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1
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Solaymani-Mohammadi S. The IL-21/IL-21R signaling axis regulates CD4+ T-cell responsiveness to IL-12 to promote bacterial-induced colitis. J Leukoc Biol 2024; 116:726-737. [PMID: 38498592 PMCID: PMC11408709 DOI: 10.1093/jleuko/qiae069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 02/21/2024] [Accepted: 03/06/2024] [Indexed: 03/20/2024] Open
Abstract
IL-21/IL-21R signaling dysregulation is linked to multiple chronic intestinal inflammatory disorders in humans and animal models of human diseases. In addition to its critical requirement for the generation and development of germinal center B cells, IL-21/IL-21R signaling can also regulate the effector functions of a variety of T-cell subsets. The antibody-mediated abrogation of IL-21/IL-21R signaling led to the impaired expression of IFN-γ by mucosal CD4+ T cells from human subjects with colitis, suggesting an IL-21/IL-21R-triggered positive feedback loop of the TH1 immune response in the colon. Despite recent advances in our understanding of the mechanisms underpinning the regulation of proinflammatory immune responses by the IL-21/IL-21R signaling axis, it remains unclear how this pathway or its downstream molecules contribute to inflammation during bacterial-induced colitis. This study found that IL-21 enhances the surface expression of IL-12Rβ2, but not IL-12Rβ1, in CD4+ T cells, leading to TH1 differentiation and stability. Consistently, these findings also point to an indispensable role of the IL-12Rβ2 signaling axis in promoting proinflammatory immune responses during Citrobacter rodentium-induced colitis. Genetic deletion of the IL-12Rβ2 signaling pathway led to the attenuation of C. rodentium-induced colitis in vivo. The genetic deletion of the IL-12Rβ2 signaling pathway did not alter the host's ability to respond adequately to C. rodentium infection or the ability of Il12rb2-/- mice to express antigen-specific cytokines (IFN-γ, IL-17A). IL-21 is a pleiotropic cytokine exerting a wide range of immunomodulatory functions in multiple tissues, and its direct targeting may result in undesirable off-target consequences. These findings highlight the possibility for targeted manipulations of signaling cascades downstream of main regulators of proinflammatory responses to control invading pathogens while preserving the integrity of host immune responses. A better understanding of the novel mechanisms by which IL-21/IL-21R signaling regulates bacterial-induced colitis will provide insights into the development of new therapeutic and preventive strategies to harness IL-21/IL-21R signaling or its downstream molecules to treat infectious colitis.
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Affiliation(s)
- Shahram Solaymani-Mohammadi
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, 1301 North Columbia Road, Suite W315, Stop 9037, Grand Forks, ND, United States
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Hong SM, Moon W. [Old and New Biologics and Small Molecules in Inflammatory Bowel Disease: Anti-interleukins]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2024; 84:65-81. [PMID: 39176462 DOI: 10.4166/kjg.2024.076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2024] [Revised: 08/13/2024] [Accepted: 08/13/2024] [Indexed: 08/24/2024]
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disease of the gastrointestinal tract. The introduction of biologics, particularly anti-interleukin (IL) agents, has revolutionized IBD treatment. This review summarizes the role of ILs in IBD pathophysiology and describes the efficacy and positioning of anti-IL therapies. We discuss the functions of key ILs in IBD and their potential as therapeutic targets. The review then discusses anti-IL therapies, focusing primarily on ustekinumab (anti-IL-12/23), risankizumab (anti-IL-23), and mirikizumab (anti-IL-23). Clinical trial data demonstrate their efficacy in inducing and maintaining remission in Crohn's disease and ulcerative colitis. The safety profiles of these agents are generally favorable. However, long-term safety data for newer agents are still limited. The review also briefly discusses emerging therapies such as guselkumab and brazikumab. Network meta-analyses suggest that anti-IL therapies perform well compared to other biological agents. These agents may be considered first- or second-line therapies for many patients, especially those with comorbidities or safety concerns. Anti-IL therapies represent a significant advancement in IBD treatment, offering effective and relatively safe options for patients with moderate to severe disease.
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Affiliation(s)
- Seung Min Hong
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan, Korea
| | - Won Moon
- Department of Internal Medicine, Kosin University College of Medicine, Busan, Korea
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3
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Nagano K, Hata E, Asano T, Tsuchiya H, Takagishi M, Yamazaki H, Tominaga S, Matsumoto T. Safety and Effectiveness of Ustekinumab for Crohn's Disease in Japanese Post-marketing Surveillance in Biologic-Naive and -Experienced Conriemed. CROHN'S & COLITIS 360 2023; 5:otad001. [PMID: 36777365 PMCID: PMC9912369 DOI: 10.1093/crocol/otad001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Indexed: 01/14/2023] Open
Abstract
Background To present the real-world evidence on the safety and effectiveness of ustekinumab (UST) through 52-week treatment for Crohn's disease (CD) under an analysis of post-market surveillance data in Japan. Methods This prospective, post-marketing surveillance study was conducted in 341 patients from 91 medical facilities in Japan. Patients received UST 90 mg injected subcutaneously once every 12 weeks (or every 8 weeks if patients show weak effectiveness) after an induction dose given intravenously. Clinical response (100-point decrease in Crohn's Disease Activity Index [CDAI] score), clinical remission (CDAI score of <150), steroid-free clinical remission, C-reactive protein, endoscopy, physician global assessment, and adverse drug reactions (ADRs) were evaluated through 52 weeks. Results The overall rate of clinical remission was 49.2% at week 8 and 56.0% at week 52. The rate of clinical remission in biologic-naive patients was 75.9% and 66.7% at weeks 8 and 52, respectively, whereas the rate in biologic-experienced patients was 41.4% and 52.6% at weeks 8 and 52, respectively. For 52 weeks, the overall incidence of ADRs and serious adverse drug reactions (SADRs) was 11.7% and 6.7%, respectively. The most frequently reported SADRs was worsening of CD (1.8%). In multivariate analysis, ADRs incidence was significantly lower in patients with ileal involvement of CD (odds ratio = 0.25, 95% CI 0.07-0.85, P = .026), although disease location has no association with effectiveness of UST. Conclusions The present study identified no new safety concerns and effectiveness for CD in Japanese patients treated with UST.
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Affiliation(s)
- Katsumasa Nagano
- Janssen Pharmaceutical K.K., Medical affairs division, Tokyo, Japan
| | - Erina Hata
- Janssen Pharmaceutical K.K., Medical affairs division, Tokyo, Japan
| | - Teita Asano
- Janssen Pharmaceutical K.K., Medical affairs division, Tokyo, Japan
| | - Hiroaki Tsuchiya
- Janssen Pharmaceutical K.K., Medical affairs division, Tokyo, Japan
| | - Masayuki Takagishi
- Janssen Pharmaceutical K.K., Research & Development division, Tokyo, Japan
| | - Hiroshi Yamazaki
- Janssen Pharmaceutical K.K., Research & Development division, Tokyo, Japan
| | - Sonoko Tominaga
- Janssen Pharmaceutical K.K., Research & Development division, Tokyo, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Iwate, Japan
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Black Seed (Nigella sativa): A Favourable Alternative Therapy for Inflammatory and Immune System Disorders. Inflammopharmacology 2022; 30:1623-1643. [PMID: 35972596 DOI: 10.1007/s10787-022-01035-6] [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: 05/09/2022] [Accepted: 07/06/2022] [Indexed: 11/09/2022]
Abstract
In the recent years, various food additives, medicinal plants, and their bioactive components have been utilized in anti-inflammatory and immunomodulatory therapy. Nigella sativa is a key dietary supplement and food additive which has a strong traditional background. It is also one of the most broadly studied seeds in the global pharmaceutical and nutraceutical sector. N. sativa seeds are potential sources of natural metabolite such as phenolic compounds and alkaloids. The anti-inflammatory and immunomodulatory abilities of these seeds, most peculiarly with reference to some inflammatory and immune mediators, are reviewed. N. sativa and its bioactive compounds modulate inflammatory and immunomodulatory mediators including tumor necrosis factor-alpha (TNF-α), interferon gamma (IFN-γ), nuclear factor kappa B (NF-kB) cyclooxygenase (COX), lipoxygenase (LOX), transforming growth factor beta (TGF-β), interleukins, and immunoglobulin levels. This paper comprehensively describes the biomarkers and signaling pathways underlying the anti-inflammatory and immunomodulatory potential of N. sativa. This review also explains the scientific basis and the pharmacological properties of core bioactive ingredients of N. sativa responsible for these biological activities which indicates that their bioactive components could be possibly regarded as favorable therapy for disorders linked to inflammation and immune-dysregulation.
