Immunopathogenesis of granulomas in chronic autoinflammatory diseases

Clinical and Translational Immunology

Volumn 5, Issue 12, 2016, Pages

  Timmermans, Wilhelmina Maria Cornelia ^a,b   van Laar, Jan Alexander Michael ^a   van Hagen, Petrus Martinus ^a   van Zelm, Menno Cornelis ^b  

^a ERASMUS MEDICAL CENTER   (Netherlands)

^b MONASH UNIVERSITY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 85088146387     PISSN: None     EISSN: 20500068     Source Type: Journal    
DOI: 10.1038/CTI.2016.75     Document Type: Review

References (190)

1. Medzhitov R. Origin and physiological roles of inflammation. Nature 2008; 454: 428–435.
2. Doria A, Zen M, Bettio S, Gatto M, Bassi N, Nalotto L et al. Autoinflammation and autoimmunity: bridging the divide. Autoimmun Rev 2012; 12: 22–30.
3. Mukhopadhyay S, Farver CF, Vaszar LT, Dempsey OJ, Popper HH, Mani H et al. Causes of pulmonary granulomas: a retrospective study of 500 cases from seven countries. J Clin Pathol 2012; 65: 51–57.
4. Williams GT, Williams WJ. Granulomatous inflammation—a review. J Clin Pathol 1983; 36: 723–733.
5. Orme IM, Basaraba RJ. The formation of the granuloma in tuberculosis infection. Semin Immunol 2014; 26: 601–609.
6. Woodard BH, Rosenberg SI, Farnham R, Adams DO. Incidence and nature of primary granulomatous inflammation in surgically removed material. Am J Surg Pathol 1982; 6: 119–129.
7. Levine S, Smith VV, Malone M, Sebire NJ. Histopathological features of chronic granulomatous disease (CGD) in childhood. Histopathology 2005; 47: 508–516.
8. Rossman MD. Chronic beryllium disease: a hypersensitivity disorder. Appl Occup Environ Hyg 2001; 16: 615–618.
9. Mukhopadhyay S, Gal AA. Granulomatous lung disease: an approach to the differential diagnosis. Arch Pathol Lab Med 2010; 134: 667–690.
10. Valeyre D, Prasse A, Nunes H, Uzunhan Y, Brillet PY, Muller-Quernheim J. Sarcoidosis. Lancet 2014; 383: 1155–1167.
11. Baumgart DC, Sandborn WJ. Crohn's disease. Lancet 2012; 380: 1590–1605.
12. Ardeniz O, Cunningham-Rundles C. Granulomatous disease in common variable immunodeficiency. Clin Immunol 2009; 133: 198–207.
13. Tas SW, Baeten DL. Recent advances in the treatment of immune-mediated inflammatory diseases. Methods Mol Biol 2016; 1371: 143–155.
14. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007; 357: 2153–2165.
15. Hunninghake GW, Costabel U, Ando M, Baughman R, Cordier JF, du Bois R et al. Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med 1999; 160: 736–755.
16. Scadding JG. Prognosis of intrathoracic sarcoidosis in England. A review of 136 cases after five years' observation. BMJ 1961; 2: 1165–1172.
17. 18F-fluorodeoxyglucose positron emission tomography as a marker of disease activity in patients with sarcoidosis: a systematic review. Sarcoidosis Vasc Diffuse Lung Dis 2011; 28: 87–94.
18. Grutters JC, Fellrath JM, Mulder L, Janssen R, van den Bosch JM, van Velzen-Blad H. Serum soluble interleukin-2 receptor measurement in patients with sarcoidosis: a clinical evaluation. Chest 2003; 124: 186–195.
19. Drent M, Cremers JP, Jansen TL, Baughman RP. Practical eminence and experiencebased recommendations for use of TNF-alpha inhibitors in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2014; 31: 91–107.
20. Patterson KC, Hogarth K, Husain AN, Sperling AI, Niewold TB. The clinical and immunologic features of pulmonary fibrosis in sarcoidosis. Transl Res 2012; 160: 321–331.
21. Burisch J, Munkholm P. The epidemiology of inflammatory bowel disease. Scand J Gastroenterol 2015; 50: 942–951.
22. Geremia A, Biancheri P, Allan P, Corazza GR, Di Sabatino A. Innate and adaptive immunity in inflammatory bowel disease. Autoimmun Rev 2014; 13: 3–10.
23. Heresbach D, Alexandre JL, Branger B, Bretagne JF, Cruchant E, Dabadie A et al. Frequency and significance of granulomas in a cohort of incident cases of Crohn's disease. Gut 2005; 54: 215–222.
