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Toskas A, Milias S, Papamitsou T, Meditskou S, Kamperidis N, Sioga A. The role of IL-19, IL-24, IL-21 and IL-33 in intestinal mucosa of inflammatory bowel disease: A narrative review. Arab J Gastroenterol 2025; 26:9-17. [PMID: 38395629 DOI: 10.1016/j.ajg.2024.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/15/2023] [Accepted: 01/03/2024] [Indexed: 02/25/2024]
Abstract
Interleukins are potential therapeutic targets that can alter the prognosis and progression of inflammatory bowel disease (IBD). The roles of IL-6, IL-10, IL-17, and IL-23 have been extensively studied, setting the stage for the development of novel treatments for patients with IBD. Other cytokines have been less extensively studied. Members of the IL-20 family, mainly IL-19 and IL-24, are involved in the pathogenesis of IBD, but their exact role remains unclear. Similarly, IL-33, a newly identified cytokine, has been shown to control the Th1 effector response and the action of colonic Tregs in animal models of colitis and patients with IBD. IL-21 is involved in the Th1, Th2, and Th17 responses. Data support a promising future use of these interleukins as biomarkers of severe diseases and as potential therapeutic targets for novel monoclonal antibodies. This review aims to summarize the existing studies involving animal models of colitis and patients with IBD to clarify their role in the intestinal mucosa.
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Affiliation(s)
- Alexandros Toskas
- Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece; St Marks Hospital, Watford Rd, Harrow, London, United Kingdom.
| | - Stefanos Milias
- Private Histopathology Laboratory, Ploutonos 27, Thessaloniki, Greece.
| | - Theodora Papamitsou
- Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
| | - Soultana Meditskou
- Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
| | | | - Antonia Sioga
- Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
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Toskas A, Milias S, Delis G, Meditskou S, Sioga A, Papamitsou T. Expression of IL-21 and IL-33 in Intestinal Mucosa of Inflammatory Bowel Disease: An Immunohistochemical Study. Diagnostics (Basel) 2023; 13:2185. [PMID: 37443579 DOI: 10.3390/diagnostics13132185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 06/21/2023] [Accepted: 06/23/2023] [Indexed: 07/15/2023] Open
Abstract
Interleukins are considered to be potential therapeutic targets that can alter the prognosis and disease progression of IBD. IL-21 has proven to be involved in effector Th1, Th2 and Th17 responses. Similarly, IL-33, a newly identified cytokine, has been shown to control the Th1 effector response and the action of the colonic Tregs in animal models of colitis and patients with IBD. In this retrospective study, we have studied the expression of these interleukins, using immunohistochemistry, in 121 patients with moderate to severe IBD before and after treatment with biologics. The results were statistically processed using SPSSTM. Increased IL-21 expression was found in the UC and CD groups versus the controls. The IL-33 expression was found to be increased in the post-treatment UC and CD groups, suggesting a protective role of this interleukin against bowel inflammation. The IL-33 expression post-treatment was reversely correlated with the activity index score in CD patients, suggesting a better response to treatment in patients with higher IL-33 mucosa levels. This is the first immunohistochemical study of the expression of those interleukins in bowel mucosa before and after treatment with biologics. These data support a possibly promising future use of these interleukins as biomarkers of severe disease and response to treatment and as potential therapeutic targets for novel monoclonal antibodies.
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Affiliation(s)
- Alexandros Toskas
- Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
- St Marks Hospital, Watford Rd, Harrow, London HA1 3UJ, UK
| | - Stefanos Milias
- Private Histopathology Laboratory, Ploutonos 27, 54655 Thessaloniki, Greece
| | - Georgios Delis
- Veterinary School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Soultana Meditskou
- Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Antonia Sioga
- Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Theodora Papamitsou
- Laboratory of Histology and Embryology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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Fang L, Liu C, Sun X, Liu Z. Case Report: Anti-TNF Treatment Failure in a Patient With Immune Checkpoint Inhibitor-Induced Severe Colitis. Front Oncol 2022; 12:925964. [PMID: 35814408 PMCID: PMC9259980 DOI: 10.3389/fonc.2022.925964] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 05/20/2022] [Indexed: 12/19/2022] Open
Abstract
Immune checkpoint inhibitor (ICI)-induced colitis is one of the known complications of therapies targeting cytotoxic programmed cell death protein 1 (PD-1), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and programmed cell death ligand 1 (PD-L1). ICI-associated colitis is routinely treated with immunosuppressive therapy, including corticosteroids and/or agents targeting tumor necrosis factor-α (TNF-α). In this report, a 69-year-old male patient developed severe ICI-induced colitis 2 weeks after anti-PD-L1 mAb (i.e., durvalumab) treatment; unexpectedly failed to respond to systemic corticosteroid, anti-TNF, and anti-integrin agents; and unfortunately died in 1 month. This case reminds clinical physicians to be on the alert for early-onset acute ICI-induced colitis and emphasizes that urgent optimized rescue measures are required for patients with severe ICI-induced colitis.
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Anti-TNF- α Monoclonal Antibody Therapy Improves Anemia through Downregulating Hepatocyte Hepcidin Expression in Inflammatory Bowel Disease. Mediators Inflamm 2019; 2019:4038619. [PMID: 31814801 PMCID: PMC6878771 DOI: 10.1155/2019/4038619] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 06/28/2019] [Accepted: 09/30/2019] [Indexed: 12/13/2022] Open
Abstract
Anemia is one of the most common complications in patients with inflammatory bowel disease (IBD). Hepcidin as a key regulator of iron metabolism is pivotal in mediating the occurrence of anemia of chronic disease. Herein, we analyzed the levels of hepcidin in sera from IBD patients by enzyme-linked immunosorbent assay and investigated its potential role in regulating the anemia in IBD. We observed that the levels of serum hepcidin were increased in active IBD patients compared with those in remitted IBD patients and healthy controls and that serum hepcidin was associated with disease activity, CRP, and ESR, respectively. Importantly, we found that the increased levels of serum hepcidin were positively correlated with the severity of anemia and the imbalance of iron metabolism in anemic UC and CD patients. Proinflammatory factors (e.g., IL-6, IL-17, and TNF-α) were positively correlated with the concentrations of serum hepcidin in IBD patients. Interestingly, hepcidin was found to be decreased in patients with Crohn's disease after successful therapy with anti-TNF-α mAb (i.e., infliximab), indicating the underlying association between TNF-α and hepcidin expression. To investigate the specific mechanisms involved, we cultured LO2 and HepG2 cell lines in vitro under stimulation with TNF-α and observed that the levels of hepcidin mRNA were markedly upregulated in caspase-3/8- and NF-κB-dependent manners. Therefore, our data suggest that TNF-α stimulates the expression of hepcidin in IBD patients, resulting in aggravated anemia and that blockage of TNF-α or the caspase-3/8 and NF-κB pathways could downregulate hepcidin expression. This study provides inspiration for the therapy and management of anemia in IBD.
