Immunopathology of Sarcoidosis
Abstract
The immunopathology of sarcoidosis remains elusive despite years of research into this multiorgan disease.However, recent studies have provided new insights into the genetics and immune components involved in the clinical manifestation of the disease.
Granulomatous inflammation is due to the host immune response to a persistent poorly degradable unknown antigen.Mycobacterium tuberculosis (MTB) is the major disease driver in many patients.
The immune mechanisms that cause this disease start with the antigenic stimulus, followed by T-cell, macrophage and dendritic cell activation via a classic MHC II–mediated pathway.
In addition, the profile of immune mediators reported in sarcoidosis indicates that the inflammasome pathway plays a critical role in disease pathogenesis. Increased understanding of the signal ransductions pathways involved in the induction of inflammatory processes in sarcoidosis could give rise to new therapeutic approaches in future.
1. Gerke AK. Hunninghake G. The Immunology of Sarcoidosis. Clin Chest Med 2008; 29(3):379–90.
2. Hunninghake GW, Crystal RG. Pulmonary sarcoidosis: a disorder mediated by excess helper T-lymphocyte activity at sites of disease activity. N Engl J Med 1981;305(8):429–34.
3. Spagnolo P, Grunewald J. Recent advances in the genetics of sarcoidosis. J Med Genet. 2013; (5):290-7.
4. Perez RL, Rivera-Marrero CA, Roman J. Pulmonary granulomatous inflammation: From sarcoidosis to tuberculosis. Semin Respir Infect 2003; 18(1):23–32.
5. Thomeer M, Demedts M, Wuyts W. Epidemiology of sarcoidosis. Eur Respir Mon 2005; 32:13–22.
6. du Bois RM, Goh N, McGrath D, Cullinan P. Is there a role for microorganisms in the pathogenesis of sarcoidosis? J Intern Med 2003; 253(1):4–17.
7. Vidal S, de la Horra C, Martin J, Montes-Cano MA, Rodríguez E, Respaldiza N, et al. Pneumocystis jirovecii colonisation in patients with interstitial lung disease. Clin Microbiol Infect 2006; 12(3):231–5.
8. Drake WP, Newman LS. Mycobacterial antigens may be important in sarcoidosis pathogenesis. Curr Opin Pulm Med 2006; 12(5):359–63.
9. Ishige I, Eishi Y, Takemura T, Kobayashi I, Nakata K, Tanaka I, et al. Propionibacterium acnes is the most common bacterium commensal in peripheral lung tissue and mediastinal lymph nodes from subjects without sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2005;22(1):33–42.
10. Oswald-Richter KA, Drake WP. The etiologic role of infectious antigens in sarcoidosis pathogenesis. Semin Respir Crit Care Med 2010; 31(4):375–9.
11. Gupta D, Agarwal R, Aggarwal AN, Jindal SK.Molecular evidence for the role of mycobacteria in sarcoidosis: a meta-analysis. Eur Respir J 2007; 30(3):508–16.
12. Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 1997; 336(17):1224-34.
13. Kataria YP, Holter JF. Immunology of sarcoidosis. Clin Chest Med 1997; 18(4):719-39.
14. Barnard J, Newman LS. Sarcoidosis: immunology, rheumatic involvement, and therapeutics. Curr Opin Rheumatol 2001; 13(1):84-91.
15. Hayashi Y, Ishii Y, Hata-Suzuki M, Arai R, Chibana K, Takemasa A, et al. Comparative analysis of circulating dendritic cell subsets in patients with atopic diseases and sarcoidosis. Respir Res 2013; 14:29.
16. Valeyre D, Prasse A, Nunes H, Uzunhan Y, Brillet PY, Müller-Quernheim J. Sarcoidosis. Lancet. 2013, S30. pii: S0140-6736(13)60680-7.
17. Oswald-Richter KA, Drake WP. The etiologic role of infectious antigens in sarcoidosis pathogenesis. Semin Respir Crit Care Med 2010; 31(4):375-9.
18. Israel-Biet D, Valeyre D. Diagnosis of pulmonary sarcoidosis. Curr Opin Pulm Med 2013; 19(5):510-5.
19. Tazi A, Bouchonnet F, Valeyre D, Cadranel J, Battesti JP, Hance AJ. Characterization of gamma/delta T- lymphocytes in the peripheral blood of patients with active tuberculosis. A comparison with normal subjects and patients with sarcoidosis. Am Rev Respir Dis 1992;146(5 Pt 1):1216-21.