24. Feakins RM. Ulcerative colitis or Crohn's disease? Pitfalls and problems. Histopathology 2014; 64: 317–335.
25. Sendid B, Colombel JF, Jacquinot PM, Faille C, Fruit J, Cortot A et al. Specific antibody response to oligomannosidic epitopes in Crohn's disease. Clin Diagn Lab Immunol 1996; 3: 219–226.
26. Mei L, Targan SR, Landers CJ, Dutridge D, Ippoliti A, Vasiliauskas EA et al. Familial expression of anti-Escherichia coli outer membrane porin C in relatives of patients with Crohn's disease. Gastroenterology 2006; 130: 1078–1085.
27. Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. NEnglJ Med 2010; 362: 1383–1395.
28. Gathmann B, Mahlaoui N, Ceredih, Gerard L, Oksenhendler E, Warnatz K et al. Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J Allergy Clin Immunol 2014; 134: 116–126.
29. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol 1999; 93: 190–197.
30. Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood 2012; 119: 1650–1657.
31. Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Drager R et al. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 2003; 4: 261–268.
32. Pan-Hammarstrom Q, Salzer U, Du L, Bjorkander J, Cunningham-Rundles C, Nelson DL et al. Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat Genet 2007; 39: 429–430.
33. van Zelm MC, Reisli I, van der Burg M, Castano D, van Noesel CJ, van Tol MJ et al. An antibody-deficiency syndrome due to mutations in the CD19 gene. NEnglJMed 2006; 354: 1901–1912.
34. van Zelm MC, Smet J, Adams B, Mascart F, Schandene L, Janssen F et al. CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. J Clin Invest 2010; 120: 1265–1274.
35. Warnatz K, Salzer U, Rizzi M, Fischer B, Gutenberger S, Bohm J et al. B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans. Proc Natl Acad Sci USA 2009; 106: 13945–13950.
36. Angulo I, Vadas O, Garcon F, Banham-Hall E, Plagnol V, Leahy TR et al. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science 2013; 342: 866–871.
37. Deau MC, Heurtier L, Frange P, Suarez F, Bole-Feysot C, Nitschke P et al. Ahuman immunodeficiency caused by mutations in the PIK3R1 gene. J Clin Invest 2014; 124: 3923–3928.
38. Fliegauf M, Bryant VL, Frede N, Slade C, Woon ST, Lehnert K et al. Haploinsufficiency of the NF-kappaB1 subunit p50 in common variable immunodeficiency. Am J Hum Genet 2015; 97: 389–403.
39. Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 2014; 345: 1623–1627.
40. Bouvry D, Mouthon L, Brillet PY, Kambouchner M, Ducroix JP, Cottin V et al. Granulomatosis-associated common variable immunodeficiency disorder: acase–control study versus sarcoidosis. Eur Respir J 2013; 41: 115–122.
41. Mannon PJ, Fuss IJ, Dill S, Friend J, Groden C, Hornung R et al. Excess IL-12 but not IL-23 accompanies the inflammatory bowel disease associated with common variable immunodeficiency. Gastroenterology 2006; 131: 748–756.
42. Bates CA, Ellison MC, Lynch DA, Cool CD, Brown KK, Routes JM. Granulomatouslymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol 2004; 114: 415–421.
43. Salzer U, Warnatz K, Peter HH. Common variable immunodeficiency: an update. Arthritis Res Ther 2012; 14: 223.
44. Turner K, Genta RM, Lujan G, Robiou C, Sonnenberg A. Significance of the epithelioid granuloma in biopsies of Crohn's colitis. Inflamm Bowel Dis 2014; 20: 2271–2275.
45. Crowley LE, Herbert R, Moline JM, Wallenstein S, Shukla G, Schechter C et al. 'Sarcoid like' granulomatous pulmonary disease in World Trade Center disaster responders. Am J Ind Med 2011; 54: 175–184.
46. Eishi Y, Suga M, Ishige I, Kobayashi D, Yamada T, Takemura T 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.
47. Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 2007; 39: 596–604.
48. Thachil E, Hugot JP, Arbeille B, Paris R, Grodet A, Peuchmaur M et al. Abnormal activation of autophagy-induced crinophagy in Paneth cells from patients with Crohn's disease. Gastroenterology 2012; 142: 1097–1099 e4.
49. Naser SA, Ghobrial G, Romero C, Valentine JF. Culture of Mycobacterium avium subspecies paratuberculosis from the blood of patients with Crohn's disease. Lancet 2004; 364: 1039–1044.
50. Bull TJ, McMinn EJ, Sidi-Boumedine K, Skull A, Durkin D, Neild P et al. Detection and verification of Mycobacterium avium subsp. paratuberculosis in fresh ileocolonic mucosal biopsy specimens from individuals with and without Crohn's disease. J Clin Microbiol 2003; 41: 2915–2923.