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Hadji H, Bouchemal K. Advances in the treatment of inflammatory bowel disease: Focus on polysaccharide nanoparticulate drug delivery systems. Adv Drug Deliv Rev 2022; 181:114101. [PMID: 34999122 DOI: 10.1016/j.addr.2021.114101] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 12/21/2021] [Accepted: 12/22/2021] [Indexed: 02/07/2023]
Abstract
The complex pathogenesis of inflammatory bowel disease (IBD) explains the several hurdles for finding an efficient approach to cure it. Nowadays, therapeutic protocols aim to reduce inflammation during the hot phase or maintain remission during the cold phase. Nonetheless, these drugs suffer from severe side effects or poor efficacy due to low bioavailability in the inflamed region of the intestinal tract. New protocols based on antibodies that target proinflammatory cytokines are clinically relevant. However, besides being expensive, their use is associated with a primary nonresponse or a loss of response following a long administration period. Accordingly, many researchers exploited the physiological changes of the mucosal barrier for designing nanoparticulate drug delivery systems to target inflamed tissues. Others exploited biocompatibility and relative affordability of polysaccharides to test their intrinsic anti-inflammatory and healing properties in IBD models. This critical review updates state of the art on advances in IBD treatment. Data on using polysaccharide nanoparticulate drug delivery systems for IBD treatment are reviewed and discussed.
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Affiliation(s)
- Hicheme Hadji
- Institut Galien Paris Saclay, CNRS UMR 8612, Université Paris-Saclay, Faculté de Pharmacie, 5 rue J-B Clément, 92296 Châtenay-Malabry, France
| | - Kawthar Bouchemal
- Institut Galien Paris Saclay, CNRS UMR 8612, Université Paris-Saclay, Faculté de Pharmacie, 5 rue J-B Clément, 92296 Châtenay-Malabry, France.
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6
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Qiu X, Wang D, Lv M, Sun H, Ren J, Wang X, Zhou H. Identification and functional characterization of interleukin-12 receptor beta 1 and 2 in grass carp (Ctenopharyngodon idella). Mol Immunol 2022; 143:58-67. [PMID: 35042118 DOI: 10.1016/j.molimm.2022.01.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/11/2022] [Accepted: 01/11/2022] [Indexed: 11/30/2022]
Abstract
Interleukin 12 (IL-12) binds its receptor complex of IL-12 receptor beta 1 (IL-12Rβ1) and IL-12Rβ2 to transduce cellular signaling in mammals. In teleosts, the function of Il-12 is drawing increasing attention, but molecular and functional features of Il-12 receptors remain obscure. Especially, the existence of multiple Il-12 isoforms in some fish species elicits the requirement to clarify their receptors. In this study, we isolated three cDNA sequences as Il-12 receptor candidates from grass carp, entitled as grass carp Il-12rβ1 (gcIl-12rβ1), gcIl-12rβ2a and gcIl-12rβ2b. In silico analysis showed that gcIl-12rβ1 and gcIl-12rβ2a shared the conserved gene locus and similar structure characteristics with their orthologues of zebrafish, frog, chicken, mouse and human, respectively. However, the Il-12rβ2b of grass carp and zebrafish was similar to IL-27Ra in non-fish species. Further locally installed BLAST and gene synteny analysis uncovered three gcIl-12 receptors being single copied genes. Tissue distribution assay revealed that gcil12rβ1 and gcil12rβ2a transcripts were predominantly expressed in head kidney, differing from the even distribution of gcil12rβ2b transcripts in all detected tissues. Subsequently, the binding ability and antagonistic effects of recombinant extracellular region of gcIl-12rβ1 with recombinant grass carp Il-12 (rgcIl-12) isoforms were explored, providing functional evidence of the newly cloned gcIl-12rβ1 being genuine orthologues of mammalian IL-12Rβ1. Moreover, our data showed that gcIl-12rβ1 and gcIl-12rβ2a but not gcIl-12rβ1 and gcIl-12rβ2b mediated the effects of rgcIl-12 isoforms on ifn-γ promoter activity, thereby revealing Il-12 receptor signaling in fish. These results identified grass carp Il-12 receptors, thereby advancing our understanding of Il-12 isoform signaling in fish.
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Affiliation(s)
- Xingyang Qiu
- School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, People's Republic of China
| | - Dan Wang
- School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, People's Republic of China
| | - Mengyuan Lv
- School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, People's Republic of China
| | - Hao Sun
- School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, People's Republic of China
| | - Jingqi Ren
- School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, People's Republic of China
| | - Xinyan Wang
- School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, People's Republic of China
| | - Hong Zhou
- School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, People's Republic of China.
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7
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Marônek M, Marafini I, Gardlík R, Link R, Troncone E, Monteleone G. Metalloproteinases in Inflammatory Bowel Diseases. J Inflamm Res 2021; 14:1029-1041. [PMID: 33790618 PMCID: PMC8001665 DOI: 10.2147/jir.s288280] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 03/09/2021] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic inflammatory diseases of the gastrointestinal tract, encompassing two main disorders: Crohn's disease (CD) and ulcerative colitis (UC). In both these pathologies, excessive and local immune response against luminal antigens promotes a pathological process leading to various degrees of gut damage. Matrix metalloproteinases (MMPs) are a family of neutral proteases with the ability to degrade all components of extracellular matrix. In physiological conditions, MMPs are produced at very low level and generally in the latent form and are involved in the normal tissue turnover. Their function is inhibited by tissue inhibitors of metalloproteinases (TIMPs). However, in inflamed tissue of IBD patients, MMPs are produced in excess and/or the activity of TIMPs is not sufficient to block MMPs, thereby making a major contribution to the IBD-related mucosal degradation. In this review, we summarize the available evidence on the expression and role of MMPs in IBD.
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Affiliation(s)
- Martin Marônek
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University in Bratislava, Bratislava, 81108, Slovakia
| | - Irene Marafini
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, 00133, Italy
| | - Roman Gardlík
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University in Bratislava, Bratislava, 81108, Slovakia
| | - René Link
- Institute of Experimental Medicine, Faculty of Medicine, University of Pavol Jozef Šafárik, Košice, 040 11, Slovakia
| | - Edoardo Troncone
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, 00133, Italy
| | - Giovanni Monteleone
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, 00133, Italy
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8
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Cordes F, Foell D, Ding JN, Varga G, Bettenworth D. Differential regulation of JAK/STAT-signaling in patients with ulcerative colitis and Crohn's disease. World J Gastroenterol 2020; 26:4055-4075. [PMID: 32821070 PMCID: PMC7403801 DOI: 10.3748/wjg.v26.i28.4055] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 05/24/2020] [Accepted: 06/18/2020] [Indexed: 02/06/2023] Open
Abstract
In 2018, the pan-Janus kinase (JAK) inhibitor tofacitinib was launched for the treatment of ulcerative colitis (UC). Although tofacitinib has proven efficacious in patients with active UC, it failed in patients with Crohn's disease (CD). This finding strongly hints at a different contribution of JAK signaling in both entities. Here, we review the current knowledge on the interplay between the JAK/signal transducer and activator of transcription (STAT) pathway and inflammatory bowel diseases (IBD). In particular, we provide a detailed overview of the differences and similarities of JAK/STAT-signaling in UC and CD, highlight the impact of the JAK/STAT pathway in experimental colitis models and summarize the published evidence on JAK/STAT-signaling in immune cells of IBD as well as the genetic association between the JAK/STAT pathway and IBD. Finally, we describe novel treatment strategies targeting JAK/STAT inhibition in UC and CD and comment on the limitations and challenges of the new drug class.