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Sorrentino D, Nguyen VQ, Chitnavis MV. Capturing the Biologic Onset of Inflammatory Bowel Diseases: Impact on Translational and Clinical Science. Cells 2019; 8:E548. [PMID: 31174359 PMCID: PMC6627618 DOI: 10.3390/cells8060548] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 05/30/2019] [Accepted: 06/04/2019] [Indexed: 12/16/2022] Open
Abstract
While much progress has been made in the last two decades in the treatment and the management of inflammatory bowel diseases (IBD)-both ulcerative colitis (UC) and Crohn's Disease (CD)-as of today these conditions are still diagnosed only after they have become symptomatic. This is a major drawback since by then the inflammatory process has often already caused considerable damage and the disease might have become partially or totally unresponsive to medical therapy. Late diagnosis in IBD is due to the lack of accurate, non-invasive indicators that would allow disease identification during the pre-clinical stage-as it is often done in many other medical conditions. Here, we will discuss what is known about the biologic onset and pre-clinical CD with an emphasis on studies conducted in patients' first degree relatives. We will then review the possible strategies to diagnose IBD very early in time including screening, available disease markers and imaging, and the possible clinical implications of treating these conditions at or close to their biologic onset. Later, we will review the potential impact of conducting translational research in IBD during the pre-clinical stage, especially focusing on the role of the microbiome in disease etiology and pathogenesis. Finally, we will highlight possible future developments in the field and how they can impact IBD management and our scientific knowledge of these conditions.
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Affiliation(s)
- Dario Sorrentino
- IBD Center, Division of Gastroenterology, Virginia Tech Carilion School of Medicine, FRACP 3 Riverside Circle, Roanoke, VA 24016, USA.
- Department of Clinical and Experimental Medical Sciences, University of Udine School of Medicine, 33100 Udine, Italy.
| | - Vu Q Nguyen
- IBD Center, Division of Gastroenterology, Virginia Tech Carilion School of Medicine, FRACP 3 Riverside Circle, Roanoke, VA 24016, USA.
| | - Maithili V Chitnavis
- IBD Center, Division of Gastroenterology, Virginia Tech Carilion School of Medicine, FRACP 3 Riverside Circle, Roanoke, VA 24016, USA.
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Wang X, Cao J, Wang H, Ye C. Risk Factors Associated with Infusion Reactions to Infliximab in Chinese Patients with Inflammatory Bowel Disease: A Large Single-Center Study. Med Sci Monit 2019; 25:2257-2264. [PMID: 30917108 PMCID: PMC6448455 DOI: 10.12659/msm.913152] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND This study investigated the risk factors of infliximab (IFX)-related infusion reactions (IR) in Chinese patients with inflammatory bowel disease (IBD). MATERIAL AND METHODS The medical records of 330 consecutive IBD patients treated with IFX between 2009 and 2017 were reviewed. The incidence of IR and adverse effects were recorded in detail, and the potential risk factors related to IR were analyzed by univariate and logistic regression analysis. RESULTS The 330 patients received a total of 2108 IFX infusions, with a median follow-up of 29 months. Eighteen patients (5.5%) experienced IR: 15 were immediate (2 severe) and 3 were late (0 severe). The patients who were treated with episodic IFX without concomitant IM therapy and at the 2nd IFX series (all P<0.001) had higher incidence of IR. Logistic regression revealed the 2nd IFX treatment series (OR=0.017, P<0.001) and episodic use of IFX (OR=0.113, P<0.001) as the significant predictors. Antibodies against infliximab (ATI) were highly positive in 10 of 14 patients (71%) with IR. Sixty-seven percent of patients finished infusions after IR through appropriate management. CONCLUSIONS IFX infusions were accompanied by IR in about 5% of Chinese IBD patients. Severe IR was rare. The patients with the 2nd series or episodic use of IFX should be monitored closely during infusion.
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Affiliation(s)
- Xiaolei Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China (mainland)
| | - Jingli Cao
- Department of Gastroenterology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China (mainland)
| | - Haichao Wang
- Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China (mainland)
| | - Chen Ye
- School of Medicine, Soochow University, Suzhou, Jiangsu, China (mainland)
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Anti-TNF- α Therapy Suppresses Proinflammatory Activities of Mucosal Neutrophils in Inflammatory Bowel Disease. Mediators Inflamm 2018; 2018:3021863. [PMID: 30595666 PMCID: PMC6282128 DOI: 10.1155/2018/3021863] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 09/05/2018] [Accepted: 09/13/2018] [Indexed: 12/28/2022] Open
Abstract
Neutrophils have been found to play an important role in the pathogenesis of inflammatory bowel disease (IBD), and anti-TNF-α mAb (i.e., infliximab) therapy is demonstrated to be effective in the induction of clinical remission and mucosal healing in these patients. However, how anti-TNF-α mAb regulates the functions of neutrophils is still unknown. Herein, we found that anti-TNF-α therapy significantly downregulated infiltration of neutrophils in inflamed mucosa of IBD patients. Importantly, anti-TNF-α mAb could inhibit neutrophils to produce proinflammatory mediators, such as ROS, calprotectin, IL-8, IL-6, and TNF-α. These data indicate that TNF-α plays a critical role in the induction of mucosal inflammatory response, and that blockade of TNF-α modulates intestinal homeostasis through balancing immune responses of neutrophils.
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Xiao N, Liu F, Zhou G, Sun M, Ai F, Liu Z. Food-specific IgGs Are Highly Increased in the Sera of Patients with Inflammatory Bowel Disease and Are Clinically Relevant to the Pathogenesis. Intern Med 2018; 57:2787-2798. [PMID: 29780153 PMCID: PMC6207831 DOI: 10.2169/internalmedicine.9377-17] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Objective Dietary antigens are common luminal antigens in the gastrointestinal tract and have been considered to contribute to the pathogenesis of inflammatory bowel disease (IBD). We analyzed the levels of food-specific IgGs against a variety of dietary antigens, explored the clinical relevance of food allergy to the pathogenesis of IBD, and investigated whether or not infliximab (IFX) treatment could regulate the immune responses induced by dietary antigens. Methods A total of 301 IBD patients, including 201 patients with Crohn's disease (CD) and 100 patients with ulcerative colitis (UC), were recruited, and their serum food-specific IgGs against 14 food antigens were detected by a semi-quantitative enzyme linked immunosorbent assay (ELISA). Total serum IgG and IgE levels were measured by immunonephelometry and fluorescent enzyme immunoassay, respectively. Simultaneously, the relevant medical records and clinical data were collected for further analyses. Results Food-specific IgGs against egg, milk, wheat, corn, rice, tomato, codfish, and soybean antigens were found to be significantly increased in the sera of CD patients compared with UC patients and healthy controls (p<0.01). The levels of total serum IgG and IgE were also significantly higher in CD patients than in healthy controls (p<0.01). The titers of corn- and tomato-specific IgGs were found to be significantly correlated with total serum IgG in CD patients (p<0.05), while the titers of egg-, milk-, and wheat-specific IgGs were correlated with total serum IgE (p<0.05). Interestingly, IFX therapy was able to down-regulate the food-specific IgG-mediated immune response markedly in active CD patients. Conclusion Food-specific IgGs against egg, milk, wheat, corn, rice, tomato, codfish, and soybean are highly increased in the sera of CD patients. IFX treatment was able to down-regulate the levels of food-specific IgGs by suppressing intestinal inflammation and promoting mucosal healing. Therefore, food-specific IgGs may serve as an important approach in the diagnosis and management of food allergy in IBD.