51. Mendoza JL, Lana R, Diaz-Rubio M. Mycobacterium avium subspecies paratuberculosis and its relationship with Crohn's disease. World J Gastroenterol 2009; 15: 417–422.
52. Boursiquot JN, Gerard L, Malphettes M, Fieschi C, Galicier L, Boutboul D et al. Granulomatous disease in CVID: retrospective analysis of clinical characteristics and treatment efficacy in a cohort of 59 patients. J Clin Immunol 2013; 33: 84–95.
53. Wheat WH, Cool CD, Morimoto Y, Rai PR, Kirkpatrick CH, Lindenbaum BA et al. Possible role of human herpesvirus 8 in the lymphoproliferative disorders in common variable immunodeficiency. J Exp Med 2005; 202: 479–484.
54. Arango Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol 2014; 5: 491.
55. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 2014; 41: 14–20.
56. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature 2013; 496: 445–455.
57. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol 2008; 8: 958–969.
58. Barros MH, Hauck F, Dreyer JH, Kempkes B, Niedobitek G. Macrophage polarisation: an immunohistochemical approach for identifying M1 and M2 macrophages. PLoS ONE 2013; 8: e80908.
59. Lissner D, Schumann M, Batra A, Kredel LI, Kuhl AA, Erben U et al. Monocyte and M1 macrophage-induced barrier defect contributes to chronic intestinal inflammation in IBD. Inflamm Bowel Dis 2015; 21: 1297–1305.
60. Wojtan P, Mierzejewski M, Osinska I, Domagala-Kulawik J. Macrophage polarization in interstitial lung diseases. Cent Eur J Immunol 2016; 41: 159–164.
61. Prokop S, Heppner FL, Goebel HH, Stenzel W. M2 polarized macrophages and giant cells contribute to myofibrosis in neuromuscular sarcoidosis. Am J Pathol 2011; 178: 1279–1286.
62. Scharl M, Huber N, Lang S, Furst A, Jehle E, Rogler G. Hallmarks of epithelial to mesenchymal transition are detectable in Crohn's disease associated intestinal fibrosis. Clin Transl Med 2015; 4: 1.
63. Spector WG. Immunologic components of granuloma formation. Epithelioid cells, giant cells, and sarcoidosis. Ann NY Acad Sci 1976; 278: 3–6.
64. Williams WJ, James EM, Erasmus DA, Davies T. The fine structure of sarcoid and tuberculous granulomas. Postgrad Med J 1970; 46: 496–500.
65. van Maarsseveen TC, Vos W, van Diest PJ. Giant cell formation in sarcoidosis: cell fusion or proliferation with non-division? Clin Exp Immunol 2009; 155: 476–486.
66. Hernandez-Pando R, Bornstein QL, Aguilar Leon D, Orozco EH, Madrigal VK, Martinez Cordero E. Inflammatory cytokine production by immunological and foreign body multinucleated giant cells. Immunology 2000; 100: 352–358.
67. Clay H, Volkman HE, Ramakrishnan L. Tumor necrosis factor signaling mediates resistance to mycobacteria by inhibiting bacterial growth and macrophage death. Immunity 2008; 29: 283–294.
68. Bean AG, Roach DR, Briscoe H, France MP, Korner H, Sedgwick JD et al. Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin. J Immunol 1999; 162: 3504–3511.
69. Liu ZX, Noguchi M, Hiwatashi N, Toyota T. Monocyte aggregation and multinucleated giant-cell formation in vitro in Crohn's disease. The effect of cell adhesion molecules. Scand J Gastroenterol 1996; 31: 706–710.
70. Okamoto H, Mizuno K, Horio T. Monocyte-derived multinucleated giant cells and sarcoidosis. JDermatolSci 2003; 31: 119–128.
71. Fehrenbach H, Zissel G, Goldmann T, Tschernig T, Vollmer E, Pabst R et al. Alveolar macrophages are the main source for tumour necrosis factor-alpha in patients with sarcoidosis. Eur Respir J 2003; 21: 421–428.
72. Pueringer RJ, Schwartz DA, Dayton CS, Gilbert SR, Hunninghake GW. The relationship between alveolar macrophage TNF, IL-1, and PGE2 release, alveolitis, and disease severity in sarcoidosis. Chest 1993; 103: 832–838.
73. Aukrust P, Lien E, Kristoffersen AK, Muller F, Haug CJ, Espevik T et al. Persistent activation of the tumor necrosis factor system in a subgroup of patients with common variable immunodeficiency—possible immunologic and clinical consequences. Blood 1996; 87: 674–681.
