Ülseratif kolitli çocukların intestinal mukozasında FOXP3+ Treg hücreleri ve interlökin-23 ekspresyonu

Year 2018, , 10 - 17, 28.06.2018

Ulas Emre Akbulut , Safak Ersoz Gokhan Tumgor , Mehmet Agin Fatih Unal Erhun Kasirga , Murat Cakir

https://doi.org/10.33204/mucosa.420098

Cited By: 1

Abstract

Amaç

Ülseratif kolitin (UK), anormal immün
yanıt sonucu geliştiği düşünülmektedir. Forkhead box P3 (FOXP3) T regülatuvar
(Treg) hücreleri ve interlökin (IL)-23/T-helper 17 yolağı, inflamatuvar
bağırsak hastalığının patogenezinde önemli bir rol oynamaktadır. Ancak bu
yolağın UK'li çocuklardaki rolü ile ilgili bilgilerimiz sınırlıdır. Bu
çalışmanın amacı UK’li çocukların bağırsak mukozasında FOXP3 ve IL-23’ün düzeylerinin
belirlenerek, hastalığın patogenezindeki rollerinin araştırılmasıdır.

Gereç
ve yöntemler

Yirmi dokuz UK’li hasta (18 pankolit,
dokuz sol kolon tutulumlu ve iki proktokolit) ve 11 kontrol hastası çalışmaya
dahil edildi. İmmünohistokimyasal boyama yöntemi ile, UK hastaların inflamasyonlu
dokularından ve kontrol hastalarının inflamasyon içermeyen dokularından alınan
biyopsi örneklerinde FOXP3⁺ Treg hücreleri ve IL-23 düzeyleri
incelendi.

Bulgular

Ülseratif kolitli hastalarda  FOXP3⁺ Treg hücre seviyesi kontrol
grubuna göre önemli oranda yüksekti (%45.67 ± 10.83 ve %22.06 ± 8.09,
p=0.007). IL-23 düzeyi de UK hastalarında kontrol grubuna göre anlamlı olarak
yüksekti (24.33% ± 13.81 vs. 12.91% ±
5.06, p=0.009). Pankolitli
hastalarda FOXP3⁺ Treg hücreleri (%43.21 ± 16.97) ve IL-23 (%25.12 ± 14.98) ekspresyonu kontrol grubundan daha yüksek olduğu görüldü (p=0.012
ve p=0.022). Ancak, kontrol grubu ile sol kolon tutulumu ve proktokoliti olan
hastalar arasında FOXP3⁺ Treg hücreleri ve IL-23 ekspresyonunda
farklılık bulunmuyordu.

Sonuçlar

Ülseratif kolitli
çocukların bağırsak mukozalarında FOXP3⁺ Treg hücreleri ve IL-23
ekspresyonu daha yüksek olduğu tespit edildi. Bu sonuçlar, IL-23 yolağını
engellemeye ve Treg hücre sayılarını yükseltmeye yönelik yeni tedavi
seçeneklerin, UK'in daha etkili bir şekilde tedavi edilmesine yardımcı
olabileceğini göstermektedir.

Keywords

Ülseratif kolit, Çocuk, İnterlökin-23, FOXP3, Sitokin

FOXP3+ Treg cells and interleukin-23 expression in the intestinal mucosa of children with ulcerative colitis

Abstract

Background/Aims

Ulcerative colitis (UC) is thought to result
from an aberrant immune response. Forkhead box P3 (FOXP3) regulatory T (Treg)
cells and Interleukin (IL)-23/T-helper 17 pathway play an important role in the
pathogenesis of inflammatory bowel disease, but little is known about their
role in children with UC. The
aim of this study was to investigate the role of FOXP3 and IL-23 in the pathogenesis of UC by determining
them in intestinal tissues of children with the disease.