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Affiliation(s)
- Nanping Xiao
- Department of Gastroenterology, The Shanghai Tenth Clinical Medicine College of Nanjing Medical University, China
- Department of Gastroenterology, Sichuan Guangyuan First People's Hospital, China
| | - Fenghua Liu
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, China
| | - Guangxi Zhou
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, China
| | - Mingming Sun
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, China
| | - Fengfu Ai
- Department of Internal Medicine, The Second People's Hospital of Linchuan district, China
| | - Zhanju Liu
- Department of Gastroenterology, The Shanghai Tenth Clinical Medicine College of Nanjing Medical University, China
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, China
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Zhou G, Wu W, Yu L, Yu T, Yang W, Wang P, Zhang X, Cong Y, Liu Z. Tripartite motif-containing (TRIM) 21 negatively regulates intestinal mucosal inflammation through inhibiting TH1/TH17 cell differentiation in patients with inflammatory bowel diseases. J Allergy Clin Immunol 2018; 142:1218-1228.e12. [DOI: 10.1016/j.jaci.2017.09.038] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 08/26/2017] [Accepted: 09/12/2017] [Indexed: 01/18/2023]
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Fang L, Pang Z, Shu W, Wu W, Sun M, Cong Y, Liu Z. Anti-TNF Therapy Induces CD4+ T-Cell Production of IL-22 and Promotes Epithelial Repairs in Patients With Crohn's Disease. Inflamm Bowel Dis 2018; 24:1733-1744. [PMID: 29718341 DOI: 10.1093/ibd/izy126] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Indexed: 12/19/2022]
Abstract
Background Anti-tumor necrosis factor (TNF) therapy appears to be effective in the treatment of Crohn's disease (CD), a chronic inflammatory disease of the gastrointestinal tract. However, the mechanisms involved are not completely understood. Methods Fifty-seven active CD patients were enrolled, and cytokine profiles in colonic biopsies of patients with active CD receiving anti-TNF monoclonal antibody (mAb) (infliximab [IFX]) treatment were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Colonic biopsies of active CD patients and healthy donors were cultured with IFX in vitro, and cytokine profiles were measured by qRT-PCR. Peripheral blood (PB)-CD4+ T cells were stimulated with anti-CD3 and anti-CD28 mAbs in the presence of human immunoglobin (HIg), IFX, recombinant human TNF-α converting enzyme (rhTACE), and aryl hydrocarbon receptor (AhR) inhibitor (CH-223191), respectively, to determine interleukin (IL)-22 expression by CD4+ T cells. Caco2 cells were also utilized to study their potential role in modulating epithelial cell barrier repairs in vitro. Results IFX therapy markedly upregulated IL-22 mRNA expression in the gut mucosa of CD patients. In vitro treatment with IFX greatly promoted CD CD4+ T cells to express IL-22, which was inhibited by rhTACE, indicating that reverse signaling through binding to membrane-bound TNF mediates anti-TNF-induced IL-22 expression of CD CD4+ T cells. However, blockade of AhR markedly inhibited anti-TNF-induced IL-22+CD4+ T (Th22) cell differentiation in CD patients. Moreover, treatment with IL-22 induced intestinal epithelial cell expression of tight junction proteins (eg, claudin1 and ZO-1) and facilitated transepithelial resistance, indicating that IL-22 protects intestinal mucosa from inflammation via maintenance of epithelial barrier integrity. Conclusions Our results uncover a novel mechanism whereby anti-TNF therapy upregulates IL-22 production in CD patients through promoting Th22 cell differentiation and contributes to intestinal epithelial barrier repairs.
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Affiliation(s)
- Leilei Fang
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - Zhi Pang
- Department of Gastroenterology, Suzhou Municipal Hospital Affiliated to Nanjing Medical University, Suzhou, China
| | - Weigang Shu
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - Wei Wu
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - Mingming Sun
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - Yingzi Cong
- Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas
| | - Zhanju Liu
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
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Hvas CL, Bendix M, Dige A, Dahlerup JF, Agnholt J. Current, experimental, and future treatments in inflammatory bowel disease: a clinical review. Immunopharmacol Immunotoxicol 2018; 40:446-460. [PMID: 29745777 DOI: 10.1080/08923973.2018.1469144] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel diseases (IBDs) may result from dysregulated mucosal immune responses directed toward the resident intestinal microbiota. This review describes the hallmark immunobiology of Crohn's disease and ulcerative colitis as well as therapeutic targets and mechanisms of action for current, experimental, and future treatments in IBD. Conventional therapies include 5-aminosalicylic acid, glucocorticosteroids, thiopurines, and methotrexate. Since 1997, monoclonal antibodies have gained widespread use. These consist of antibodies directed against pro-inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)-12, and IL-23, or anti-homing antibodies directed against α4β7 integrin. Emerging oral therapies include modulators of intracellular signal transduction such as Janus kinase inhibitors. Vitamin D may help to regulate innate and adaptive immune responses. Modulation of the intestinal microbiota, using live microorganisms (probiotics), substrates for the colonic microbiota (prebiotics), or fecal microbiota transplantation (FMT), is in development. Dietary supplements are in widespread use, but providing evidence for their benefit is challenging. Stem cell treatment and nervous stimulation are promising future treatments.
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Affiliation(s)
- Christian L Hvas
- a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark
| | - Mia Bendix
- a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark.,b Medical Department, Randers Regional Hospital , Randers , Denmark
| | - Anders Dige
- a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark
| | - Jens F Dahlerup
- a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark
| | - Jørgen Agnholt
- a Department of Hepatology and Gastroenterology , Aarhus University Hospital , Aarhus C , Denmark
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12
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Critical role of ROCK2 activity in facilitating mucosal CD4 + T cell activation in inflammatory bowel disease. J Autoimmun 2018; 89:125-138. [DOI: 10.1016/j.jaut.2017.12.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Revised: 12/11/2017] [Accepted: 12/12/2017] [Indexed: 12/18/2022]
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Dige A, Magnusson MK, Uhrenholt C, Rasmussen TK, Kragstrup T, Öhman L, Dahlerup J, Agnholt J. Effects of Anti-TNF α Treatment on Mucosal Expression of IL-17A, IL-21, and IL-22 and Cytokine-Producing T Cell Subsets in Crohn's Disease. Mediators Inflamm 2018; 2018:3279607. [PMID: 29853788 PMCID: PMC5944277 DOI: 10.1155/2018/3279607] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 03/12/2018] [Accepted: 04/03/2018] [Indexed: 02/07/2023] Open
Abstract
T helper 17 (Th17) cells produce interleukin (IL) 17-A. In addition, Th17 cells produce IL-21 and IL-22. Th17 cells have a disease-promoting role in Crohn's disease (CD). We investigated the effects of anti-TNFα treatment on mucosal gene expression (qPCR) of IL-17A, IL-21, and IL-22 as well as on the frequency of lamina propria (LP) T cell subsets producing these cytokines (flow cytometry) in 12 active CD patients before and after 4 weeks of anti-TNFα treatment with adalimumab. At baseline, in inflamed mucosa we found increased gene expression of IL-17A and IL-22 but not IL-21 when compared to noninflamed mucosa. There were increased frequencies of IL-21-producing LP T cells but no differences in the frequencies of IL-17A- or IL-22-producing LP T cells when comparing inflamed versus noninflamed mucosa at baseline. There were no changes in the mucosal gene expression of IL-17A, IL-21, and IL-22 or the frequencies of IL-17A-, IL-21- and IL-22-producing LP T cell subsets between baseline and following 4 weeks of adalimumab initiation. Our results do not support the hypothesis that anti-TNFα treatment has an early effect on the mucosal levels of IL-17A, IL-21, and IL-22 or LP T cell production of these cytokines in CD.