74. Mullighan CG, Fanning GC, Chapel HM, Welsh KI. TNF and lymphotoxin-alpha polymorphisms associated with common variable immunodeficiency: role in the pathogenesis of granulomatous disease. JImmunol1997; 159: 6236–6241.
75. Mullighan CG, Marshall SE, Bunce M, Welsh KI. Variation in immunoregulatory genes determines the clinical phenotype of common variable immunodeficiency. Genes Immun 1999; 1: 137–148.
76. Kamada N, Hisamatsu T, Okamoto S, Chinen H, Kobayashi T, Sato T et al. Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis. J Clin Invest 2008; 118: 2269–2280.
77. Smith AM, Rahman FZ, Hayee B, Graham SJ, Marks DJ, Sewell GW et al. Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease. JExpMed2009; 206: 1883–1897.
78. Elliott TR, Hudspith BN, Rayment NB, Prescott NJ, Petrovska L, Hermon-Taylor J et al. Defective macrophage handling of Escherichia coli in Crohn's disease. J Gastroenterol Hepatol 2015; 30: 1265–1274.
79. Vazeille E, Buisson A, Bringer MA, Goutte M, Ouchchane L, Hugot JP et al. Monocytederived macrophages from Crohn's disease patients are impaired in the ability to control intracellular adherent-invasive Escherichia coli and exhibit disordered cytokine secretion profile. J Crohns Colitis 2015; 9: 410–420.
80. Darfeuille-Michaud A. Adherent-invasive Escherichia coli: a putative new E. coli pathotype associated with Crohn's disease. Int J Med Microbiol 2002; 292: 185–193.
81. Ryan P, Kelly RG, Lee G, Collins JK, O'Sullivan GC, O'Connell J et al. Bacterial DNA within granulomas of patients with Crohn's disease—detection by laser capture microdissection and PCR. Am J Gastroenterol 2004; 99: 1539–1543.
82. Meconi S, Vercellone A, Levillain F, Payre B, Al Saati T, Capilla F et al. Adherentinvasive Escherichia coli isolated from Crohn's disease patients induce granulomas in vitro. Cell Microbiol 2007; 9: 1252–1261.
83. Casanova JL, Abel L. Revisiting Crohn's disease as a primary immunodeficiency of macrophages. JExpMed2009; 206: 1839–1843.
84. Marks DJ, Rahman FZ, Sewell GW, Segal AW. Crohn's disease: an immune deficiency state. Clin Rev Allergy Immunol 2010; 38: 20–31.
85. Leung S, Liu X, Fang L, Chen X, Guo T, Zhang J. The cytokine milieu in the interplay of pathogenic Th1/Th17 cells and regulatory T cells in autoimmune disease. Cell Mol Immunol 2010; 7: 182–189.
86. Chen ES, Moller DR. Sarcoidosis—scientific progress and clinical challenges. Nat Rev Rheumatol 2011; 7: 457–467.
87. 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. JImmunol1996; 156: 4952–4960.
88. Inui N, Chida K, Suda T, Nakamura H. TH1/TH2 and TC1/TC2 profiles in peripheral blood and bronchoalveolar lavage fluid cells in pulmonary sarcoidosis. J Allergy Clin Immunol 2001; 107: 337–344.
89. Bianco A, Spiteri MA. Peripheral anergy and local immune hyperactivation in sarcoidosis: a paradox or birds of a feather. Clin Exp Immunol 1997; 110: 1–3.
90. Nemoz G, Prigent AF, Aloui R, Charpin G, Gormand F, Gallet H et al. Impaired G-proteins and cyclic nucleotide phosphodiesterase activity in T-lymphocytes from patients with sarcoidosis. Eur J Clin Invest 1993; 23: 18–27.
91. + T cells and correlate with disease severity in sarcoidosis. Clin Vaccine Immunol 2011; 18: 223–234.
92. Monteleone G, Biancone L, Marasco R, Morrone G, Marasco O, Luzza F et al. Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. Gastroenterology 1997; 112: 1169–1178.
93. +CD28null T cells. J Clin Immunol 2004; 24: 185–196.
94. de Souza HS, Fiocchi C. Immunopathogenesis of IBD: current state of the art. Nat Rev Gastroenterol Hepatol 2016; 13: 13–27.
95. Cosmi L, Liotta F, Maggi E, Romagnani S, Annunziato F. Th17 and non-classic Th1 cells in chronic inflammatory disorders: two sides of the same coin. Int Arch Allergy Immunol 2014; 164: 171–177.
96. Genovese MC, Durez P, Richards HB, Supronik J, Dokoupilova E, Mazurov V et al. Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann Rheum Dis 2013; 72: 863–869.
97. Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med 2007; 13: 139–145.
98. Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B et al. Phenotypic and functional features of human Th17 cells. J Exp Med 2007; 204: 1849–1861.
99. Harbour SN, Maynard CL, Zindl CL, Schoeb TR, Weaver CT. Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc Natl Acad Sci USA 2015; 112: 7061–7066.
100. Gagliani N, Amezcua Vesely MC, Iseppon A, Brockmann L, Xu H, Palm NW et al. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 2015; 523: 221–225.
101. Ten Berge B, Paats MS, Bergen IM, van den Blink B, Hoogsteden HC, Lambrecht BN et al. Increased IL-17A expression in granulomas and in circulating memory T cells in sarcoidosis. Rheumatology 2012; 51: 37–46.
102. Barbosa RR, Silva SP, Silva SL, Melo AC, Pedro E, Barbosa MP et al. Primary B-cell deficiencies reveal a link between human IL-17-producing CD4 T-cell homeostasis and B-cell differentiation. PLoS ONE 2011; 6: e22848.
103. Wehr C, Kivioja T, Schmitt C, Ferry B, Witte T, Eren E et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood 2008; 111: 77–85.
104. + regulatory T cells in the human immune system. Nat Rev Immunol 2010; 10: 490–500.
105. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. JImmunol 1995; 155: 1151–1164.
106. Gambineri E, Perroni L, Passerini L, Bianchi L, Doglioni C, Meschi F et al. Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: inconsistent correlation between forkhead box protein 3 expression and disease severity. J Allergy Clin Immunol 2008; 122: 1105–1112.e1.
107. Miyar M, Amoura Z, Parizot C, Badoual C, Dorgham K, Trad S et al. The immune paradox of sarcoidosis and regulatory T cells. JExpMed 2006; 203: 359–370.
108. + subset dysfunction is associated with spontaneous clinical resolution of pulmonary sarcoidosis. J Immunol 2013; 190: 5446–5453.
109. Rappl G, Pabst S, Riemann D, Schmidt A, Wickenhauser C, Schutte W et al. Regulatory T cells with reduced repressor capacities are extensively amplified in pulmonary sarcoid lesions and sustain granuloma formation. Clin Immunol 2011; 140: 71–83.
110. + regulatory T cells suppress early stages of granuloma formation but have little impact on sarcoidosis lesions. Am J Pathol 2009; 174: 497–508.
111. +CD25bright T cells in human intestinal lamina propria as regulatory cells. JImmunol 2004; 173: 3119–3130.
112. + CD25(high) T cells in inflammatory bowel disease. Gastroenterology 2005; 128: 1868–1878.
113. Mouillot G, Carmagnat M, Gerard L, Garnier JL, Fieschi C, Vince N et al. B-cell and T-cell phenotypes in CVID patients correlate with the clinical phenotype of the disease. JClinImmunol2010; 30: 746–755.
114. Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med 2014; 20: 1410–1416.
115. Zeissig S, Petersen BS, Tomczak M, Melum E, Huc-Claustre E, Dougan SK et al. Early-onset Crohn's disease and autoimmunity associated with a variant in CTLA-4. Gut 2015; 64: 1889–1897.
116. Broos CE, van Nimwegen M, In 't Veen JC, Hoogsteden HC, Hendriks RW, van den Blink B et al. Decreased cytotoxic T-lymphocyte antigen 4 expression on regulatory T cells and Th17 cells in sarcoidosis: double trouble? Am J Respir Crit Care Med 2015; 192: 763–765.
117. Gonzalez-Juarrero M, Turner OC, Turner J, Marietta P, Brooks JV, Orme IM. Temporal and spatial arrangement of lymphocytes within lung granulomas induced by aerosol infection with Mycobacterium tuberculosis. Infect Immun 2001; 69: 1722–1728.
118. Kamphuis LS, van Zelm MC, Lam KH, Rimmelzwaan GF, Baarsma GS, Dik WA et al. Perigranuloma localization and abnormal maturation of B cells: emerging key players in sarcoidosis? Am J Respir Crit Care Med 2013; 187: 406–416.
119. Geboes K, van den Oord J, De Wolf-Peeters C, Desmet V, Rutgeerts P, Janssens J et al. The cellular composition of granulomas in mesenteric lymph nodes from patients with Crohn's disease. Virchows Arch A 1986; 409: 679–692.
120. Fazel SB, Howie SE, Krajewski AS, Lamb D. B lymphocyte accumulations in human pulmonary sarcoidosis. Thorax 1992; 47: 964–967.