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Affiliation(s)
- Friederike Cordes
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster D-48149, Germany
| | - Dirk Foell
- Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Münster, Münster D-48149, Germany
| | - John Nik Ding
- Department of Gastroenterology, St. Vincent’s Hospital, Melbourne 3002, Australia
- Department of Medicine, University of Melbourne, East Melbourne 3002, Australia
| | - Georg Varga
- Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Münster, Münster D-48149, Germany
| | - Dominik Bettenworth
- Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster D-48149, Germany
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Yang C, Mai H, Peng J, Zhou B, Hou J, Jiang D. STAT4: an immunoregulator contributing to diverse human diseases. Int J Biol Sci 2020; 16:1575-1585. [PMID: 32226303 PMCID: PMC7097918 DOI: 10.7150/ijbs.41852] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 02/13/2020] [Indexed: 12/12/2022] Open
Abstract
Signal transducer and activator of transcription 4 (STAT4) is a member of the STAT family and localizes to the cytoplasm. STAT4 is phosphorylated after a variety of cytokines bind to the membrane, and then dimerized STAT4 translocates to the nucleus to regulate gene expression. We reviewed the essential role played by STAT4 in a wide variety of cells and the pathogenesis of diverse human diseases, especially many kinds of autoimmune and inflammatory diseases, via activation by different cytokines through the Janus kinase (JAK)-STAT signaling pathway.
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Affiliation(s)
| | | | | | | | | | - Deke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
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Tindemans I, Joosse ME, Samsom JN. Dissecting the Heterogeneity in T-Cell Mediated Inflammation in IBD. Cells 2020; 9:E110. [PMID: 31906479 PMCID: PMC7016883 DOI: 10.3390/cells9010110] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 12/20/2019] [Accepted: 12/26/2019] [Indexed: 12/12/2022] Open
Abstract
Infiltration of the lamina propria by inflammatory CD4+ T-cell populations is a key characteristic of chronic intestinal inflammation. Memory-phenotype CD4+ T-cell frequencies are increased in inflamed intestinal tissue of IBD patients compared to tissue of healthy controls and are associated with disease flares and a more complicated disease course. Therefore, a tightly controlled balance between regulatory and inflammatory CD4+ T-cell populations is crucial to prevent uncontrolled CD4+ T-cell responses and subsequent intestinal tissue damage. While at steady state, T-cells display mainly a regulatory phenotype, increased in Th1, Th2, Th9, Th17, and Th17.1 responses, and reduced Treg and Tr1 responses have all been suggested to play a role in IBD pathophysiology. However, it is highly unlikely that all these responses are altered in each individual patient. With the rapidly expanding plethora of therapeutic options to inhibit inflammatory T-cell responses and stimulate regulatory T-cell responses, a crucial need is emerging for a robust set of immunological assays to predict and monitor therapeutic success at an individual level. Consequently, it is crucial to differentiate dominant inflammatory and regulatory CD4+ T helper responses in patients and relate these to disease course and therapy response. In this review, we provide an overview of how intestinal CD4+ T-cell responses arise, discuss the main phenotypes of CD4+ T helper responses, and review how they are implicated in IBD.
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Affiliation(s)
| | | | - Janneke N. Samsom
- Laboratory of Pediatrics, Division Gastroenterology and Nutrition, Erasmus MC-Sophia Children’s Hospital, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands
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11
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Dara N, Nemati S, Teimourian S, Imanzadeh F, Hosseini A, Tajalli S, Sayyari AA, Najafi A, Rohani P, Khatami K, Motevaseli E, de Boer M, Kuijpers TW. Diagnostic Challenges in the Early Onset of Inflammatory Bowel Disease: A Case Report. INTERNATIONAL JOURNAL OF MOLECULAR AND CELLULAR MEDICINE 2019; 7:251-257. [PMID: 31516885 PMCID: PMC6709932 DOI: 10.22088/ijmcm.bums.7.4.251] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Accepted: 02/22/2019] [Indexed: 11/18/2022]
Abstract
Inflammatory bowel disease (IBD) with very early onset manifestations (younger than six years of age) is an essential pediatric gastrointestinal disease that encompasses a group of diverse and rare genetic defects. It may be associated with chronicity, premalignant nature, and high morbidity and mortality during childhood. Because of overlapping phenotypes, the definitive diagnosis based on conventional strategies is frequently a challenge. However, many patients with different molecular pathologies are treated with the same therapeutic strategy. In this context, it is essential to define a more reliable method to provide an opportunity for a rapid and accurate diagnosis. Here we report a novel homozygous exonic variant in a patient with an IBD-like lesion in the colon during the infancy period. A 7 months old boy who was born of a consanguineous marriage developed gastrointestinal disorders early in life. After complete diagnostic workups, this case underwent conventional therapy of IBD for five months; but clinical remission was not achieved. We identified a novel homozygous mutation (c.684C>T p(=)) in exon 7 of IL-12RB1 gene that in silico studies indicated its significance in the splicing process. At the 14th month of age, this case died. Our finding reveals the importance of genetic screening as an early diagnostic tool in the identification of the underlying causes of IBD with very early onset manifestations, particularly infantile (< 2 years of age) IBD. This strategy makes an opportunity in prompt diagnosis and targeted therapy.
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Affiliation(s)
- Naghi Dara
- Pediatric Gastroenterology, Hepatology and Nutrition Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sharam Nemati
- Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Sharam Teimourian
- Department of Medical Genetics, Iran University of Medical Sciences, Tehran, Iran
| | - Farid Imanzadeh
- Pediatric Gastroenterology, Hepatology and Nutrition Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amirhossein Hosseini
- Pediatric Gastroenterology, Hepatology and Nutrition Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saleheh Tajalli
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Akbar Sayyari
- Pediatric Gastroenterology, Hepatology and Nutrition Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Najafi
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Pejman Rohani
- Pediatric Gastroenterology, Hepatology and Nutrition Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Katayoun Khatami
- Pediatric Gastroenterology, Hepatology and Nutrition Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Elahe Motevaseli
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Martin de Boer
- Sanquin Blood Supply Organization, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Taco W Kuijpers
- Sanquin Blood Supply Organization, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
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Marafini I, Sedda S, Dinallo V, Monteleone G. Inflammatory cytokines: from discoveries to therapies in IBD. Expert Opin Biol Ther 2019; 19:1207-1217. [PMID: 31373244 DOI: 10.1080/14712598.2019.1652267] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Introduction: Although the etiology of inflammatory bowel diseases (IBD) remains unknown, accumulating evidence suggests that the intestinal tissue damage in these disorders is due to a dynamic interplay between immune cells and non-immune cells, which is mediated by cytokines produced within the inflammatory microenvironment. Areas covered: We review the available data about the role of inflammatory cytokines in IBD pathophysiology and provide an overview of the therapeutic options to block the function of such molecules. Expert opinion: Genome studies, in vitro experiments with patients' samples and animal models of colitis, have largely advanced our understanding of how cytokines modulate the ongoing mucosal inflammation in IBD. However, not all the cytokines produced within the damaged gut seem to play a major role in the amplification and perpetuation of the IBD-associated inflammatory cascade. Indeed, while some of the anti-cytokine compounds are effective in some subgroups of IBD patients, others have no benefit. In this complex scenario, a major unmet need is the identification of biomarkers that can predict response to therapy and facilitate a personalized therapeutic approach, which maximizes the benefits and limits the adverse events.