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Affiliation(s)
- Anders Dige
- Gastro-Immuno Research Laboratory (GIRL), Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Maria K. Magnusson
- Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Claus Uhrenholt
- Gastro-Immuno Research Laboratory (GIRL), Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Tue Kruse Rasmussen
- Department of Biomedicine, Aarhus University Hospital, 8000 Aarhus C, Denmark
- Department of Rheumatology, Aarhus University Hospital, 8000 Aarhus C, Denmark
| | - Tue Kragstrup
- Department of Biomedicine, Aarhus University Hospital, 8000 Aarhus C, Denmark
- Department of Rheumatology, Aarhus University Hospital, 8000 Aarhus C, Denmark
| | - Lena Öhman
- Department of Microbiology and Immunology, Institute for Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Internal Medicine and Clinical Nutrition, Institute for Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Jens Dahlerup
- Gastro-Immuno Research Laboratory (GIRL), Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Jørgen Agnholt
- Gastro-Immuno Research Laboratory (GIRL), Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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14
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Evaluating IL-21 as a Potential Therapeutic Target in Crohn's Disease. Gastroenterol Res Pract 2018; 2018:5962624. [PMID: 29849593 PMCID: PMC5914125 DOI: 10.1155/2018/5962624] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 02/05/2018] [Accepted: 02/13/2018] [Indexed: 12/20/2022] Open
Abstract
Background and Aim Interleukin-21 (IL-21) is primarily a T cell-derived cytokine; it is upregulated in patients with Crohn's Disease (CD) and could be a potential new therapeutic target in CD. Methods In human material, IL-21 and IL-21R expression was investigated by in situ hybridization (ISH) and immunohistochemistry (IHC) in noninflammatory bowel disease (non-IBD) controls and patients with CD. The pathologic role of IL-21 was examined in murine models of T cell-dependent and T cell-independent colitis, either with a neutralizing monoclonal antibody against IL-21 or with the transfer of CD4+CD45RBhighIL-21R-/- T cells. Colonic pathology was examined by endoscopy, histopathology, IHC, ELISA, and Luminex. Results In the human intestine, IL-21 and IL-21R mRNA and protein-expressing cells were observed in the mucosa, in lymphoid aggregates of submucosa in non-IBD controls, and in lymphoid aggregates of muscularis externa in patients with CD. IL-21 expression was most abundant in germinal centers (GCs) of the lymphoid aggregates, and IL-21R expression assessed semiquantitatively, was significantly higher in patients with CD compared to non-IBD controls. Following prophylactic and interventive anti-IL-21 mAb treatment in the adoptive transfer (AdTr) model, clinical and pathological parameters were significantly reduced. The most persistent finding was a reduction in colonic infiltrating neutrophils. As well, Rag2-/- mice receiving CD4+CD45RBhighIL-21R-/- T cells developed less severe colitis compared to Rag2-/- mice receiving CD4+CD45RBhighIL-21R+/+ T cells. No effect of reduced IL-21 signalling was observed in T cell-independent colitis. Conclusion Our study shows that patients with CD have significant expression of IL-21 and IL-21R in the gut. As well, we show that neutralization of IL-21 in experimental T cell-driven colitis is associated with a reduction in clinical and pathological findings. This amelioration seems to be associated with a reduction in colon-infiltrating neutrophils.
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Abstract
BACKGROUND Inflammatory bowel disease (IBD), composed of Crohn's disease (CD) and ulcerative colitis (UC), is an inflammatory autoimmune disease. CD99 has been reported to participate in migration of leukocytes and T cell activation. However, the roles of CD99 in IBD are obscure. MATERIALS AND METHODS CD99 expression was examined in peripheral blood mononuclear cells (PBMCs) and inflamed mucosa from IBD patients by qRT-PCR. Serum TNF-α and IL-17A levels were detected by ELISA. Correlations of CD99 expression with TNF-α, IL-17A, Crohn's disease activity index (CDAI), simple endoscopic score for CD (SES-CD), Mayo index, and Truelove grading were performed by Pearson's correlation. RESULTS CD99 expression was increased in PBMCs and inflamed mucosa from active CD and UC patients, and CD99 expression was also increased in the inflamed mucosa compared with unaffected control from the same patients. Serum TNF-α and IL-17A levels were increased in active CD or UC patients, and positively correlated with CD99 expression in PBMCs (CD: r = .402, p = .009; r = .350, p = .025. UC: r = .289, p = .028; r = .322, p = .014). Moreover, CD99 expression in inflamed mucosa was correlated with CDAI, SES-CD, Mayo index, and Truelove grading (r = .410, p = .012; r = .341, p = .005; r = .366, p = .002; r = .312, p = .011). CONCLUSION CD99 expression is increased in patients with active IBD, and positively correlated with disease activity. Therefore, CD99 expression can be used as an index to evaluate the activity of IBD.
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Affiliation(s)
- Guangxi Zhou
- a Department of Gastroenterology , The Shanghai Tenth People's Hospital, Tongji University , Shanghai , China
| | - Wenjing Yang
- a Department of Gastroenterology , The Shanghai Tenth People's Hospital, Tongji University , Shanghai , China
| | - Lin Yu
- a Department of Gastroenterology , The Shanghai Tenth People's Hospital, Tongji University , Shanghai , China
| | - Tianming Yu
- a Department of Gastroenterology , The Shanghai Tenth People's Hospital, Tongji University , Shanghai , China
| | - Zhanju Liu
- a Department of Gastroenterology , The Shanghai Tenth People's Hospital, Tongji University , Shanghai , China
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16
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Sun M, He C, Wu W, Zhou G, Liu F, Cong Y, Liu Z. Hypoxia inducible factor-1α-induced interleukin-33 expression in intestinal epithelia contributes to mucosal homeostasis in inflammatory bowel disease. Clin Exp Immunol 2016; 187:428-440. [PMID: 27921309 DOI: 10.1111/cei.12896] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Revised: 10/13/2016] [Accepted: 11/02/2016] [Indexed: 01/05/2023] Open
Abstract
Intestinal epithelial cells (IECs), an important barrier to gut microbiota, are subject to low oxygen tension, particularly during intestinal inflammation. Hypoxia inducible factor-1α (HIF-1α) is expressed highly in the inflamed mucosa of inflammatory bowel disease (IBD) and functions as a key regulator in maintenance of intestinal homeostasis. However, how IEC-derived HIF-1α regulates intestinal immune responses in IBD is still not understood completely. We report here that the expression of HIF-1α and IL-33 was increased significantly in the inflamed mucosa of IBD patients as well as mice with colitis induced by dextran sulphate sodium (DSS). The levels of interleukin (IL)-33 were correlated positively with that of HIF-1α. A HIF-1α-interacting element was identified in the promoter region of IL-33, indicating that HIF-1α activity regulates IL-33 expression. Furthermore, tumour necrosis factor (TNF) facilitated the HIF-1α-dependent IL-33 expression in IEC. Our data thus demonstrate that HIF-1α-dependent IL-33 in IEC functions as a regulatory cytokine in inflamed mucosa of IBD, thereby regulating the intestinal inflammation and maintaining mucosal homeostasis.
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Affiliation(s)
- M Sun
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - C He
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - W Wu
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - G Zhou
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - F Liu
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - Y Cong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA
| | - Z Liu
- Department of Gastroenterology, The Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
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Timmermans WMC, van Laar JAM, van Hagen PM, van Zelm MC. Immunopathogenesis of granulomas in chronic autoinflammatory diseases. Clin Transl Immunology 2016; 5:e118. [PMID: 28090320 PMCID: PMC5192066 DOI: 10.1038/cti.2016.75] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2016] [Revised: 11/11/2016] [Accepted: 11/12/2016] [Indexed: 12/23/2022] Open
Abstract
Granulomas are clusters of immune cells. These structures can be formed in reaction to infection and display signs of necrosis, such as in tuberculosis. Alternatively, in several immune disorders, such as sarcoidosis, Crohn's disease and common variable immunodeficiency, non-caseating granulomas are formed without an obvious infectious trigger. Despite advances in our understanding of the human immune system, the pathogenesis underlying these non-caseating granulomas in chronic inflammatory diseases is still poorly understood. Here, we review the current knowledge about the immunopathogenesis of granulomas, and we discuss how the involved immune cells can be targeted with novel therapeutics.