20. Hirshaut Y, Glade P, Vieira LO, Ainbender E, Dvorak B, Siltzbach LE. Sarcoidosis, Another Disease Associated with Serologic Evidence for Herpes-like Virus Infection. N Engl J Med 1970; 283(10):502-6.
21. Sokoloff L, Bunim JJ. Clinical and Pathological Studies of Joint Involvement in Sarcoidosis. N Engl J Med 1959;260(17):841-7.
22. Welker L, Jorres RA, Costabel U, Magnussen H.Predictive value of BAL cell differentials in the diagnosis of interstitial lung diseases. Eur Respir J 2004;24(6):1000-6.
23. Zissel G, Prasse A, Muller-Quernheim J. Sarcoidosis-- immunopathogenetic concepts. Semin Respir Crit Care Med 2007; 28(1):3-14.
24. Moller DR. Treatment of sarcoidosis—from a basic science point of view. J Intern Med 2003; 253(1):31–40.
25. Grunewald J, Olerup O, Persson U, Ohrn MB,Wigzell H, Eklund A. 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 USA 1994; 91(11):4965-9.
26. Jones RE, Chatham WW. Update on sarcoidosis. Curr Opin Rheumatol 1999; 11(1):83-7.
27. Eklund A, Grunewald J. The riddle of sarcoidosis: have novel techniques brought any new insights as to the causative agent? J Intern Med 1996; 240(2):59-62.
28. Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med 1997; 336(17):1224-34.
29. Epstein WL, James DG. Multiple benign sarcoid of the skin. Arch Dermatol 1999;135:1450.
30. Wahlstrom J, Katchar K, Wigzell H, Olerup O, Eklund A, Grunewald J. Analysis of intracellular cytokines in CD4and CD8lung and blood T cells in sarcoidosis. Am J Respir Crit Care Med 2001; 163(1):115–21.
31. Baughman RP, Strohofer SA, Buchsbaum J, Lower EE.Release of tumor necrosis factor by alveolar macrophages of patients with sarcoidosis. J Lab Clin Med 1990;115(1):36–42.
32. Kennon B, Konnell JM. ACE gene polymorphism and diabetic complications: is there a connection? BioDrugs 2000; 14(2):73–81.
33. Gentilucci UV, Picardi A, Manfiini S, D'Avola D, Costantino S, Pozzilli P. Granulomatous thyroiditis: an unexpected finding leading to the diagnosis of sarcoidosis. Acta Biomed 2004; 75(1):69-73.
34. Spiteri MA, Poulter LW, Geraint-James D. The macrophage in sarcoid granuloma formation. Sarcoidosis 1989; (Suppl 1):12-4.
35. Ota M, Amakawa R, Uehira K, Ito T, Yagi Y, Oshiro A, et al. Involvement of dendritic cells in sarcoidosis. Thorax 2004; 59(5):408–13.
36. Agostini C, Trentin L, Zambello R, Bulian P, Siviero F, Masciarelli M, et al. CD8 alveolitis in sarcoidosis: incidence, phenotypic characteristics, and clinical features. Am J Med 1993; 95(5):466-72.
37. Facco M, Cabrelle A, Teramo A, Olivieri V, Gnoato M, Teolato S, et al. Sarcoidosis is a TH1/TH17 multisystem disorder. Thorax 2011; 66(2):144-50.
38. Grunewald J, Eklund A. Role of CD4+ T Cells in Sarcoidosis. Proc Am Thor Soc 2007; 4(5):461-4.
39. Greene CM, Meachery G, Taggart CC, Rooney CP, Coakley R, O'Neill SJ, et al. Role of IL-18 in CD4+ T lymphocyte activation in sarcoidosis. J Immunol 2000;165(8):4718-24.
40. Larousserie F, Pflanz S, Coulomb-L'Herminé A, Brousse N, Kastelein R, Devergne O. Expression of IL-27 in human Th1-associated granulomatous diseases. J Pathol 2004; 202(2):164-71.