Materials and Methods

We
studied 29 patients with UC (18 pancolitis, nine left-sided colitis, and two
proctocolitis) and 11 control subjects. Immunohistochemistry was used to
examine FOXP3⁺ Treg cells and IL-23
in intestinal biopsy specimens from UC patients and from non-inflamed tissues
in the control group.

Results

UC patients’ FOXP3+ Treg cells were
significantly higher than those of the control group (45.67% ± 10.83 vs. 22.06%
± 8.09, p=0.007). IL-23 expression in
patients with UC were significantly higher than those of the control subjects
(24.33% ± 13.81 vs. 12.91% ± 5.06, p=0.009). FOXP3+ Treg cells (43.21% ± 16.97) and IL-23 (25.12% ± 14.98) expression in patients with
pancolitis were higher than in the control group (p=0.012 vs p=0.022). However,
no differences were determined in FOXP3⁺ Treg cells and IL-23 in
patients with left colon involvement and proctocolitis compared to the control
group.

Conclusions

FOXP3⁺
Treg cell and IL-23 expression were higher in the intestinal mucosa of children
with UC. These data indicate that new therapeutic options directed toward
inhibiting the IL23 pathway and raising Treg cell numbers may permit more
efficacious treatment of UC.

Keywords

Ulcerative colitis; children; interleukin-23; FOXP3; cytokine

References

• Nikolaus S, Schreiber S. Diagnostics of inflammatory bowel disease. Gastroenterology. 2007; 133: 1670–89.
• Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007; 448: 427–34.
• Wang Y, Lıu XP, Zhao ZB, et al. Expression of CD4+ forkhead box P3 (FOXP3)+ regulatory T cells in inflammatory bowel disease. J Dig Dis 2011; 12: 286-94
• Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammatory by producing interleukin 17. Nat. Immunol 2005; 6: 1133–41.
• Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol 2005; 6: 1123–32
• Liu Z, Yadav PK, Xu X, Su J, et al. The increased expression of IL-23 in inflammatory bowel disease promotes intraepithelial and lamina propria lymphocyte inflammatory responses and cytotoxicity. J Leukoc Biol 2011; 89: 597-606
• Yang J, Xu L. Elevated IL-23R Expression and Foxp3+Rorgt+ Cells in Intestinal Mucosa During Acute and Chronic Colitis. Med Sci Monit 2016; 22: 2785-92.
• Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL-23R as an inflammatory bowel disease gene. Science 2006; 314: 1461–3.
• Sakaguchi S, Sakaguchi N, Asano M, et al. 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. J Immunol 1995; 155: 1151-64
• Mottet C, Uhlig HH, Powrie F. Cutting edge: cure of colitis by CD4(+) CD25(+) regulatory T cells. J Immunol 2003; 170: 3939–43.
• Ziegler SF. FOXP3: of mice and men. Annu Rev Immunol 2006; 24: 209–26.
• Bennett CL, Ochs HD. IPEX is a unique X-linked syndrome characterized by immune dysfunction, polyendocrinopathy, enteropathy, and a variety of autoimmune phenomena. Curr Opin Pediatr 2001; 13: 533–8.
• Wildin RS, Ramsdell F, Peake J, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 2001; 27: 18–20.
• Voskens CJ, Fischer A, Roessner S, et al. Characterization and Expansion of Autologous GMP-ready Regulatory T Cells for TREG-based Cell Therapy in Patients with Ucerative Colitis. Inflamm Bowel Dis 2017; 23: 1348-1359
• Abraham C, Cho JH. Inflammatory bowel disease. N. Engl. J. Med 2009; 361: 2066-78
• Izcue A, Hue S, Buonocore, et al. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 2008; 28: 559-70
• Geremia A, Jewell DP. The IL-23/IL-17 pathway in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2012; 6: 223-37
• McGovern D, Powrie F. The IL23 axis plays a key role in the pathogenesis of IBD. Gut 2007; 56: 1333–36.
• Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012; 491: 119-24.
• Pidasheva S, Trifari S, Phillips A, et al: Functional studies on the IBD susceptibility gene IL23R implicate reduced receptor function in the protective genetic variant R381Q. PLoS One, 2011; 6: e25038
• Kim SW, Kim ES, Moon CM et al: Genetic polymorphisms of IL-23R and IL-17A and novel insights into their associations with inflammatory bowel disease. Gut, 2011; 60: 1527–36
• Rosen MJ, Karns R, Vallance JE, et al. Mucosal Expression of Type 2 and Type 17 Immune Response Genes Distinguishes Ulcerative Colitis From Colon-Only Crohn’s Disease in Treatment-Naive Pediatric Patients. Gastroenterology. 2017; 152: 1345-1357
• Uhlig HH, Coombes J, Mottet C, et al. Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J Immunol 2006; 177: 5852-60.
• Gad M. Regulatory T cells in experimental colitis. Curr Top Microbiol Immunol 2005; 293: 179-208.
• Miura Y, Thoburn CJ, Bright EC, et al. Association of Foxp3 regulatory gene expression with graft-versus-host disease. Blood 2004; 104: 2187-93
• Rieger K, Loddenkemper C, Maul J, et al. Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD. Blood 2006; 107: 1717-23.
• Makita S, Kanai T, Oshima S, et al. CD4+CD25bright T cells in human intestinal lamina propria as regulatory cells. J Immunol 2004; 173: 3119-30.
• Yu QT, Saruta M, Avanesyan A, et al. Expression and functional characterization of FOXP3+ CD4+ regulatory T cells in ulcerative colitis. Inflamm Bowel Dis 2007; 13: 191-9.
• Pasare C, Medzhitov R. Toll pathway-dependent blockade of CD4(+)CD25(+) T cell-mediated suppression by dendritic cells. Science 2003; 299: 1033–6.
• Peng GY, Guo Z, Kiniwa Y et al. Toll-like, receptor 8-mediated reversal of CD4(+) regulatory T cell function. Science 2005; 309: 1380–4.
• Baecher-Allan C, Viglietta V, Hafler DA. Inhibition of human CD4(+)CD25(+high) regulatory T cell function. J Immunol 2002; 169: 6210–7.
• Lord JD. Promises and paradoxes of regulatory T cells in inflammatory bowel disease. World J Gastroenterol 2015; 21: 11236-45.
• Dulai PS, Siegel CA. The risk of malignancy associated with the use of biological agents in patients with inflammatory bowel disease. Gastroenterol Clin North Am 2014; 43: 525-41.
• Dulai PS, Thompson KD, Blunt HB, et al. Risks of serious infection or lymphoma with anti-tumor necrosis factor therapy for pediatric inflammatory bowel disease: a systematic review. Clin Gastroenterol Hepatol 2014; 12: 1443-51.
• Ogawa A, Andoh A, Araki Y, et al. Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin Immunol 2004; 110: 55-62.
• Zhang Z, Zheng M, Bindas J, et al. Critical role of IL-17 receptor signaling in acute TNBS-induced colitis. Inflamm Bowel Dis 2006; 12: 382-8.
• Maxwell JR, Zhang Y, Brown WA, et al. Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation. Immunity 2015; 43: 739-50.
• Lee JS, Tato CM, Joyce-Shaikh B, et al. Interleukin-23-Independent IL-17 Production Regulates Intestinal Epithelial Permeability. Immunity 2015; 43: 727-38
• Abraham C, Dulai PS, Vermeire S, et al. Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases. Gastroenterology 2017; 152: 374-388.
• Elson CO, Cong Y, Weaver CT, et al. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology 2007; 132: 2359-70.
• Yen D, Cheung J, Scheerens H, et al. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest 2006; 116: 1310-6.
• Kullberg MC, Jankovic D, Feng CG, et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J Exp Med 2006; 203: 2485-94.
• Desreumaux P, Foussat A, Allez M, et al. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn’s disease. Gastroenterology 2012; 143: 1207-17