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Affiliation(s)
- Wilhelmina Maria Cornelia Timmermans
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Jan Alexander Michael van Laar
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Petrus Martinus van Hagen
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
- Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Menno Cornelis van Zelm
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
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Barber GE, Yajnik V, Khalili H, Giallourakis C, Garber J, Xavier R, Ananthakrishnan AN. Genetic Markers Predict Primary Non-Response and Durable Response To Anti-TNF Biologic Therapies in Crohn's Disease. Am J Gastroenterol 2016; 111:1816-1822. [PMID: 27596696 PMCID: PMC5143156 DOI: 10.1038/ajg.2016.408] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 08/03/2016] [Indexed: 12/11/2022]
Abstract
OBJECTIVES One-fifth of patients with Crohn's disease (CD) are primary non-responders to anti-tumor necrosis factor (anti-TNF) therapy, and an estimated 10-15% will fail therapy annually. Little is known about the genetics of response to anti-TNF therapy. The aim of our study was to identify genetic factors associated with primary non-response (PNR) and loss of response to anti-TNFs in CD. METHODS From a prospective registry, we characterized the response of 427 CD patients to their first anti-TNF therapy. Patients were designated as achieving primary response, durable response, and non-durable response based on clinical, endoscopic, and radiologic criteria. Genotyping was performed on the Illumina Immunochip. Separate genetic scores based on presence of predictive genetic alleles were calculated for PNR and durable response and performance of clinical and genetics models were compared. RESULTS From 359 patients, 36 were adjudged to have PNR (10%), 200 had durable response, and 74 had non-durable response. PNRs had longer disease duration and were more likely to be smokers. Fifteen risk alleles were associated with PNR. Patients with PNR had a significantly higher genetic risk score (GRS) (P =8 × 10-12). A combined clinical-genetic model more accurately predicted PNR when compared with a clinical only model (0.93 vs. 0.70, P <0.001). Sixteen distinct single nucleotide polymorphisms predicted durable response with a higher GRS (P =7 × 10-13). The GRSs for PNR and durable response were not mutually correlated, suggesting distinct mechanisms. CONCLUSIONS Genetic risk alleles can predict primary non-response and durable response to anti-TNF therapy in CD.
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Affiliation(s)
- Grant E Barber
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School
| | - Vijay Yajnik
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School
| | - Hamed Khalili
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School
| | - Cosmas Giallourakis
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School
| | - John Garber
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School
| | - Ramnik Xavier
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School
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Billmeier U, Dieterich W, Neurath MF, Atreya R. Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases. World J Gastroenterol 2016; 22:9300-9313. [PMID: 27895418 PMCID: PMC5107694 DOI: 10.3748/wjg.v22.i42.9300] [Citation(s) in RCA: 161] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Revised: 09/15/2016] [Accepted: 10/10/2016] [Indexed: 02/06/2023] Open
Abstract
Anti-tumor necrosis factor (TNF) antibodies are successfully used in the therapy of inflammatory bowel diseases (IBD). However, the molecular mechanism of action of these agents is still a matter of debate. Apart from neutralization of TNF, influence on the intestinal barrier function, induction of apoptosis in mucosal immune cells, formation of regulatory macrophages as well as other immune modulating properties have been discussed as central features. Nevertheless, clinically effective anti-TNF antibodies were shown to differ in their mode-of-action in vivo and in vitro. Furthermore, the anti-TNF agent etanercept is effective in the treatment of rheumatoid arthritis but failed to induce clinical response in Crohn’s disease patients, suggesting different contributions of TNF in the pathogenesis of these inflammatory diseases. In the following, we will review different aspects regarding the mechanism of action of anti-TNF agents in general and analyze comparatively different effects of each anti-TNF agent such as TNF neutralization, modulation of the immune system, reverse signaling and induction of apoptosis. We discuss the relevance of the membrane-bound form of TNF compared to the soluble form for the immunopathogenesis of IBD. Furthermore, we review reports that could lead to personalized medicine approaches regarding treatment with anti-TNF antibodies in chronic intestinal inflammation, by predicting response to therapy.
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Lo WC, Arsenescu V, Arsenescu RI, Friedman A. Inflammatory Bowel Disease: How Effective Is TNF-α Suppression? PLoS One 2016; 11:e0165782. [PMID: 27824890 PMCID: PMC5100971 DOI: 10.1371/journal.pone.0165782] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 10/18/2016] [Indexed: 12/13/2022] Open
Abstract
Crohn’s Disease (CD) results from inappropriate response toward commensal flora. Earlier studies described CD as a Th1 mediated disease. Current models view both phenotypes as a continuum of various permutations between Th1, Th2 and Th17 pathways compounded by a range of Treg disfunctions. In the present paper, we develop a mathematical model, by a system of differential equations, which describe the dynamic relations among these T cells and their cytokines. The model identities four groups of CD patients according to up/down regulation of Th1 and Th2. The model simulations show that immunosuppression by TNF-α blockage benefits the group with Th1High/Th2Low while, by contrast, the group with Th1Low/Th2High will benefit from immune activation.
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Affiliation(s)
- Wing-Cheong Lo
- Department of Mathematics, City University of Hong Kong, Hong Kong, Hong Kong SAR
- * E-mail:
| | | | - Razvan I. Arsenescu
- Digestive Health Institute, Inflammatory Bowel Diseases Center of Excellence Morristown Medical Center, Morristown, New Jersey, United States of America
| | - Avner Friedman
- Mathematical Biosciences Institute, Department of Mathematics, The Ohio State University, Columbus, Ohio, United States of America
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Blockade of PLD2 Ameliorates Intestinal Mucosal Inflammation of Inflammatory Bowel Disease. Mediators Inflamm 2016; 2016:2543070. [PMID: 27721573 PMCID: PMC5046040 DOI: 10.1155/2016/2543070] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Revised: 08/15/2016] [Accepted: 08/21/2016] [Indexed: 12/19/2022] Open
Abstract
Background. Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronically remittent and progressive inflammatory disorders. Phospholipase D2 (PLD2) is reported to be involved in the pathogenesis of several inflammatory diseases. However, the exact role of PLD2 in IBD is obscure. Methods. PLD2 expression was determined in peripheral blood cells and inflamed mucosa from patients with IBD by qRT-PCR. Colonic biopsies were also obtained from CD patients before and after infliximab (IFX) treatment to examine PLD2 expression. PLD2 selective inhibitor (CAY10594) was administrated daily by oral gavage in DSS-induced colitis mice. Bone marrow neutrophils from colitis mice were harvested to examine the migration using Transwell plate. Results. PLD2 was found to be significantly increased in peripheral blood cells and inflamed mucosa in patients with active IBD. Treatment with IFX could significantly decrease PLD2 expression in intestinal mucosa in patients with CD. Moreover, blockade of PLD2 with CAY10594 could markedly ameliorate DSS-induced colitis in mice and promote neutrophil migration. Conclusions. PLD2 plays a critical role in the pathogenesis of IBD. Blockade of PLD2 may serve as a new therapeutic approach for treatment of IBD.