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Affiliation(s)
- Irene Marafini
- Department of Systems Medicine, Gastroenterology, University of Rome "Tor Vergata" , Rome , Italy
| | - Silvia Sedda
- Department of Systems Medicine, Gastroenterology, University of Rome "Tor Vergata" , Rome , Italy
| | - Vincenzo Dinallo
- Department of Systems Medicine, Gastroenterology, University of Rome "Tor Vergata" , Rome , Italy
| | - Giovanni Monteleone
- Department of Systems Medicine, Gastroenterology, University of Rome "Tor Vergata" , Rome , Italy
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Leonard MM, Bai Y, Serena G, Nickerson KP, Camhi S, Sturgeon C, Yan S, Fiorentino MR, Katz A, Nath B, Richter J, Sleeman M, Gurer C, Fasano A. RNA sequencing of intestinal mucosa reveals novel pathways functionally linked to celiac disease pathogenesis. PLoS One 2019; 14:e0215132. [PMID: 30998704 PMCID: PMC6472737 DOI: 10.1371/journal.pone.0215132] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 03/27/2019] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND & AIMS The early steps in the pathophysiology of celiac disease (CD) leading to loss of tolerance to gluten are poorly described. Our aim was to use RNA sequencing of duodenal biopsies in patients with active CD, CD in remission, and non-CD controls to gain insight into CD pathophysiology, identify additional genetic signatures linked to CD, and possibly uncover targets for future therapeutic agents. METHODS We performed whole transcriptome shotgun sequencing of intestinal biopsies in subjects with active and remission CD and non-CD controls. We also performed functional pathway analysis of differentially expressed genes to identify statistically significant pathways that are up or down regulated in subjects with active CD compared to remission CD. RESULTS We identified the upregulation of novel genes including IL12R, ITGAM and IGSF4 involved in the immune response machinery and cell adhesion process in the mucosa of subjects with active CD compared to those in remission. We identified a unique signature of genes, related to innate immunity, perturbed exclusively in CD irrespective of disease status. Finally, we highlight novel pathways of interest that may contribute to the early steps of CD pathogenesis and its comorbidities such as the spliceosome, pathways related to the innate immune response, and pathways related to autoimmunity. CONCLUSIONS Our study confirmed previous findings based on GWAS and immunological studies pertinent to CD pathogenesis and describes novel genes and pathways that with further validation may be found to contribute to the early steps in the pathogenesis of CD, ongoing inflammation, and comorbidities associated with CD.
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Affiliation(s)
- Maureen M. Leonard
- Mass General Hospital for Children and Division of Pediatric Gastroenterology and Nutrition, Harvard Medical School, Boston, Massachusetts, United States of America
- Center for Celiac Research and Treatment, Mucosal Immunology and Biology Research Center, Boston, Massachusetts, United States of America
- Celiac Research Program, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Yu Bai
- Regeneron Pharmaceuticals, Tarrytown, New York, United States of America
| | - Gloria Serena
- Center for Celiac Research and Treatment, Mucosal Immunology and Biology Research Center, Boston, Massachusetts, United States of America
- Celiac Research Program, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Kourtney P. Nickerson
- Center for Celiac Research and Treatment, Mucosal Immunology and Biology Research Center, Boston, Massachusetts, United States of America
| | - Stephanie Camhi
- Center for Celiac Research and Treatment, Mucosal Immunology and Biology Research Center, Boston, Massachusetts, United States of America
| | - Craig Sturgeon
- Graduate Program in Life Sciences, University of Maryland, Baltimore, Maryland, United States of America
| | - Shu Yan
- Center for Celiac Research and Treatment, Mucosal Immunology and Biology Research Center, Boston, Massachusetts, United States of America
| | - Maria R. Fiorentino
- Center for Celiac Research and Treatment, Mucosal Immunology and Biology Research Center, Boston, Massachusetts, United States of America
| | - Aubrey Katz
- Mass General Hospital for Children and Division of Pediatric Gastroenterology and Nutrition, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Barbara Nath
- Department of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
| | - James Richter
- Department of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
| | - Matthew Sleeman
- Regeneron Pharmaceuticals, Tarrytown, New York, United States of America
| | - Cagan Gurer
- Regeneron Pharmaceuticals, Tarrytown, New York, United States of America
| | - Alessio Fasano
- Mass General Hospital for Children and Division of Pediatric Gastroenterology and Nutrition, Harvard Medical School, Boston, Massachusetts, United States of America
- Center for Celiac Research and Treatment, Mucosal Immunology and Biology Research Center, Boston, Massachusetts, United States of America
- Celiac Research Program, Harvard Medical School, Boston, Massachusetts, United States of America
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Effect of Herb-Partitioned Moxibustion on Autophagy and Immune-Associated Gene Expression Profiles in a Rat Model of Crohn's Disease. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 2019:3405146. [PMID: 30956679 PMCID: PMC6431444 DOI: 10.1155/2019/3405146] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 01/09/2019] [Accepted: 02/03/2019] [Indexed: 02/07/2023]
Abstract
Objective To investigate the immune regulation mechanism of herb-partitioned moxibustion in rats with Crohn's disease (CD) focusing on autophagy. Methods Rats were randomly divided into normal (N) group, CD model (M) group, CD model with herb-partitioned moxibustion (MM) group, normal with herb-partitioned moxibustion (NM) group, CD model with mesalazine (western medicine, Med ) group, and normal saline (NS) group, with 10 rats in each group. The CD model rats were prepared by trinitrobenzene sulphonic expect for the N group and NM group. After the CD rats model were established, the rats in the MM and NM groups were treated with herb-partitioned moxibustion at Tianshu (ST25) and Qihai (CV6) acupoints once daily for 7 days, and rats in the Med and NS groups were respectively treated with mesalazine enteric coated tablet and normal saline once daily for 7 days. After intervention, hematoxylin-eosin staining was used to observe the histological changes of colon; RNA sequencing was used to observe the changes in autophagy- and immune-associated gene expression profiles. In addition, autophagy- and immune-associated cytokines and signaling pathways in CD rats were also screened. Results HPM significantly increased the body weight of CD rats (P<0.01) and improved the pathological injury of colon in CD rats (P<0.01). HPM also changed the expression of many autophagy- and immune-associated genes, especially downregulating the expression of autophagy-associated Nod2, Irgm genes as well as the receptor of immune-associated Il12b, Il22 (Il12rb1, Il22ra2) genes in the colon of CD rats. HPM also changed the enrichment levels of differentially expressed genes in the human T-cell leukemia virus type-1 infection pathway, the Epstein-Barr virus infection pathway, and the cell adhesion molecule pathway. In addition, the expression levels of Nod2, Irgm, IL-12b, and IL-22 mRNA were increased (all P< 0.01) in the M group compared to the N group, while the expression levels of Nod2, Irgm, IL-12b, and IL-22 mRNA were decreased (P<0.05 or P<0.01) in the MM and Med groups compared to the M group. Conclusion Herb-partitioned moxibustion may effectively attenuate intestinal inflammation and promote the repair of colon mucosal injury of CD rats through the regulation of autophagy- and immune-associated gene expression and signaling pathways.
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Aggeletopoulou I, Assimakopoulos SF, Konstantakis C, Triantos C. Interleukin 12/interleukin 23 pathway: Biological basis and therapeutic effect in patients with Crohn's disease. World J Gastroenterol 2018; 24:4093-4103. [PMID: 30271076 PMCID: PMC6158482 DOI: 10.3748/wjg.v24.i36.4093] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Revised: 08/02/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
Considering that both innate and adaptive immune responses are involved in the pathogenesis of Crohn’s disease (CD), novel therapeutic options have significantly been developed. Biological agents represent an important addition to the conventional treatments for immuno-inflammatory conditions, acting as antagonists of adhesion molecules or various inflammatory cytokines. The interleukin 12 (IL-12)/IL-23 common pathway has been found to play a determinant role in the induction of inflammation in adaptive immune responses. In particular, IL-23 promotes the differentiation of naïve T helper cells into Th17 phenotype with the concomitant secretion of several inflammatory cytokines such as IL-17 and IL-22, whereas IL-12 induces the Th1 polarization and production of critical cytokines such as interferon-γ and tumor necrosis factor. Nowadays, there is increased interest regarding the role of IL-23 as a therapeutic target of CD through the blockage of IL-23 mediated pathways. In this editorial, we focus on the role of IL-12/IL-23 pathway in the regulation of mucosal immunity and in the induction and maintenance of chronic inflammation. In parallel, we critically discuss the available data regarding the therapeutic effect of the IL-12/IL-23 inhibitors and especially of ustekinumab, a human monoclonal antibody which has been recently approved by the United States Food and Drug Administration for the management of moderate-to-severe CD and its potential to be used as first-line therapy in everyday clinical practice.