121. Hermaszewski RA, Webster AD. Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications. QJMed1993; 86: 31–42.
122. Rosen FS, Cooper MD, Wedgwood RJ. The primary immunodeficiencies (1). NEnglJ Med 1984; 311: 235–242.
123. Chen H, Liao D, Holl TM, Snowden P, Ueda Y, Kelsoe G. Genetic regulation of pristane-induced oil granuloma responses. Int J Exp Pathol 2010; 91: 472–483.
124. LeBien TW, Tedder TF. B lymphocytes: how they develop and function. Blood 2008; 112: 1570–1580.
125. Ueda-Hayakawa I, Tanimura H, Osawa M, Iwasaka H, Ohe S, Yamazaki F et al. Elevated serum BAFF levels in patients with sarcoidosis: association with disease activity. Rheumatology 2013; 52: 1658–1666.
126. Saussine A, Tazi A, Feuillet S, Rybojad M, Juillard C, Bergeron A et al. Active chronic sarcoidosis is characterized by increased transitional blood B cells, increased IL-10producing regulatory B cells and high BAFF levels. PLoS ONE 2012; 7: e43588.
127. Lee NS, Barber L, Akula SM, Sigounas G, Kataria YP, Arce S. Disturbed homeostasis and multiple signaling defects in the peripheral blood B-cell compartment of patients with severe chronic sarcoidosis. Clin Vaccine Immunol 2011; 18: 1306–1316.
128. Di Sabatino A, Rosado MM, Ciccocioppo R, Cazzola P, Morera R, Corazza GR et al. Depletion of immunoglobulin M memory B cells is associated with splenic hypofunction in inflammatory bowel disease. Am J Gastroenterol 2005; 100: 1788–1795.
129. Lawrance IC, Rogler G, Bamias G, Breynaert C, Florholmen J, Pellino G et al. Cellular and molecular mediators of intestinal fibrosis. J Crohns Colitis (e-pub ahead of print 2 November 2015; doi:10.1016/j.crohns.2014.09.008).
130. Timmermans WM, van Laar JA, van der Houwen TB, Kamphuis LS, Bartol SJ, Lam KH et al. B-cell dysregulation in Crohn's disease is partially restored with infliximab therapy. PLoS ONE 2016; 11: e0160103.
131. Thorarinsdottir K, Camponeschi A, Gjertsson I, Martensson IL. CD21 −/low B cells: a Snapshot of a unique B cell subset in health and disease. Scand J Immunol 2015; 82: 254–261.
132. Bogaert DJ, Dullaers M, Lambrecht BN, Vermaelen KY, De Baere E, Haerynck F. Genes associated with common variable immunodeficiency: one diagnosis to rule them all? J Med Genet 2016; 53: 575–590.
133. Mizoguchi E, Mizoguchi A, Preffer FI, Bhan AK. Regulatory role of mature B cells in a murine model of inflammatory bowel disease. Int Immunol 2000; 12: 597–605.
134. Buttgereit F, Saag KG, Cutolo M, da Silva JA, Bijlsma JW. The molecular basis for the effectiveness, toxicity, and resistance to glucocorticoids: focus on the treatment of rheumatoid arthritis. Scand J Rheumatol 2005; 34: 14–21.
135. Joshi P, Dhaneshwar SS. An update on disease modifying antirheumatic drugs. Inflamm Allergy Drug Targets 2014; 13: 249–261.
136. Glaesener S, Quach TD, Onken N, Weller-Heinemann F, Dressler F, Huppertz HI et al. Distinct effects of methotrexate and etanercept on the B cell compartment in patients with juvenile idiopathic arthritis. Arthritis Rheumatol 2014; 66: 2590–2600.
137. Eickenberg S, Mickholz E, Jung E, Nofer JR, Pavenstadt HJ, Jacobi AM. Mycophenolic acid counteracts B cell proliferation and plasmablast formation in patients with systemic lupus erythematosus. Arthritis Res Ther 2012; 14: R110.
138. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002; 359: 1541–1549.
139. Baughman RP, Drent M, Kavuru M, Judson MA, Costabel U, du Bois R et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med 2006; 174: 795–802.
140. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. NEnglJMed2001; 345: 1098–1104.
141. Franxman TJ, Howe LE, Baker JR Jr. Infliximab for treatment of granulomatous disease in patients with common variable immunodeficiency. J Clin Immunol 2014; 34: 820–827.
142. Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann RM, Weaver AL et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. NEnglJMed1997; 337: 141–147.
143. Sandborn WJ, Hanauer SB, Katz S, Safdi M, Wolf DG, Baerg RD et al. Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2001; 121: 1088–1094.
144. Louie GH, Chitkara P, Ward MM. Relapse of sarcoidosis upon treatment with etanercept. Ann Rheum Dis 2008; 67: 896–898.