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22
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McNamee EN, Rivera-Nieves J. Ectopic Tertiary Lymphoid Tissue in Inflammatory Bowel Disease: Protective or Provocateur? Front Immunol 2016; 7:308. [PMID: 27579025 PMCID: PMC4985530 DOI: 10.3389/fimmu.2016.00308] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Accepted: 07/29/2016] [Indexed: 12/15/2022] Open
Abstract
Organized lymphoid tissues like the thymus first appeared in jawed vertebrates around 500 million years ago and have evolved to equip the host with a network of specialized sites, strategically located to orchestrate strict immune-surveillance and efficient immune responses autonomously. The gut-associated lymphoid tissues maintain a mostly tolerant environment to dampen our responses to daily dietary and microbial products in the intestine. However, when this homeostasis is perturbed by chronic inflammation, the intestine is able to develop florid organized tertiary lymphoid tissues (TLT), which heralds the onset of regional immune dysregulation. While TLT are a pathologic hallmark of Crohn's disease (CD), their role in the overall process remains largely enigmatic. A critical question remains; are intestinal TLT generated by the immune infiltrated intestine to modulate immune responses and rebuild tolerance to the microbiota or are they playing a more sinister role by generating dysregulated responses that perpetuate disease? Herein, we discuss the main theories of intestinal TLT neogenesis and focus on the most recent findings that open new perspectives to their role in inflammatory bowel disease.
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Affiliation(s)
- Eóin N McNamee
- Mucosal Inflammation Program, Department of Anesthesiology, School of Medicine, University of Colorado - Anschutz Medical Campus , Aurora, CO , USA
| | - Jesús Rivera-Nieves
- Division of Gastroenterology, Inflammatory Bowel Disease Center, San Diego VAMC, University of California San Diego , La Jolla, CA , USA
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23
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Dahlén R, Magnusson MK, Bajor A, Lasson A, Ung KA, Strid H, Öhman L. Global mucosal and serum cytokine profile in patients with ulcerative colitis undergoing anti-TNF therapy. Scand J Gastroenterol 2016; 50:1118-26. [PMID: 25877762 DOI: 10.3109/00365521.2015.1031167] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND OBJECTIVE The knowledge of the effects of anti-tumour necrosis factor (TNF) treatment on the global cytokine profile in patients with ulcerative colitis (UC) is limited. A better understanding of these mechanisms could improve the ability to select patients that should undergo the therapy. Therefore, the aim was to determine the global mucosal and serum cytokine profile before and during induction therapy with anti-TNF in UC patients. MATERIALS AND METHODS In total, mucosal biopsies (n = 28) and serum samples (n = 42) were collected from UC patients (total n = 48) before anti-TNF therapy. At week 14 response to the therapy was evaluated and again mucosal biopsies (n = 14) and serum samples (n = 42) were collected. Quantitative real-time PCR was used to determine mucosal cytokine mRNA expression and the MSD MULTI-ARRAY assay system platform was used for analysis of cytokines in serum. The global cytokine profile was evaluated by multivariate factor analysis. RESULTS At baseline, the global profile of mucosal cytokine mRNA expression and serum cytokines discriminated therapy responders from non-responders. Responders had lower mucosal mRNA expression of interleukin 1β (IL-1β), IL-17A, IL-6 and interferon γ (IFN-γ) than non-responders. Fourteen weeks after therapy start mucosal IL-1β and IL-6 were down-regulated in therapy responders but not in non-responders. At week 14, serum levels of IL-6 were decreased in therapy responders whereas IFN-γ and IL-12p70 were increased in non-responders. CONCLUSIONS Our data suggest that patients with a therapy failure have a more severe pro-inflammatory cytokine profile before start of anti-TNF treatment, which is less well suppressed by the treatment as compared to therapy responders.
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Affiliation(s)
- Rahil Dahlén
- Department of Microbioloy and Immunology, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
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Olesen CM, Coskun M, Peyrin-Biroulet L, Nielsen OH. Mechanisms behind efficacy of tumor necrosis factor inhibitors in inflammatory bowel diseases. Pharmacol Ther 2016; 159:110-9. [PMID: 26808166 DOI: 10.1016/j.pharmthera.2016.01.001] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Biological treatment with tumor necrosis factor (TNF) inhibitors is successful in the management of inflammatory bowel disease (IBD). All TNF inhibitors antagonize the pro-inflammatory cytokine TNF-α but with varying efficacies in IBD. The variations in efficacy probably are caused by structural differences between the agents that affect their mechanisms of action and pharmacokinetic properties. Several mechanisms have been proposed, such as modulation of the expression of pro-inflammatory mediators and a reduction in the number of activated immune cells. However, it seems that clinical efficacy is the result of a number of different mechanisms and that binding of transmembrane TNF by TNF inhibitors. Knowledge of the mechanisms of action has been obtained mainly through the use of in vitro assays that may differ significantly from the situation in vivo. This review discusses the available data on TNF inhibitors in order to identify mechanisms of importance for their efficacy in IBD. Thus, a better understanding of the mechanistic basis for clinical efficacy can lead to a more rational use of TNF inhibitors in the management of IBD.
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Affiliation(s)
- Caroline Meyer Olesen
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark
| | - Mehmet Coskun
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark.
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Inserm U954, Nancy University Hospital, Lorraine University, Vandoeuvre, France
| | - Ole Haagen Nielsen
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Herlev, Denmark
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Slevin SM, Egan LJ. New Insights into the Mechanisms of Action of Anti-Tumor Necrosis Factor-α Monoclonal Antibodies in Inflammatory Bowel Disease. Inflamm Bowel Dis 2015; 21:2909-20. [PMID: 26348448 DOI: 10.1097/mib.0000000000000533] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Tumor necrosis factor alpha (TNF-α) has been widely accepted as a therapeutic target for inflammatory disorders including inflammatory bowel disease. Anti-TNF-α monoclonal antibodies (mAbs) including infliximab, adalimumab, golimumab, and certolizumab pegol have revolutionized therapy for these chronic inflammatory disorders. These agents are potent inhibitors of TNF-α, but significant evidence points to the fact that their actions extend beyond simple neutralization of the cytokine. Recent advances in understanding the mechanism of action of anti-TNF-α mAbs has discovered a number of previously unrecognized actions that are likely to be relevant in mediating their anti-inflammatory effects. Many of those actions are mediated by the binding of the antibodies to transmembrane TNF-α (tmTNF-α) and involve complex interactions with other molecular factors and cells. In this review, we have highlighted new information on the mechanism of actions of anti-TNF-α mAbs, from in vitro and in vivo studies. Despite obvious benefits in many patients, the clinical use of these antibodies are hampered by the fact that some patients do not respond to them, and among patients who do respond, many will develop recurrent disease despite continued dosing. Although pharmacokinetic factors explain some of the observed cases of partial or complete resistance to the effects of anti-TNF-α mAbs, other nonresponder patients may be resistant to those agents mechanism of action. A more thorough understanding of the mechanism of action of anti-TNF-α mAbs may allow the development of strategies to individualize therapy and to overcome resistance.
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Affiliation(s)
- Stephanie M Slevin
- *Immunology Research Group, REMEDI, National University of Ireland, Galway, Ireland; and †Department of Pharmacology and Therapeutics, Clinical Science Institute, National University of Ireland, Galway, Ireland
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Divalent metal-ion transporter 1 is decreased in intestinal epithelial cells and contributes to the anemia in inflammatory bowel disease. Sci Rep 2015; 5:16344. [PMID: 26572590 PMCID: PMC4648093 DOI: 10.1038/srep16344] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 10/12/2015] [Indexed: 12/16/2022] Open
Abstract
Divalent metal-ion transporter 1 (DMT1) has been found to play an important role in the iron metabolism and hemogenesis. However, little is known about the potential role of DMT1 in the pathogenesis of anemia from patients with inflammatory bowel disease (IBD). Herein, we investigated expression of DMT1 in the intestinal mucosa by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry, and found that DMT1 was significantly decreased in the inflamed mucosa of active IBD patients compared with that in those patients at remission stage and healthy controls. To further study the mechanism, we cultured HCT 116 cell line in vitro. Expression of DMT1 in HCT116 was demonstrated to be markedly decreased under stimulation with TNF for 24 and 48 h, while JNK inhibitor (JNK-IN-7) could significantly reverse the decrease. Interestingly, anti-TNF therapy successfully improved anemia in clinical responsive Crohn’s disease patients, and DMT1 was found to be markedly up-regulated in intestinal mucosa. Taken together, our studies demonstrate that decreased expression of DMT1 in intestinal mucosa leads to compromised absorption and transportation of iron and that blockade of TNF could rescue anemia and promote DMT1 expression in gut mucosa. This work provides a therapeutic approach in the management of anemia in IBD.
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Genetic Polymorphisms of IL-17F and TRAF3IP2 Could Be Predictive Factors of the Long-Term Effect of Infliximab against Crohn's Disease. BIOMED RESEARCH INTERNATIONAL 2015; 2015:416838. [PMID: 26558270 PMCID: PMC4628975 DOI: 10.1155/2015/416838] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 09/27/2015] [Indexed: 12/18/2022]
Abstract
Background. We aimed to identify certain genes related to response to infliximab (IFX) and biomarkers to predict the IFX effect for Japanese Crohn's disease (CD) patients by performing an association study of single nucleotide polymorphisms (SNPs) in candidate genes in the interleukin- (IL-) 17 signaling pathway with response to IFX after 1 year of treatment. Methods. A total of 103 patients were divided into two groups, responders and nonresponders. Twenty-eight tag SNPs in 5 genes were genotyped. The frequencies of alleles and genotypes of each SNP were compared between responders and nonresponders in three different inheritance models. A genetic test was performed using a combination of the associated SNPs as biomarkers. Results. Multivariate logistic regression analysis indicated that the four variable factors, concomitant use of immunomodulators, penetrating disease, a G/G genotype of rs766748 in IL-17F, and a C/C or C/A genotype of rs1883136 in TRAF3IP2, independently contributed to response to IFX after 1 year of treatment. Genetic test using the polymorphisms of these genes perfectly predicted the responder and nonresponder CD patients with both concomitant use of immunomodulators and penetrating disease. Conclusion. IL17F and TRAF3IP2 are one of IFX-related genes, useful as biomarkers of IFX response, and may be target molecules for new therapeutic drugs.
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Wang Z, Ding L, Wang Z, Wang J, Zhu N, Diao Y, Demmy TA, Haitsma JM, Lech-Maranda EE, Bangia NN, Czuczman MA, Qian X, Kovacs KL. Circulating CD4+CXCR5+T Cells Exacerbate B Cell Antibody Production in Crohn's Disease Through IL-21 Secretion. Immunol Invest 2015; 44:665-77. [DOI: 10.3109/08820139.2015.1074246] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Serum Levels of Lipopolysaccharide and 1,3-β-D-Glucan Refer to the Severity in Patients with Crohn's Disease. Mediators Inflamm 2015; 2015:843089. [PMID: 26106258 PMCID: PMC4464677 DOI: 10.1155/2015/843089] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Revised: 01/19/2015] [Accepted: 01/26/2015] [Indexed: 12/17/2022] Open
Abstract
Objectives. Interactions between the host and gut microbial community contribute to the pathogenesis of Crohn's disease (CD). In this study, we aimed to detect lipopolysaccharide (LPS) and 1,3-β-D-glucan (BG) in the sera of CD patients and clarify the potential role in the diagnosis and therapeutic approaches. Materials and Methods. Serum samples were collected from 46 patients with active CD (A-CD), 22 CD patients at remission stage (R-CD), and 20 healthy controls, and the levels of LPS, BG, and TNF in sera were determined by ELISA. Moreover, sixteen patients with A-CD received anti-TNF monoclonal antibody therapy (infliximab, IFX) at a dose of 5 mg/kg body weight at weeks 0, 2, and 6, and the levels of LPS and BG were also tested at week 12 after the first intravenous infusion. Results. Serum levels of LPS and BG were found to be markedly increased in A-CD patients compared with R-CD patients and healthy controls (P < 0.05). They were also observed to be positively correlated with CDAI, ESR, and SES-CD, respectively (P < 0.05). Furthermore, the levels of TNF in sera had a significant correlation with LPS and BG, respectively. The concentrations of LPS and BG were demonstrated to be significantly downregulated in the sera of A-CD patients 12 weeks after IFX treatment (P < 0.05), suggesting that blockade of TNF could inhibit bacterial endotoxin absorption, partially through improving intestinal mucosal barrier. Conclusions. Serum levels of LPS and BG are significantly increased in A-CD patients and positively correlated with the severity of the disease. Blockade of intestinal mucosal inflammation with IFX could reduce the levels of LPS and BG in sera. Therefore, this study has shed some light on measurement of serum LPS and BG in the diagnosis and treatment of CD patients.
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Infliximab preferentially induces clinical remission and mucosal healing in short course Crohn's disease with luminal lesions through balancing abnormal immune response in gut mucosa. Mediators Inflamm 2015; 2015:793764. [PMID: 25873771 PMCID: PMC4383520 DOI: 10.1155/2015/793764] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Accepted: 10/10/2014] [Indexed: 01/25/2023] Open
Abstract
This study was undertaken to evaluate the efficacy of infliximab (IFX) in treatment of Crohn's disease (CD) patients. 106 CD patients were undergoing treatment with IFX from five hospitals in Shanghai, China. Clinical remission to IFX induction therapy was defined as Crohn's disease activity index (CDAI) < 150. Clinical response was assessed by a decrease in CDAI ≥ 70, and the failure as a CDAI was not significantly changed or increased. Ten weeks after therapy, 61 (57.5%) patients achieved clinical remission, 17 (16.0%) had clinical response, and the remaining 28 (26.4%) were failed. In remission group, significant changes were observed in CDAI, the Simple Endoscopic Score for Crohn's Disease (SES-CD), and serum indexes. Patients with short disease duration (22.2 ± 23.2 months) and luminal lesions showed better effects compared to those with long disease duration (71.0 ± 58.2 months) or stricturing and penetrating lesions. IFX markedly downregulated Th1/Th17-mediated immune response but promoted IL-25 production in intestinal mucosa from remission group. No serious adverse events occurred to terminate treatment. Taken together, our studies demonstrated that IFX is efficacious and safe in inducing clinical remission, promoting mucosal healing, and downregulating Th1/Th17-mediated immune response in short course CD patients with luminal lesions.
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Leal RF, Planell N, Kajekar R, Lozano JJ, Ordás I, Dotti I, Esteller M, Masamunt MC, Parmar H, Ricart E, Panés J, Salas A. Identification of inflammatory mediators in patients with Crohn's disease unresponsive to anti-TNFα therapy. Gut 2015; 64:233-42. [PMID: 24700437 DOI: 10.1136/gutjnl-2013-306518] [Citation(s) in RCA: 109] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Anti-tumour necrosis factor α (TNFα) therapy effectively induces and maintains remission in Crohn's disease (CD). Up to 40% of patients, however, fail to respond to anti-TNFα. OBJECTIVE To identify the mechanisms underlying the persistence of mucosal lesions in patients who fail to respond to anti-TNFα therapy. DESIGN An observational study based on whole-genome transcriptional analysis was carried out using intestinal biopsy specimens from patients with CD receiving (n=12) or not (n=10) anti-TNFα therapy. The transcriptional signature of responders was compared with that of non-responders after anti-TNFα therapy. Controls with non-inflammatory bowel disease (non-IBD) (n=17) were used for comparisons. Genes of interest were validated by real-time RT-PCR in an independent cohort of patients with CD receiving (n=17) or not (n=16) anti-TNFα and non-IBD controls (n=7). RESULTS We confirmed that response to anti-TNFα is accompanied by significant regulation of a large number of genes, including IL1B, S100A8, CXCL1, which correlated with endoscopic activity. Remarkably, patients who failed to respond to anti-TNFα showed a mixed signature, maintaining increased expression of IL1B, IL17A and S100A8, while showing significant modulation of other genes commonly upregulated in active CD, including IL6 and IL23p19. CONCLUSIONS Our results show that anti-TNFα therapy significantly downregulates a subset of inflammatory genes even in patients who fail to achieve endoscopic remission, suggesting that these genes may not be dominant in driving inflammation in non-responders. On the other hand, we identified IL1B and IL17A as genes that remained altered in non-responders, pointing to potentially more relevant targets for modulating mucosal damage in refractory patients.