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Affiliation(s)
- Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | | | - Christos Konstantakis
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, Medical School, University of Patras, Patras 26504, Greece
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Adedokun OJ, Xu Z, Gasink C, Jacobstein D, Szapary P, Johanns J, Gao LL, Davis HM, Hanauer SB, Feagan BG, Ghosh S, Sandborn WJ. Pharmacokinetics and Exposure Response Relationships of Ustekinumab in Patients With Crohn's Disease. Gastroenterology 2018; 154:1660-1671. [PMID: 29409871 DOI: 10.1053/j.gastro.2018.01.043] [Citation(s) in RCA: 193] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 12/19/2017] [Accepted: 01/24/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND & AIMS Ustekinumab is a monoclonal antibody that binds with high affinity to the p40 subunit of human interleukin 12 (IL12 and IL23) that has been approved for treatment of patients with moderate to severe Crohn's disease (CD). However, there are few data on its pharmacokinetic properties or the relationship between drug exposure levels and patient response. We collected data from 2 Phase 3 induction studies and 1 maintenance study to determine ustekinumab's pharmacokinetic features, relationship between exposure and response, and optimal serum concentrations for efficacy. METHODS We collected data on serum concentrations of ustekinumab and efficacy from induction studies of patients with moderate to severe CD given ustekinumab for 8 weeks following a single intravenous dose (either 130 mg or approximately 6 mg/kg). We collected the same data from a maintenance study of patients with a response to ustekinumab in the induction study who then received subcutaneous injections (90 mg) every 8 or 12 weeks for 44 weeks. At week 44 of the maintenance study (52 weeks after treatment began), patients were evaluated for the primary endpoint of clinical remission (defined as a CD activity index score below 150 points), endoscopic markers of efficacy, and serum level of C-reactive protein. Ustekinumab concentration data were categorized into quartiles and relationships between exposure and response were assessed. Optimal concentration cutoff values were evaluated using receiver operating characteristic curve analysis. RESULTS Serum concentrations of ustekinumab over time were proportional to dose and did not differ significantly between the induction studies. In the maintenance study, ustekinumab concentration reached the steady state by the second maintenance dose; the median trough concentration was approximately threefold higher in patients given ustekinumab at 8-week intervals compared with 12-week intervals. Ustekinumab serum concentrations associated with rates of clinical remission and endoscopic efficacy endpoints, correlated inversely with level of C-reactive protein, and did not associate with use of immunomodulators. Trough concentrations of ustekinumab of 0.8 (or even up to 1.4 μg/mL) or greater were associated with maintenance of clinical remission in a higher proportion of patients than patients with lower trough concentrations. CONCLUSIONS In an analysis of data from Phase 3 studies of patients with moderate to severe CD, we found serum concentrations of ustekinumab to be proportional to dose and associate with treatment efficacy. Concentrations of ustekinumab did not seem to be affected by cotreatment with immunomodulators. Clinicaltrials.gov no. NCT01369329 (UNITI 1), NCT01369342 (UNITI 2), and NCT01369355 (IM-UNITI).
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Affiliation(s)
| | - Zhenhua Xu
- Janssen Research & Development, LLC., Spring House, Pennsylvania
| | | | | | - Philippe Szapary
- Janssen Research & Development, LLC., Spring House, Pennsylvania
| | - Jewel Johanns
- Janssen Research & Development, LLC., Spring House, Pennsylvania
| | - Long-Long Gao
- Janssen Scientific Affairs, LLC, Spring House, Pennsylvania
| | - Hugh M Davis
- Janssen Research & Development, LLC., Spring House, Pennsylvania
| | - Stephen B Hanauer
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois
| | - Brian G Feagan
- Robarts Research Institute, University of Western Ontario, London, Ontario, Canada
| | - Subrata Ghosh
- Institute of Translational Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - William J Sandborn
- Division of Gastroenterology, University of California San Diego, La Jolla, California
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Nemati S, Teimourian S, Tabrizi M, Najafi M, Dara N, Imanzadeh F, Ahmadi M, Aghdam MK, Tavassoli M, Rohani P, Madani SR, de Boer M, Kuijpers TW, Roos D. Very early onset inflammatory bowel disease: Investigation of the IL-10 signaling pathway in Iranian children. Eur J Med Genet 2017; 60:643-649. [PMID: 28864178 DOI: 10.1016/j.ejmg.2017.08.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 07/10/2017] [Accepted: 08/27/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIM Comparing to adult inflammatory bowel disease (IBD), those with early onset manifestations have different features in terms of the underlying molecular pathology, the course of disease and the response to therapy. We investigated the IL-10 signaling pathway previously reported as an important cause of infantile (Very Early Onset) IBD to find any possible variants. METHOD With the next generation sequencing technique we screened IL-10, IL-10RA and IL10RB genes of 15 children affected by very early onset-GI (gastrointestinal) disorders. Additionally, we analyzed them based on Thermo Fisher immune deficiency panel for genes either having a known role in IBD pathogenesis or cause the disorders with overlapping manifestations. We performed multiple functional analyses only for the cases showing variants in IL-10- related genes. RESULT In 3 out of 15 patients we identified variants including a homozygous and heterozygote mutations in IL-10RA and a novel homozygous mutation in IL-12RB1. Our functional studies reveal that in contrast to the IL-10RA heterozygote mutation that does not have deleterious effects, the homozygous mutation abrogates the IL-10 signaling pathway. CONCLUSION Our study suggests we need to modify the classical diagnostic approach from functional assays followed by candidate- gene or genes sequencing to the firstly parallel genomic screening followed by functional studies.
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Affiliation(s)
- Shahram Nemati
- Department of Medical Genetics, Tehran University of Medical Sciences, International Campus (TUMS-IC), Tehran, Iran
| | - Shahram Teimourian
- Department of Medical Genetics, Iran University of Medical Sciences, Tehran, Iran; Pediatric Infectious Diseases Research Center, Department of Infectious Diseases, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mina Tabrizi
- Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehri Najafi
- Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Naghi Dara
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farid Imanzadeh
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mitra Ahmadi
- Department of Pediatric Gastroenterology, Jondishapoor University of Medical Sciences, Ahvaz, Iran
| | | | - Mohmoud Tavassoli
- Department of Allergy and Clinical Immunology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Pejman Rohani
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyyed Ramin Madani
- Department of Pediatric Gastroenterology, Kashan University of Medical Sciences, Kashan, Iran
| | - Martin de Boer
- Sanquin Blood Supply Organization, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - T W Kuijpers
- Sanquin Blood Supply Organization, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Dirk Roos
- Sanquin Blood Supply Organization, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
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Schurich A, Raine C, Morris V, Ciurtin C. The role of IL-12/23 in T cell–related chronic inflammation: implications of immunodeficiency and therapeutic blockade. Rheumatology (Oxford) 2017; 57:246-254. [DOI: 10.1093/rheumatology/kex186] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Indexed: 12/27/2022] Open
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Park JH, Peyrin-Biroulet L, Eisenhut M, Shin JI. IBD immunopathogenesis: A comprehensive review of inflammatory molecules. Autoimmun Rev 2017; 16:416-426. [PMID: 28212924 DOI: 10.1016/j.autrev.2017.02.013] [Citation(s) in RCA: 211] [Impact Index Per Article: 26.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 01/19/2017] [Indexed: 02/06/2023]
Abstract
Inflammatory molecules play a crucial role in the pathogenesis of inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn's disease, both of which are chronic inflammatory conditions of the gastrointestinal tract. Abnormal expressions of pro- and anti-inflammatory molecules have been described to cause an imbalance to the gut innate and adaptive immunity, and recently a large portion of research in IBD has been geared towards identifying novel molecules that may be used as potential therapeutic targets. Understanding of these inflammatory molecules has suggested that although ulcerative colitis and Crohn's disease share many common clinical symptoms and signs, they are in fact two separate clinical entities characterized by different immunopathogenesis. In this review, we comprehensively discuss the roles of numerous inflammatory molecules including but not limited to cytokines, chemokines, inflammasomes, microRNAs and neuropeptides and their expression status in ulcerative colitis and Crohn's disease in relation to their effects on the overall intestinal inflammatory process.
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Affiliation(s)
- Jae Hyon Park
- Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea
| | - Laurent Peyrin-Biroulet
- Inserm U954 and Department of Gastroenterology, Nancy University Hospital, Université de Lorraine, France
| | - Michael Eisenhut
- Department of Paediatrics, Luton & Dunstable University Hospital NHS Foundation Trust, Lewsey Road, Luton, LU40DZ, United Kingdom
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Severance Children's Hospital, Seoul, Republic of Korea.
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20
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Popp V, Gerlach K, Mott S, Turowska A, Garn H, Atreya R, Lehr HA, Ho IC, Renz H, Weigmann B, Neurath MF. Rectal Delivery of a DNAzyme That Specifically Blocks the Transcription Factor GATA3 and Reduces Colitis in Mice. Gastroenterology 2017; 152:176-192.e5. [PMID: 27639807 DOI: 10.1053/j.gastro.2016.09.005] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 09/01/2016] [Accepted: 09/06/2016] [Indexed: 01/10/2023]
Abstract
BACKGROUND & AIMS GATA3 is a transcription factor that regulates T-cell production of cytokines. We investigated the role of GATA3 in development of colitis in mice. METHODS We performed quantitative polymerase chain reaction and immunofluorescence analyses of colon tissues from patients with Crohn's disease (n = 61) or ulcerative colitis (UC, n = 74) or from patients without inflammatory bowel diseases (n = 22), to measure levels of GATA3. Colitis was induced by administration of oxazolone or 2,4,6-trinitrobenzenesulfonic acid to control mice, mice with T-cell-specific deletion of GATA3, and mice with deletion of tumor necrosis factor receptor (TNFR) 1 and TNFR2 (TNFR double knockouts); some mice were given a GATA3-specific DNAzyme (hgd40) or a control DNAzyme via intrarectal administration, or systemic injections of an antibody to TNF before or during sensitization and challenge phase of colitis induction. Colon tissues were collected and immunofluorescence and histochemical analyses were performed. Lamina propria mononuclear cells and T cells were isolated and analyzed by flow cytometry or cytokine assays. Colonic distribution of labeled DNAzyme and inflammation were monitored by in vivo imaging (endoscopy) of mice. RESULTS Levels of GATA3 messenger RNA were higher in colon tissues from patients with UC, but not ileal Crohn's disease, than control tissues; levels of GATA3 correlated with levels of inflammatory cytokines (interleukin [IL] 9, IL17A, IL6, IL5, IL4, IL13, and TNF). We observed increased expression of GATA3 by lamina propria T cells from mice with colitis compared with controls. Mice with T-cell-specific deletion of GATA3 did not develop colitis and their colonic tissues did not produce inflammatory cytokines (IL6, IL9, or IL13). The DNAzyme hgd40 inhibited expression of GATA3 messenger RNA by unstimulated and stimulated T cells, and distributed throughout the inflamed colons of mice with colitis. Colon tissues from mice given hgd40 had reduced expression of GATA3 messenger RNA, compared with mice given a control DNAzyme. Mice given hgd40 did not develop colitis after administration of oxazolone or 2,4,6-trinitrobenzenesulfonic acid; lamina propria cells from these mice expressed lower levels of IL6, IL9, and IL13 than cells from mice given the control DNAzyme. Mini-endoscopic images revealed that hgd40 and anti-TNF reduced colon inflammation over 3 days; hgd40 reduced colitis in TNFR double-knockout mice. CONCLUSIONS Levels of GATA3 are increased in patients with UC and correlate with production of inflammatory cytokines in mice and humans. A DNAzyme that prevents expression of GATA3 reduces colitis in mice, independently of TNF, and reduces levels of cytokines in the colon. This DNAzyme might be developed for treatment of patients with UC.
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Affiliation(s)
- Vanessa Popp
- Department of Medicine, University of Erlangen-Nürnberg, Kussmaul Research Campus, Erlangen, Germany
| | - Katharina Gerlach
- Department of Medicine, University of Erlangen-Nürnberg, Kussmaul Research Campus, Erlangen, Germany
| | - Stefanie Mott
- Department of Medicine, University of Erlangen-Nürnberg, Kussmaul Research Campus, Erlangen, Germany
| | | | - Holger Garn
- Institute of Laboratory Medicine and Pathobiochemistry, Medical Faculty, Philipps University of Marburg, Marburg, Germany
| | - Raja Atreya
- Department of Medicine, University of Erlangen-Nürnberg, Kussmaul Research Campus, Erlangen, Germany
| | - Hans-Anton Lehr
- Institute of Pathology, Campus Bodensee, Friedrichshafen, Germany
| | - I-Cheng Ho
- Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts
| | - Harald Renz
- Institute of Laboratory Medicine and Pathobiochemistry, Medical Faculty, Philipps University of Marburg, Marburg, Germany
| | - Benno Weigmann
- Department of Medicine, University of Erlangen-Nürnberg, Kussmaul Research Campus, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine, University of Erlangen-Nürnberg, Kussmaul Research Campus, Erlangen, Germany.
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Russo I, Zeppa P, Iovino P, Del Giorno C, Zingone F, Bucci C, Puzziello A, Ciacci C. The culture of gut explants: A model to study the mucosal response. J Immunol Methods 2016; 438:1-10. [PMID: 27475701 DOI: 10.1016/j.jim.2016.07.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Revised: 07/16/2016] [Accepted: 07/25/2016] [Indexed: 02/07/2023]
Abstract
Various experimental model designs have been used to analyze the inflammatory pathways in human gastrointestinal illnesses. Traditionally, analytical techniques and animal models are popular experimental tools to study the inflammation process of intestinal diseases. However, the comparison of results between animal and human models is difficult for the inconsistency of outcomes. Although there are different animal models for studying the intestinal diseases, none of them fully represents the physiological and environmental conditions typical of the human species. Also, there is currently a concerted effort to decrease the experimental use of animals. On the converse, experimental protocols using the culture of gut mucosa had become popular with the advent of endoscopy which allows explanting multiple fragments from the intestine. The peculiar characteristic of this model is the ability to preserve in vitro the features that we found in vivo, thus also the response to various stimuli that differs from person to person. The aim of the present paper is to provide a review of some of the possible uses of the organ intestinal mucosa culture.
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Affiliation(s)
- Ilaria Russo
- Department of Medicine and Surgery, University Hospital San Giovanni di Dio e Ruggi d'Aragona, University of Salerno, Italy
| | - Pio Zeppa
- Department of Medicine and Surgery, University Hospital San Giovanni di Dio e Ruggi d'Aragona, University of Salerno, Italy
| | - Paola Iovino
- Department of Medicine and Surgery, University Hospital San Giovanni di Dio e Ruggi d'Aragona, University of Salerno, Italy
| | - Chiara Del Giorno
- Department of Medicine and Surgery, University Hospital San Giovanni di Dio e Ruggi d'Aragona, University of Salerno, Italy
| | - Fabiana Zingone
- Department of Medicine and Surgery, University Hospital San Giovanni di Dio e Ruggi d'Aragona, University of Salerno, Italy
| | - Cristina Bucci
- Department of Medicine and Surgery, University Hospital San Giovanni di Dio e Ruggi d'Aragona, University of Salerno, Italy
| | - Alessandro Puzziello
- Department of Medicine and Surgery, University Hospital San Giovanni di Dio e Ruggi d'Aragona, University of Salerno, Italy
| | - Carolina Ciacci
- Department of Medicine and Surgery, University Hospital San Giovanni di Dio e Ruggi d'Aragona, University of Salerno, Italy.
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Raad MA, Chams NH, Sharara AI. New and Evolving Immunotherapy in Inflammatory Bowel Disease. Inflamm Intest Dis 2016; 1:85-95. [PMID: 29922662 PMCID: PMC5988105 DOI: 10.1159/000445986] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 03/22/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Crohn's disease and ulcerative colitis are chronic inflammatory disorders associated with a dysregulated adaptive and innate immune response to gut commensals in genetically susceptible individuals. The pathogenesis of inflammatory bowel disease is complex, and the disease is characterized by significant phenotypic and genotypic heterogeneity. SUMMARY The introduction of anti-TNF biologics has resulted in improved clinical outcomes in patients with severe and moderately severe disease, but the current treatment paradigm continues to depend on systemic immunosuppression (steroids and immunomodulators) and surgical intervention in a significant number of patients, underscoring a significant unmet need. More recently, a number of genetic and immunologic abnormalities have been unraveled including aberrant intestinal mucosal defense function, abnormal intestinal permeability, dysregulated bacterial antigen processing by macrophages and presentation to T cells, cellular immune regulation and signaling, cytokine production, and leukocyte trafficking. KEY MESSAGES Understanding these molecular mechanisms and effector pathways presents an opportunity for the development of new and improved targeted therapies.
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Affiliation(s)
- Mohamad A. Raad
- School of Medicine, American University of Beirut, Beirut, Lebanon
| | - Nour H. Chams
- School of Medicine, American University of Beirut, Beirut, Lebanon
| | - Ala I. Sharara
- Division of Gastroenterology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
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Izzo R, Bevivino G, Monteleone G. Tofacitinib for the treatment of ulcerative colitis. Expert Opin Investig Drugs 2016; 25:991-7. [PMID: 27177233 DOI: 10.1080/13543784.2016.1189900] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Management of patients with active ulcerative colitis (UC), one of the most frequent inflammatory bowel diseases in human beings, is mainly based on the use of mesalamine and corticosteroids. Since in the long-term, these two drugs may be ineffective in nearly one third of the patients, immunosuppressants and/or biologics are needed to control disease activity. AREAS COVERED The marked activation of JAK/STAT molecules in inflamed mucosa of UC patients and the demonstration that UC-associated mucosal injury is driven by soluble factors that signal through JAK/STAT pathways led to investigation of JAK inhibitors for the treatment of active UC. Tofacitinib, an oral inhibitor of the cytokine-driven JAK-STAT signalling cascade, has recently been proposed for the treatment of moderate-to-severe UC. Phase 2 study showed the efficacy of tofacitinib to induce clinical and endoscopic improvement/remission and the safety profile of the drug. Herein the authors review this compound. EXPERT OPINION The results obtained from clinical trials with tofacitinib suggest that this drug could be a new treatment option for patients with moderate to severe UC. However, further experimentation is needed to assess the efficacy of this drug in selected subgroups of patients as well as to maintain remission and to determine the long-term safety profile of the drug.
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Affiliation(s)
- Roberta Izzo
- a Department of Systems Medicine , University of Rome 'Tor Vergata' , Rome , Italy
| | - Gerolamo Bevivino
- a Department of Systems Medicine , University of Rome 'Tor Vergata' , Rome , Italy
| | - Giovanni Monteleone
- a Department of Systems Medicine , University of Rome 'Tor Vergata' , Rome , Italy
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Gómez-Gómez GJ, Masedo &A, Yela C, Martínez-Montiel MDP, Casís B. Current stage in inflammatory bowel disease: What is next? World J Gastroenterol 2015; 21:11282-11303. [PMID: 26525013 PMCID: PMC4616205 DOI: 10.3748/wjg.v21.i40.11282] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 07/12/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
In recent years, the incidence of inflammatory bowel disease (IBD) has been on the rise, extending to countries where it was infrequent in the past. As a result, the gap between high and low incidence countries is decreasing. The disease, therefore, has an important economic impact on the healthcare system. Advances in recent years in pharmacogenetics and clinical pharmacology have allowed for the development of treatment strategies adjusted to the patient profile. Concurrently, new drugs aimed at inflammatory targets have been developed that may expand future treatment options. This review examines advances in the optimization of existing drug treatments and the development of novel treatment options for IBD.
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Bravatà I, Fiorino G, Allocca M, Repici A, Danese S. New targeted therapies such as anti-adhesion molecules, anti-IL-12/23 and anti-Janus kinases are looking toward a more effective treatment of inflammatory bowel disease. Scand J Gastroenterol 2015; 50:113-20. [PMID: 25523561 DOI: 10.3109/00365521.2014.993700] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Antitumor necrosis factor α agents have dramatically changed the management of inflammatory bowel disease (IBD). However, a significant proportion of patients does not respond or lose response over time. Hence, there is an urgent need for new molecules, with different mechanisms of action, and with a targeted and more effective approach. These new drugs include either small molecules or biological agents. We describe the three most promising classes of molecules in the field of IBD: anti-adhesion, anti-interleukin 12/23 and anti-Janus Kinases therapies.
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Affiliation(s)
- Ivana Bravatà
- Department of Gastroenterology, Endoscopy Unit, Humanitas Research Hospital , Rozzano, Milan , Italy
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26
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Crohn’s Disease. Mucosal Immunol 2015. [DOI: 10.1016/b978-0-12-415847-4.00082-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
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27
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Leung Y, Panaccione R. Update on ustekinumab for the treatment of Crohn's disease. Gastroenterol Clin North Am 2014; 43:619-30. [PMID: 25110262 DOI: 10.1016/j.gtc.2014.05.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Despite the success of antitumor necrosis factor (TNF) therapy in Crohn's disease, there remains a need for biologic therapy that targets other immune pathways of disease. Ustekinumab is a fully human monoclonal immunoglobulin antibody that targets the interleukin (IL)-12 and IL-23 shared P40 subunit. It has been studied in 2 phase 2 randomized, double-blind, placebo-controlled trials in Crohn's disease. This article reviews the clinical efficacy and safety data of ustekinumab in Crohn's disease in anticipation of the final results of the phase III development program in moderate to severe Crohn's disease.
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Affiliation(s)
- Yvette Leung
- Division of Gastroenterology, Department of Medicine, University of Calgary, 3280 Hospital Drive Northwest, Calgary, Alberta T2N 4N1, Canada
| | - Remo Panaccione
- Division of Gastroenterology, Department of Medicine, University of Calgary, 3280 Hospital Drive Northwest, Calgary, Alberta T2N 4N1, Canada.
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Abstract
INTRODUCTION STAT4, which acts as the major signaling transducing STATs in response to IL-12, is a central mediator in generating inflammation during protective immune responses and immune-mediated diseases. AREAS COVERED This review summarizes that STAT4 is essential for the differentiation and function of a wide variety of immune cells, including natural killer cells, mast cells, dendritic cells and T helper cells. In addition, STAT4-mediated signaling promoted the production of autoimmune-associated components, which are implicated in the pathogenesis of autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and psoriasis. EXPERT OPINION Due to its crucial roles in inflammation and autoimmunity, STAT4 may have promise as an effective therapeutic target for autoimmune diseases. Understanding the molecular mechanisms driving STAT4, together with knowledge on the ability of current immunosuppressive treatment to target this process, may open an avenue to novel therapeutic options.
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Affiliation(s)
- Yan Liang
- Anhui Medical University, School of Public Health, Department of Epidemiology and Biostatistics , Anhui, PR China
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29
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Abstract
Cytokines have a crucial role in the pathogenesis of inflammatory bowel diseases (IBDs), such as Crohn's disease and ulcerative colitis, where they control multiple aspects of the inflammatory response. In particular, the imbalance between pro-inflammatory and anti-inflammatory cytokines that occurs in IBD impedes the resolution of inflammation and instead leads to disease perpetuation and tissue destruction. Recent studies suggest the existence of a network of regulatory cytokines that has important implications for disease progression. In this Review, we discuss the role of cytokines produced by innate and adaptive immune cells, as well as their relevance to the future therapy of IBD.
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Affiliation(s)
- Markus F Neurath
- Department of Medicine 1, University of Erlangen-Nürnberg, Kussmaul Campus for Medical Research, 91054 Erlangen, Germany
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30
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Diosdado B, Wijmenga C. Molecular mechanisms of the adaptive, innate and regulatory immune responses in the intestinal mucosa of celiac disease patients. Expert Rev Mol Diagn 2014; 5:681-700. [PMID: 16149872 DOI: 10.1586/14737159.5.5.681] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Celiac disease is a complex genetic disorder that affects the small intestine of genetically predisposed individuals when they ingest gluten, a dietary protein. Although several genome screens have been successful in identifying susceptibility loci in celiac disease, the only genetic contributors identified so far are the human leukocyte antigen (HLA)-DQ2/DQ8 molecules. One of the most important aspects in the pathogenesis of celiac disease is the activation of a T-helper 1 immune response, when the antigen-presenting cells that express HLA-DQ2/DQ8 molecules present the toxic gluten peptides to reactive CD4(+) T-cells. Recently, new insights into the activation of an innate immune response have also been described. It is generally accepted that the immune response triggers destruction of the mucosa in the small intestine of celiac disease patients. Hence, the activation of a detrimental immune response in the intestine of celiac disease patients appears to be key in the initiation and progression of the disease. This review summarizes the immunologic pathways that have been studied in celiac disease thus far, and will point to new potential candidate genes and pathways involved in the etiopathogenesis of celiac disease, which should lead to novel alternatives for diagnosis and treatment.