145. Ehlers S. Tumor necrosis factor and its blockade in granulomatous infections: differential modes of action of infliximab and etanercept? Clin Infect Dis 2005; 41 (Suppl 3): S199–S203.
146. Ruddle NH. Lymphotoxin and TNF: how it all began—a tribute to the travelers. Cytokine & growth factor reviews 2014; 25: 83–89.
147. Di Sabatino A, Rosado MM, Cazzola P, Biancheri P, Tinozzi FP, Laera MR et al. Splenic function and IgM-memory B cells in Crohn's disease patients treated with infliximab. Inflamm Bowel Dis 2008; 14: 591–596.
148. Sandborn WJ, Colombel JF, Sands BE, Rutgeerts P, Targan SR, Panaccione R et al. Abatacept for Crohn's disease and ulcerative colitis. Gastroenterology 2012; 143: 62–69 e4.
149. Kremer JM, Westhovens R, Leon M, Di Giorgio E, Alten R, Steinfeld S et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 2003; 349: 1907–1915.
150. Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PD et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebocontrolled trial. Gut 2012; 61: 1693–1700.
151. Targan SR, Feagan BG, Vermeire S, Panaccione R, Melmed GY, Blosch C et al. A randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and efficacy of AMG 827 in subjects with moderate to severe Crohn’s disease. Gastroenterology 2012; 143: E26.
152. Sandborn WJ, Gasink C, Gao LL, Blank MA, Johanns J, Guzzo C et al. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. NEnglJMed2012; 367: 1519–1528.
153. Kopylov U, Afif W, Cohen A, Bitton A, Wild G, Bessissow T et al. Subcutaneous ustekinumab for the treatment of anti-TNF resistant Crohn's disease—the McGill experience. J Crohns Colitis 2014; 8: 1516–1522.
154. Judson MA, Baughman RP, Costabel U, Drent M, Gibson KF, Raghu G et al. Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis. Eur Respir J 2014; 44: 1296–1307.
155. Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE et al. Vedolizumab as induction and maintenance therapy for Crohn's disease. NEnglJMed 2013; 369: 711–721.
156. Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994; 83: 435–445.
157. Sweiss NJ, Lower EE, Mirsaeidi M, Dudek S, Garcia JG, Perkins D et al. Rituximab in the treatment of refractory pulmonary sarcoidosis. Eur Respir J 2014; 43: 1525–1528.
158. Papadakis KA, Rosenbloom B, Targan SR. Anti-CD2O chimeric monoclonal antibody (rituximab) treatment of immune-mediated thrombocytopenia associated with Crohn's disease. Gastroenterology 2003; 124: 583.
159. Liu C, Xia X, Wu W, Wu R, Tang M, Chen T et al. Anti-tumour necrosis factor therapy enhances mucosal healing through down-regulation of interleukin-21 expression and T helper type 17 cell infiltration in Crohn's disease. Clin Exp Immunol 2013; 173: 102–111.
160. Ignatenko S, Skrumsager BK, Mouritzen U. Safety PK and PD of recombinant antiinterleukin-21 monoclonal antibody in a first-in-human trial. Int J Clin Pharmacol Ther 2016; 54: 243–252.
161. Kotlarz D, Zietara N, Uzel G, Weidemann T, Braun CJ, Diestelhorst J et al. Loss-offunction mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome. J Exp Med 2013; 210: 433–443.
162. Salzer E, Kansu A, Sic H, Majek P, Ikinciogullari A, Dogu FE et al. Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by IL-21 deficiency. J Allergy Clin Immunol 2014; 133: 1651–9 e12.
163. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 2007; 27: 111–122.
164. +) T-cell proliferative capacity. Am J Respir Crit Care Med 2014; 190: 560–571.
165. Philips GK, Atkins M. Therapeutic uses of anti-PD-1 and anti-PD-L1 antibodies. Int Immunol 2015; 27: 39–46.
166. Cousin S, Toulmonde M, Kind M, Cazeau AL, Bechade D, Coindre JM et al. Pulmonary sarcoidosis induced by the anti-PD1 monoclonal antibody pembrolizumab. Ann Oncol 2016; 27: 1178–1179.
167. Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 2010; 42: 1118–1125.
168. Sakthivel P, Grunewald J, Eklund A, Bruder D, Wahlstrom J. Pulmonary sarcoidosis is associated with high-level inducible co-stimulator (ICOS) expression on lung regulatory Tcells—possible implications for the ICOS/ICOS-ligand axis in disease course and resolution. Clin Exp Immunol 2016; 183: 294–306.
169. Sullivan BA, Tsuji W, Kivitz A, Peng J, Arnold GE, Boedigheimer MJ et al. Inducible T-cell co-stimulator ligand (ICOSL) blockade leads to selective inhibition of anti-KLH IgG responses in subjects with systemic lupus erythematosus. Lupus Sci Med 2016; 3: e000146.
170. Vincent FB, Morand EF, Schneider P, Mackay F. The BAFF/APRIL system in SLE pathogenesis. Nat Rev Rheumatol 2014; 10: 365–373.
171. Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M, Schneider P et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med 1999; 190: 1697–1710.
172. Baert F, Noman M, Vermeire S, Van Assche G, G DH, Carbonez A et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. NEnglJ Med 2003; 348: 601–608.
173. 18F-FDG PET in sarcoidosis: an observational study in 12 patients treated with infliximab. Sarcoidosis Vasc Diffuse Lung Dis 2008; 25: 143–149.
174. Vorselaars AD, van Moorsel CH, Zanen P, Ruven HJ, Claessen AM, van Velzen-Blad H et al. ACE and sIL-2R correlate with lung function improvement in sarcoidosis during methotrexate therapy. Respir Med 2015; 109: 279–285.
175. Verwoerd A, Hijdra D, Vorselaars AD, Crommelin HA, van Moorsel CH, Grutters JC et al. Infliximab therapy balances regulatory T cells, TNFR2 expression and sTNFR2 in sarcoidosis. Clin Exp Immunol 2016; 185: 263–270.
176. − Type 1 regulatory-like T cells in inflammatory bowel diseases during anti-tumor necrosis factor therapy. Inflamm Bowel Dis 2015; 21: 2418–2428.
177. Kakazu T, Hara J, Matsumoto T, Nakamura S, Oshitani N, Arakawa T et al. Type 1 T-helper cell predominance in granulomas of Crohn's disease. Am J Gastroenterol 1999; 94: 2149–2155.
178. Senju M, Hulstaert F, Lowder J, Jewell DP. Flow cytometric analysis of peripheral blood lymphocytes in ulcerative colitis and Crohn's disease. Gut 1991; 32: 779–783.
179. Naser SA, Romero C, Urbina P, Naser N, Valentine J. Cellular infiltration and cytokine expression correlate with fistulizing state in Crohn's disease. Clin Vaccine Immunol 2011; 18: 1416–1419.
180. Facco M, Cabrelle A, Teramo A, Olivieri V, Gnoato M, Teolato S et al. Sarcoidosis is a Th1/Th17 multisystem disorder. Thorax 2011; 66: 144–150.
181. Rezaei N, Aghamohammadi A, Kardar GA, Nourizadeh M. Pourpak Z. T-helper 1 and 2 cytokine assay in patients with common variable immunodeficiency. J Invest Allergol Clin Immunol 2008; 18: 449–453.
182. Parronchi P, Romagnani P, Annunziato F, Sampognaro S, Becchio A, Giannarini L et al. Type 1 T-helper cell predominance and interleukin-12 expression in the gut of patients with Crohn's disease. Am J Pathol 1997; 150: 823–832.
183. Karttunnen R, Breese EJ, Walker-Smith JA, MacDonald TT. Decreased mucosal interleukin-4 (IL-4) production in gut inflammation. J Clin Pathol 1994; 47: 1015–1018.
184. Sweiss NJ, Salloum R, Gandhi S, Alegre ML, Sawaqed R, Badaracco M et al. Significant CD4, CD8, and CD19 lymphopenia in peripheral blood of sarcoidosis patients correlates with severe disease manifestations. PLoS ONE 2010; 5: e9088.
185. Valour F, Senechal A, Dupieux C, Karsenty J, Lustig S, Breton P et al. Actinomycosis: etiology, clinical features, diagnosis, treatment, and management. Infect Drug Resist 2014; 7: 183–197.
186. Petersen HJ, Smith AM. The role of the innate immune system in granulomatous disorders. Front Immunol 2013; 4: 120.
187. Fais S, Pallone F. Inability of normal human intestinal macrophages to form multinucleated giant cells in response to cytokines. Gut 1995; 37: 798–801.
188. Vos AC, Wildenberg ME, Duijvestein M, Verhaar AP, van den Brink GR, Hommes DW. Anti-tumor necrosis factor-alpha antibodies induce regulatory macrophages in an Fc region-dependent manner. Gastroenterology 2011; 140: 221–230.
189. Vos AC, Wildenberg ME, Arijs I, Duijvestein M, Verhaar AP, de Hertogh G et al. Regulatory macrophages induced by infliximab are involved in healing in vivo and in vitro. Inflamm Bowel Dis 2012; 18: 401–408.
190. Neurath MF, Travis SP. Mucosal healing in inflammatory bowel diseases: a systematic review. Gut 2012; 61: 1619–1635.