41. Agostini C, Semenzato G. Cytokines in sarcoidosis.Semin Respir Infect 1998; 13(3):184-96;
42. Ahmadzai H, Cameron B, Chui J, Lloyd A, Wakefield D, Thomas PS. Measurement of neopterin, TGF-β1 and ACE in the exhaled breath condensate of patients with sarcoidosis. J Breath Res 2013; 7(4):046003.
43. Agostini C, Cabrelle A, Calabrese F, Bortoli M, Scquizzato E, Carraro S, 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(10):1290-8.
44. Geyer AI, Kraus T, Roberts M, Wisnivesky J, Eber CD, Hiensch R, et al. Plasma level of interferon γ induced protein 10 is a marker of sarcoidosis disease activity. Cytokine 2013; 64(1):152-7.
45. Ehrt S, Schnappinger D, Bekiranov S, Drenkow J, Shi S, Gingeras TR, et al. Reprogramming of the macrophage transcriptome in response to interferon-y and Mycobacterium tuberculosis: signaling roles of nitric oxide synthase-2 and phagocyte oxidase. J Exp Med2001; 194(8):1123-40.
46. Agostini C, Trentin L, Facco M, Sancetta R, Cerutti A, Tassinari C, et al. Role of IL-15, IL-2, and their receptors in the development of T cell alveolitis in pulmonary sarcoidosis. J Immunol 1996; 157(2):910-8.
47. Moller DR, Forman JD, Liu MC, Noble PW, Greenlee BM, Vyas P, et al. Enhanced expression of IL-12 associated with TH1 cytokine profiles in active pulmonary sarcoidosis. J Immunol 1996; 156(12):4952-60.
48. Walker C, Bauer W, Braun RK, Menz G, Braun P, Schwarz F, et al. Activated T cells and cytokines in bronchoalveolar lavages from patients with various lung diseases associated with eosinophilia. Am J Respir Crit Care Med 1994; 150(4):1038-48.
49. Hauber HP, Gholami D, Meyer A, Pforte A. Increased interleukin-13 expression in).patients with sarcoidosis. Thorax 2003; 58(6):519-24.
50. Newman LS. Aetiologies of sarcoidosis. Eur Resp Mon 2005; 32:23–48.
51. Brownell I, Ramirez-Valle F, Sanchez M, Prystowsky S.Evidence for mycobacteria in sarcoidosis. Excellent summary of available literature for and against role of mycobacteria in causation of sarcoidosis. Am J Respir Cell Mol Biol 2011; 45(5):899-905.
52. Dumouchel-Champagne H, Charlier-Woerther C, Boibieux A, Ffrench M, Carret G, Chidiac C, et al. Disseminated nontuberculous infections with Mycobacterium genavense during sarcoidosis. Eur Respir Rev 2009; 18(114):299-301.
53. Pabst S, Baumgarten G, Stremmel A, Lennarz M, Knüfermann P, Gillissen A, et al. Toll-like receptor (TLR) 4 polymorphisms are associated with a chronic course of sarcoidosis. Clin Exp Immunol 2006;143(3):420-6.
54. Bafica A, Scanga CA, Feng CG, Leifer C, Cheever A, Sher A. TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis. J Exp Med 2005;202(12):1715-24.
55. Romics L Jr, Dolganiuc A, Velayudham A, Kodys K, Mandrekar P, Golenbock D, et al. Toll-like receptor 2 mediates inflammatory cytokine induction but not sensitization for liver injury by Propioni- bacterium acnes. J Leukoc Biol 2005; 78(6):1255-64.
56. Yim JJ, Lee HW, Lee HS, Kim YW, Han SK, Shim YS, et al. The association between microsatellite polymorphisms in intron II of the human Toll-like receptor 2 gene and tuberculosis among Koreans. Genes Immun 2006; 7(2):150-5.
57. Liu H, Komai-Koma M, Xu D, Liew FY. Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc Natl Acad Sci USA 2006;103(18):7048-53.
58. Miyara M, Amoura Z, Parizot C, Badoual C, Dorgham K, Trad S, et al. The immune paradox of sarcoidosis and regulatory T cells. J Exp Med 2006; 203(2):359-70.