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Affiliation(s)
- Raquel Franco Leal
- Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain Postdoctoral CAPES fellow, Brazil
| | - Núria Planell
- Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain Bioinformatics Platform, CIBERehd, Barcelona, Spain
| | - Radhika Kajekar
- Hoffmann-La Roche, Nutley, New Jersey, USA Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
| | | | - Ingrid Ordás
- Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain
| | - Isabella Dotti
- Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain
| | - Miriam Esteller
- Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain
| | - M Carme Masamunt
- Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain
| | - Harsukh Parmar
- Hoffmann-La Roche, Nutley, New Jersey, USA EMD Serono Research & Development Institute, Boston, Massachusetts, USA
| | - Elena Ricart
- Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain
| | - Julián Panés
- Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain
| | - Azucena Salas
- Department of Gastroenterology, IDIBAPS, Hospital Clínic, CIBERehd, Barcelona, Spain
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TL1A increased the differentiation of peripheral Th17 in rheumatoid arthritis. Cytokine 2014; 69:125-30. [DOI: 10.1016/j.cyto.2014.04.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2013] [Revised: 03/01/2014] [Accepted: 04/18/2014] [Indexed: 01/29/2023]
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Qiu H, Sun X, Sun M, He C, Li Z, Liu Z. Serum bacterial toxins are related to the progression of inflammatory bowel disease. Scand J Gastroenterol 2014; 49:826-33. [PMID: 24853095 DOI: 10.3109/00365521.2014.919018] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is an autoimmune disease. Disorder of intestinal microbes is thought to play a critical role in the pathogenesis of IBD. Detection of bacterial toxins could become a new approach to judge the situation of this disease. MATERIALS AND METHODS Serum samples were collected from 142 IBD patients and 40 healthy donors as well as 15 CD patients with anti-tumor necrosis factor (TNF) monoclonal antibody (infliximab [IFX]). Enzyme-linked immunosorbent assay kits for Clostridium difficile, Escherichia coli O157, salmonella, and Staphylococcus aureus were used to analyze these bacterial toxins in sera. RESULTS The positive rates of bacterial toxins from C. difficile, E. coli O157, salmonella, and S. aureus in the IBD patients were found in low incidences and associated with disease duration, colonic involvement, and treatment with prednisone and immunomodulators. The active CD and UC patients had significant higher positive rates of these bacterial toxins than those in remission or healthy controls. Blockage of TNF with IFX in CD patients resulted in significant decreases of the levels of toxins of C. difficile, E. coli O157, salmonella, and S. aureus in sera. CONCLUSIONS Some bacterial toxins are present in the sera of active IBD patients, and patients with long disease duration, colonic involvement, or treatment with prednisone and immunomodulators are more susceptible to bacterial infection. Inhibition of inflammation with IFX would reduce the bacterial toxins via improvement of intestinal inflammation. Detecting bacteria-derived toxins in sera can be used to predict the progression of IBD.
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Affiliation(s)
- Huajing Qiu
- Department of Gastroenterology, the Shanghai Tenth People's Hospital, Tongji University , Shanghai , China
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Stopping anti-TNF agents in patients with Crohn's disease in remission: is it a feasible long-term strategy? Inflamm Bowel Dis 2014; 20:757-66. [PMID: 24572206 DOI: 10.1097/01.mib.0000442680.47427.bf] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Xu XR, Liu CQ, Feng BS, Liu ZJ. Dysregulation of mucosal immune response in pathogenesis of inflammatory bowel disease. World J Gastroenterol 2014; 20:3255-3264. [PMID: 24695798 PMCID: PMC3964397 DOI: 10.3748/wjg.v20.i12.3255] [Citation(s) in RCA: 171] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2013] [Revised: 11/02/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis. The exact etiology and pathology of IBD remain unknown. Available evidence suggests that an abnormal immune response against the microorganisms in the intestine is responsible for the disease in genetically susceptible individuals. Dysregulation of immune response in the intestine plays a critical role in the pathogenesis of IBD, involving a wide range of molecules including cytokines. On the other hand, besides T helper (Th) 1 and Th2 cell immune responses, other subsets of T cells, namely Th17 and regulatory T cells, are likely associated with disease progression. Studying the interactions between various constituents of the innate and adaptive immune systems will certainly open new horizons of the knowledge about the immunologic mechanisms in IBD.
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Xiao F, Zhang HY, Liu YJ, Zhao D, Shan YX, Jiang YF. Higher frequency of peripheral blood interleukin 21 positive follicular helper T cells in patients with ankylosing spondylitis. J Rheumatol 2013; 40:2029-37. [PMID: 24187103 DOI: 10.3899/jrheum.130125] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
OBJECTIVE The role of follicular Th (TFH) cells remains unclear in the pathogenesis of ankylosing spondylitis (AS). Our study examined the frequency of different subsets of circulating CXCR5+CD4+ T cells in patients with AS before and after receiving therapy. METHODS Percentages of peripheral blood inducible costimulator (ICOS)+, programmed death 1 (PD-1)+, and interleukin 21 (IL-21)+ CXCR5+CD4+ T cells in 26 patients with AS and 12 healthy controls (HC) were examined by flow cytometry, and the disease activity of individual patients was measured by Bath AS Disease Activity Index (BASDAI). The concentrations of serum IL-21, IgG, IgA, IgM, and C-reactive protein (CRP) were examined and the values of erythrocyte sedimentation rate (ESR) were measured. The potential association among these measures was analyzed. RESULTS In comparison with that in HC, significantly increased percentages of CXCR5+CD4+, CXCR5+CD4+PD-1+, and CXCR5+CD4+IL-21+, but not CXCR5+CD4+ICOS+ and PD-1+ICOS+CXCR5+CD4+ T cells, and elevated concentrations of serum IL-21 were detected in patients with AS (p = 0.001, p = 0.012, p < 0.001, p = 0.233, p = 0.216, p < 0.001, respectively). Treatment with meloxicam, thalidomide, and etanercept for 1 month significantly reduced percentages of IL-21+CXCR5+CD4+ T cells and concentrations of serum IL-21 (p < 0.001, p < 0.001, respectively), accompanied by significantly minimized disease activity in drug responders, but not in the drug nonresponders. Further, percentages of IL-21+CXCR5+CD4+ T cells were positively correlated with BASDAI in patients (r = 0.6, p = 0.0012) and in the drug-responders 1 month after treatment (r = 0.68, p = 0.005), while the percentages of PD-1+CXCR5+CD4+ T cells were negatively correlated with BASDAI (r = -0.58, p = 0.0018). CONCLUSION These data suggest that IL-21+CXCR5+CD4+ T cells may be associated with development of AS and that the frequency of IL-21+CXCR5+CD4+ T cells may be a biomarker for evaluation of disease activity and drug responses in patients with AS, particularly in drug-responding patients.
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Affiliation(s)
- Fei Xiao
- From the Key Laboratory of Zoonosis Research, Ministry of Education, the Second Part of First Hospital, Jilin University, Changchun, 130032, China
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