Journal of Korean Medical Science

Korean Acad Medical Sciences (대한의학회)
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Mucosal Immunity Related to FOXP3+ Regulatory T Cells, Th17 Cells and Cytokines in Pediatric Inflammatory Bowel Disease

  • Cho, Jinhee (Department of Veterinary Medicine, Jeju National University) ;
  • Kim, Sorina (Department of Pediatrics, Jeju National University Hospital) ;
  • Yang, Da Hee (Department of Pediatrics, Jeju National University Hospital) ;
  • Lee, Juyeon (Department of Pediatrics, Jeju National University Hospital) ;
  • Park, Kyeong Won (Department of Pediatrics, Jeju National University Hospital) ;
  • Go, Junyong (Department of Pediatrics, Jeju National University Hospital) ;
  • Hyun, Chang-Lim (Department of Pathology, Jeju National University School of Medicine) ;
  • Jee, Youngheun (Department of Veterinary Medicine, Jeju National University) ;
  • Kang, Ki Soo (Department of Pediatrics, Jeju National University Hospital)
  • Received : 2018.07.03
  • Accepted : 2018.09.06
  • Published : 2018.12.24
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Abstract

Background: We aimed to investigate mucosal immunity related to forkhead box P3 ($FOXP3^+$) regulatory T (Treg) cells, T helper 17 (Th17) cells and cytokines in pediatric inflammatory bowel disease (IBD). Methods: Mucosal tissues from terminal ileum and colon and serum samples were collected from twelve children with IBD and seven control children. Immunohistochemical staining was done using anti-human FOXP3 and anti-$ROR{\gamma}t$ antibodies. Serum levels of cytokines were analyzed using a multiplex assay covering interleukin $(IL)-1{\beta}$, IL-4, IL-6, IL-10, IL-17A/F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, interferon $(IFN)-{\gamma}$, soluble CD40L, and tumor necrosis factor-${\alpha}$. Results: $FOXP3^+$ Treg cells in the lamina propria (LP) of terminal ileum of patients with Crohn's disease were significantly (P < 0.05) higher than those in the healthy controls. $ROR{\gamma}t^+$ T cells of terminal ileum tended to be higher in Crohn's disease than those in the control. In the multiplex assay, serum concentrations (pg/mL) of IL-4 ($9.6{\pm}1.5$ vs. $12.7{\pm}3.0$), IL-21 ($14.9{\pm}1.5$ vs. $26.4{\pm}9.1$), IL-33 ($14.3{\pm}0.9$ vs. $19.1{\pm}5.3$), and $IFN-{\gamma}$ ($15.2{\pm}5.9$ vs. $50.2{\pm}42.4$) were significantly lower in Crohn's disease than those in the control group. However, serum concentration of IL-6 ($119.1{\pm}79.6$ vs. $52.9{\pm}39.1$) was higher in Crohn's disease than that in the control. Serum concentrations of IL-17A ($64.2{\pm}17.2$ vs. $28.3{\pm}10.0$) and IL-22 ($37.5{\pm}8.8$ vs. $27.2{\pm}3.7$) were significantly higher in ulcerative colitis than those in Crohn's disease. Conclusion: Mucosal immunity analysis showed increased $FOXP3^+$ T reg cells in the LP with Crohn's disease while Th17 cell polarizing and signature cytokines were decreased in the serum samples of Crohn's disease but increased in ulcerative colitis.

Keywords

Acknowledgement

Supported by : Jeju National University Hospital

References

  1. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med 2009;361(21):2066-78. https://doi.org/10.1056/NEJMra0804647
  2. Kang B, Choe YH. Early biologic treatment in pediatric Crohn's disease: catching the therapeutic window of opportunity in early disease by treat-to-target. Pediatr Gastroenterol Hepatol Nutr 2018;21(1):1-11. https://doi.org/10.5223/pghn.2018.21.1.1
  3. Jung D, Lee S, Jeong I, Oh SH, Kim KM. Short-term outcome of infliximab therapy in pediatric Crohn's disease: a single-center experience. Pediatr Gastroenterol Hepatol Nutr 2017;20(4):236-43. https://doi.org/10.5223/pghn.2017.20.4.236
  4. Shen X, Du J, Guan W, Zhao Y. The balance of intestinal Foxp3+ regulatory T cells and Th17 cells and its biological significance. Expert Rev Clin Immunol 2014;10(3):353-62. https://doi.org/10.1586/1744666X.2014.882232
  5. Ueno A, Jeffery L, Kobayashi T, Hibi T, Ghosh S, Jijon H. Th17 plasticity and its relevance to inflammatory bowel disease. J Autoimmun 2018;87:38-49. https://doi.org/10.1016/j.jaut.2017.12.004
  6. Ban H, Andoh A, Shioya M, Nishida A, Tsujikawa T, Fujiyama Y. Increased number of FoxP3+CD4+ regulatory T cells in inflammatory bowel disease. Mol Med Rep 2008;1(5):647-50. https://doi.org/10.3892/mmr_00000006
  7. Lord JD, Valliant-Saunders K, Hahn H, Thirlby RC, Ziegler SF. Paradoxically increased FOXP3+ T cells in IBD do not preferentially express the isoform of FOXP3 lacking exon 2. Dig Dis Sci 2012;57(11):2846-55. https://doi.org/10.1007/s10620-012-2292-3
  8. Gil JH, Oh JE, Seo JW, Cho MS, Cho KY, Yoo ES. FOXP3+ T cells and TGF-${\beta}1$ in colonic mucosa of children with Crohn's disease. Korean J Pediatr Gastroenterol Nutr 2011;14(3):258-68. https://doi.org/10.5223/kjpgn.2011.14.3.258
  9. Lord JD. Promises and paradoxes of regulatory T cells in inflammatory bowel disease. World J Gastroenterol 2015;21(40):11236-45. https://doi.org/10.3748/wjg.v21.i40.11236
  10. Eastaff-Leung N, Mabarrack N, Barbour A, Cummins A, Barry S. Foxp3+ regulatory T cells, Th17 effector cells, and cytokine environment in inflammatory bowel disease. J Clin Immunol 2010;30(1):80-9. https://doi.org/10.1007/s10875-009-9345-1
  11. Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol 2014;14(5):329-42. https://doi.org/10.1038/nri3661
  12. Strober W, Fuss IJ. Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology 2011;140(6):1756-67. https://doi.org/10.1053/j.gastro.2011.02.016
  13. Guidi L, Felice C, Procoli A, Bonanno G, Martinelli E, Marzo M, et al. FOXP3+ T regulatory cell modifications in inflammatory bowel disease patients treated with anti-$TNF{\alpha}$ agents. BioMed Res Int 2013;2013:286368.
  14. Ueno A, Jijon H, Chan R, Ford K, Hirota C, Kaplan GG, et al. Increased prevalence of circulating novel IL-17 secreting Foxp3 expressing CD4+ T cells and defective suppressive function of circulating Foxp3+ regulatory cells support plasticity between Th17 and regulatory T cells in inflammatory bowel disease patients. Inflamm Bowel Dis 2013;19(12):2522-34. https://doi.org/10.1097/MIB.0b013e3182a85709
  15. Makita S, Kanai T, Oshima S, Uraushihara K, Totsuka T, Sawada T, et al. CD4+CD25bright T cells in human intestinal lamina propria as regulatory cells. J Immunol 2004;173(5):3119-30. https://doi.org/10.4049/jimmunol.173.5.3119
  16. Yu QT, Saruta M, Avanesyan A, Fleshner PR, Banham AH, Papadakis KA. Expression and functional characterization of FOXP3+ CD4+ regulatory T cells in ulcerative colitis. Inflamm Bowel Dis 2007;13(2):191-9. https://doi.org/10.1002/ibd.20053
  17. Saruta M, Yu QT, Fleshner PR, Mantel PY, Schmidt-Weber CB, Banham AH, et al. Characterization of FOXP3+CD4+ regulatory T cells in Crohn's disease. Clin Immunol 2007;125(3):281-90. https://doi.org/10.1016/j.clim.2007.08.003
  18. Fantini MC, Monteleone G. Update on the therapeutic efficacy of tregs in IBD: thumbs up or thumbs down? Inflamm Bowel Dis 2017;23(10):1682-8. https://doi.org/10.1097/MIB.0000000000001272
  19. Desreumaux P, Foussat A, Allez M, Beaugerie L, Hebuterne X, Bouhnik Y, et al. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn's disease. Gastroenterology 2012;143(5):1207-1217.e2. https://doi.org/10.1053/j.gastro.2012.07.116
  20. Choi P, Reiser H. IL-4: role in disease and regulation of production. Clin Exp Immunol 1998;113(3):317-9. https://doi.org/10.1046/j.1365-2249.1998.00690.x
  21. Park SH, Kim MS, Lim HX, Cho D, Kim TS. IL-33-matured dendritic cells promote Th17 cell responses via IL-$1{\beta}$ and IL-6. Cytokine 2017;99:106-13. https://doi.org/10.1016/j.cyto.2017.07.022
  22. Matsuura T, West GA, Levine AD, Fiocchi C. Selective resistance of mucosal T-cell activation to immunosuppression in Crohn's disease. Dig Liver Dis 2000;32(6):484-94. https://doi.org/10.1016/S1590-8658(00)80005-5
  23. West GA, Matsuura T, Levine AD, Klein JS, Fiocchi C. Interleukin 4 in inflammatory bowel disease and mucosal immune reactivity. Gastroenterology 1996;110(6):1683-95. https://doi.org/10.1053/gast.1996.v110.pm8964392
  24. Mikhalkevich N, Becknell B, Caligiuri MA, Bates MD, Harvey R, Zheng WP. Responsiveness of naive CD4 T cells to polarizing cytokine determines the ratio of Th1 and Th2 cell differentiation. J Immunol 2006;176(3):1553-60. https://doi.org/10.4049/jimmunol.176.3.1553
  25. Fuss IJ, Neurath M, Boirivant M, Klein JS, de la Motte C, Strong SA, et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol 1996;157(3):1261-70.
  26. Reinisch W, Hommes DW, Van Assche G, Colombel JF, Gendre JP, Oldenburg B, et al. A dose escalating, placebo controlled, double blind, single dose and multidose, safety and tolerability study of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe Crohn's disease. Gut 2006;55(8):1138-44. https://doi.org/10.1136/gut.2005.079434
  27. Leonard WJ, Wan CK. IL-21 signaling in immunity. F1000 Res 2016;5:5.
  28. Tangye SG. Advances in IL-21 biology - enhancing our understanding of human disease. Curr Opin Immunol 2015;34:107-15. https://doi.org/10.1016/j.coi.2015.02.010
  29. Pastorelli L, Garg RR, Hoang SB, Spina L, Mattioli B, Scarpa M, et al. Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis. Proc Natl Acad Sci U S A 2010;107(17):8017-22. https://doi.org/10.1073/pnas.0912678107
  30. Sakuraba A, Sato T, Kamada N, Kitazume M, Sugita A, Hibi T. Th1/Th17 immune response is induced by mesenteric lymph node dendritic cells in Crohn's disease. Gastroenterology 2009;137(5):1736-45. https://doi.org/10.1053/j.gastro.2009.07.049
  31. 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 placebo-controlled trial. Gut 2012;61(12):1693-700. https://doi.org/10.1136/gutjnl-2011-301668

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