59. Mroz RM, Korniluk M, Stasiak-Barmuta A, Ossolinska M, Chyczewska E. Increased levels of Treg cells in bronchoalveolar lavage fluid and induced sputum of patients with active pulmonary sarcoidosis.Eur J Med Res 2009; (14 Suppl 4):165-9.
60. Taflin C, Miyara M, Nochy D, Valeyre D, Naccache JM, Altare F, et al. FoxP3+ regulatory T cells suppress early stages of granuloma formation but have little impact on sarcoidosis lesions. Am J Pathol 2009; 174(2):497-508.
61. Gabrilovich MI, Walrath J, van Lunteren J, Nethery D, Seifu M, Kern JA, et al. Disordered Toll-like receptor 2 responses in the pathogenesis of pulmonary sarcoidosis. Clin Exp Immunol 2013; 173(3):512-22.
62. Liu DH, Cui W, Chen Q, Huang CM. Can circulating interleukin-18 differentiate between sarcoidosis and idiopathic pulmonary fibrosis? Scand J Clin Lab Invest 2011; 71(7):593-7.
63. Liu DH, Yao YT, Cui W, Chen K. The association between interleukin-18 and pulmonary sarcoidosis: a meta-analysis. Scand J Clin Lab Invest 2010; 70(6):428-32.
64. Mroz RM, Korniluk M, Stasiak-Barmuta A, Chyczewska E. Increased levels of interleukin-12 and interleukin-18 in bronchoalveolar lavage fluid of patients with pulmonary sarcoidosis. J Physiol Pharmacol 2008; (59 Suppl 6):507-13.
65. Antoniou KM, Tzouvelekis A, Alexandrakis MG, Tsiligianni I, Tzanakis N, Sfiridaki K, et al. Upregulation of Th1 cytokine profile (IL-12, IL-18) in bronchoalveolar lavage fluid in patients with pulmonary sarcoidosis. J Interferon Cytokine Res 2006; 26(6):400-5.
66. Balamugesh T, Behera D, Bhatnagar A, Majumdar S.Inflammatory cytokine levels in induced sputum and bronchoalveolar lavage fluid in pulmonary sarcoidosis. Indian J Chest Dis Allied Sci 2006; 48(3):177-81.
67. Kelly DM, Greene CM, Meachery G, O'Mahony M, Gallagher PM, Taggart CC, et al. Endotoxin up-regulates interleukin-18: potential role for gram-negative colonization in sarcoidosis. Am J Respir Crit Care Med 2005; 172(10):1299-307.
68. Smith DE. The biological paths of IL-1 family members IL-18 and IL-33. J Leukoc Biol 2011; 89(3):383-92.
69. Arend WP, Palmer G, Gabay C. IL-1, IL-18, and IL-33 families of cytokines. Immunol Rev 2008; 223:20-38.
70. Kanazawa N, Okafuji I, Kambe N, Nishikomori R, Nakata-Hizume M, Nagai S, et al. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor- kappaB activation: common genetic etiology with Blau syndrome. Blood 2005; 105(3):1195-7.
71. Wikén M, Grunewald J, Eklund A, Wahlström J.Highermonocyteexpression of TLR2 and TLR4, and enhancedpro-inflammatorysynergy of TLR2 with NOD2stimulation in sarcoidosis. J Clin Immunol 2009;29(1):78-89.
72. Sakai H, Ito S, Nishikomori R, Takaoka Y, Kawai T, Saito M, et al. A case of early-onset sarcoidosis with a six-base deletion in the NOD2 gene. Rheumatology 2010;49(1):194-6.
73. Okafuji I, Nishikomori R, Kanazawa N, Kambe N, Fujisawa A, Yamazaki S, et al. Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early-onset sarcoidosis. Arthritis Rheum 2009; 60(1):242-50.
74. Coto-Segura P, Mallo-Garcia S, Costa-Romero M, Arostegui JI, Yague J, Ramos-Polo E, Santos-Juanes J. A sporadic case of early-onset sarcoidosis resembling Blau syndrome due to the recurrent R334W missense mutation on the NOD2 gene. B r J Dermatol 2007; 157(6):1257-9.
Files | ||
Issue | Vol 13, No 5 (2014) | |
Section | Articles | |
Keywords | ||
Inflammatory cells Sarcoidosis Tuberculosis |
Rights and permissions | |
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |