensue SW, Warmington K, Ruth J, Lincoln P, Kuo MC, Kunkel SL (1994) Cytokine responses during mycobacterial and schistosomal antigen-induced pulmonary granuloma formation. Production of Th1 and Th2 cytokines and relative contribution of tumor necrosis factor. Am J Pathol 145:1105–1113

    CAS  PubMed Central  PubMed  Google Scholar 

  191. Wahlstrom 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 163:115–121

    CAS  PubMed  Google Scholar 

  192. Kunkel SL, Lukacs NW, Strieter RM, Chensue SW (1996) Th1 and Th2 responses regulate experimental lung granuloma development. Sarcoidosis Vasc Diffuse Lung Dis 13:120–128

    CAS  PubMed  Google Scholar 

  193. Conron M, du Bois R (2001) Immunological mechanisms in sarcoidosis. Clin Exp Allergy 31:543–554

    CAS  PubMed  Google Scholar 

  194. Spagnolo P, Luppi F, Roversi P, Cerri S, Fabbri LM, Richeldi L (2012) Sarcoidosis: challenging diagnostic aspects of an old disease. Am J Med 125:118–125

    PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Swedish Heart-Lung Foundation (grant number 20100254), the Swedish Research Council (grant number K2013-57X-14182-12-3), through the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet (grant number 20120025) and Karolinska Institutet.

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Paolo Spagnolo serves as consultant for Roche and has received consulting fees from Boehringer Ingelheim. Johan Grunewald, Jan Wahlström and Anders Eklund declare that they have no conflict of interest.

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    1. Respiratory Medicine Unit, Department of Medicine Solna and CMM, Karolinska Institutet and Karolinska University Hospital, Solna, Sweden

      Johan Grunewald, Jan Wahlström & Anders Eklund

    2. Medical University Clinic, Canton Hospital Baselland and University of Basel, Rheinstrasse 26, 4410, Liestal, Switzerland

      Paolo Spagnolo

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    Johan Grunewald and Paolo Spagnolo contributed equally to this work.

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    Grunewald, J., Spagnolo, P., Wahlström, J. et al. Immunogenetics of Disease-Causing Inflammation in Sarcoidosis. Clinic Rev Allerg Immunol 49, 19–35 (2015). https://doi.org/10.1007/s12016-015-8477-8

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