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Affiliation(s)
- Begoña Diosdado
- University Medical Centre, Complex Genetics Section, Stratenum 2.117, Department of Biomedical Genetics, PO Box 85060, 3508 AB Utrecht, The Netherlands.
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31
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Systematic functional regulatory assessment of disease-associated variants. Proc Natl Acad Sci U S A 2013; 110:9607-12. [PMID: 23690573 DOI: 10.1073/pnas.1219099110] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Genome-wide association studies have discovered many genetic loci associated with disease traits, but the functional molecular basis of these associations is often unresolved. Genome-wide regulatory and gene expression profiles measured across individuals and diseases reflect downstream effects of genetic variation and may allow for functional assessment of disease-associated loci. Here, we present a unique approach for systematic integration of genetic disease associations, transcription factor binding among individuals, and gene expression data to assess the functional consequences of variants associated with hundreds of human diseases. In an analysis of genome-wide binding profiles of NFκB, we find that disease-associated SNPs are enriched in NFκB binding regions overall, and specifically for inflammatory-mediated diseases, such as asthma, rheumatoid arthritis, and coronary artery disease. Using genome-wide variation in transcription factor-binding data, we find that NFκB binding is often correlated with disease-associated variants in a genotype-specific and allele-specific manner. Furthermore, we show that this binding variation is often related to expression of nearby genes, which are also found to have altered expression in independent profiling of the variant-associated disease condition. Thus, using this integrative approach, we provide a unique means to assign putative function to many disease-associated SNPs.
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32
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Shi F, Guo X, Jiang X, Zhou P, Xiao Y, Zhou T, Chen G, Zhao Z, Xiao H, Hou C, Li X, Yang X, Wang R, Feng J, Shen B, Li Y, Han G. Dysregulated Tim-3 expression and its correlation with imbalanced CD4 helper T cell function in ulcerative colitis. Clin Immunol 2012; 145:230-40. [DOI: 10.1016/j.clim.2012.09.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Revised: 08/21/2012] [Accepted: 09/04/2012] [Indexed: 12/14/2022]
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Eskandari-Nasab E, Sepanjnia A, Moghadampour M, Hadadi-Fishani M, Rezaeifar A, Asadi-Saghandi A, Sadeghi-Kalani B, Manshadi MD, Pourrajab F, Pourmasoumi H. Circulating levels of interleukin (IL)-12 and IL-13 in Helicobacter pylori-infected patients, and their associations with bacterial CagA and VacA virulence factors. ACTA ACUST UNITED AC 2012; 45:342-9. [PMID: 23163894 DOI: 10.3109/00365548.2012.737930] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE The aim of this study was to determine the association of the Helicobacter pylori virulence factors, cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA) antibodies, with serum levels of interleukin (IL)-12 and IL-13 in H. pylori-infected duodenal ulcer (DU) patients and H. pylori-infected asymptomatic (AS) carriers in order to elucidate any correlation between them. METHODS A total of 67 DU patients, 48 AS individuals, and 26 healthy H. pylori-negative subjects were enrolled in this study. Serum concentrations of IL-12 and IL-13 were determined by enzyme-linked immunosorbent assay (ELISA) method. Patient sera were tested by Western blot method to determine the presence of serum antibodies to bacterial virulence antigens p120 (CagA) and p95 (VacA). Serum concentrations of IL-12 and IL-13 were compared in 9 groups, including 4 AS phenotypes (CagA⁺VacA⁺, CagA⁺VacA⁻, CagA⁻VacA⁺, CagA⁻VacA⁻), 4 DU phenotypes (CagA⁺VacA⁺, CagA⁺VacA⁻, CagA⁻VacA⁺, CagA⁻VacA⁻), and 1 control group. RESULTS The results revealed that DU patients positive for CagA, independent of the anti-VacA antibody status, showed drastically elevated levels of IL-12 (251 ± 43 pg/ml) when compared with the other groups (p = 0.0001). No significant difference was found between groups regarding levels of IL-13 (p > 0.05). CONCLUSIONS Our findings indicate that in the DU group, the serum concentrations of IL-12 but not of IL-13 were influenced by bacterial CagA, independent of the VacA status, suggesting that high IL-12 levels may contribute to susceptibility to DU in CagA-positive individuals. These findings could possibly be considered to improve the predictive or prognostic values of inflammatory cytokines for DU, and also to design possible novel therapeutic approaches.
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Affiliation(s)
- Ebrahim Eskandari-Nasab
- Infectious Diseases and Tropical Medicine Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
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MacDonald TT, Biancheri P, Sarra M, Monteleone G. What's the next best cytokine target in IBD? Inflamm Bowel Dis 2012; 18:2180-9. [PMID: 22508526 DOI: 10.1002/ibd.22967] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2012] [Accepted: 03/05/2012] [Indexed: 12/13/2022]
Abstract
In the gut of patients with inflammatory bowel disease (IBD), immune and nonimmune cells produce large amounts of cytokines that drive the inflammatory process leading to the tissue damage. Cytokine blockers, such as anti-tumor necrosis factor alpha (TNF-α), have been used with some success in IBD. However, not all patients respond, and the therapeutic effects wane with time, demonstrating the need for more effective and long-lasting antiinflammatory strategies. A key question is whether neutralizing other proinflammatory cytokines such as interleukin (IL)-12, IL-21, IL-27, or IL-33 will lead to a better clinical response than with anti-TNF-α antibodies. Equally, we now know that IBD-related inflammation is marked by defective production/activity of antiinflammatory cytokines, and there are strategies to correct these defects. An alternative approach is to try to target individual therapies to individual patients, to improve clinical efficacy in subsets of patients, but this has proven difficult. Here we try to evaluate the potential of each of these choices.
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Affiliation(s)
- Thomas T MacDonald
- Centre for Immunology and Infectious Disease, Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK.
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35
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Dohi T, Burkly LC. The TWEAK/Fn14 pathway as an aggravating and perpetuating factor in inflammatory diseases; focus on inflammatory bowel diseases. J Leukoc Biol 2012; 92:265-79. [DOI: 10.1189/jlb.0112042] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Affiliation(s)
- Taeko Dohi
- Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Linda C. Burkly
- Department of Immunology, Biogen Idec, Cambridge, Massachusetts, USA
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36
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Caprioli F, Caruso R, Sarra M, Pallone F, Monteleone G. Disruption of inflammatory signals by cytokine-targeted therapies for inflammatory bowel diseases. Br J Pharmacol 2012; 165:820-8. [PMID: 21806600 DOI: 10.1111/j.1476-5381.2011.01614.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Gut inflammation occurring in patients with inflammatory bowel diseases (IBD) is associated with an excessive immune response that is directed against constituents of the normal bacterial flora and results in the production of large amounts of inflammatory cytokines. Anti-cytokine compounds, such as the neutralizing TNF antibodies, have been employed with clinical success in patients with IBD. However, nearly half of IBD patients are refractory to such treatments, response can wane with time, and anti-TNF treatment can associate with severe side effects and/or development/exacerbation of extra-intestinal immune-mediated pathologies. These observations, and the demonstration that, in IBD, the pathological process is also characterized by defects in the production and/or activity of counter-regulatory cytokines, have boosted further studies aimed at delineating novel strategies to combat the IBD-associated tissue-damaging immune response.
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Affiliation(s)
- Flavio Caprioli
- Unit of Gastroenterology 2, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy
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37
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Khan MW, Kale AA, Bere P, Vajjala S, Gounaris E, Pakanati KC. Microbes, intestinal inflammation and probiotics. Expert Rev Gastroenterol Hepatol 2012; 6:81-94. [PMID: 22149584 DOI: 10.1586/egh.11.94] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Inflammatory bowel disease (IBD) is known for causing disturbed homeostatic balance among the intestinal immune compartment, epithelium and microbiota. Owing to the emergence of IBD as a major cause of morbidity and mortality, great efforts have been put into understanding the sequence of intestinal inflammatory events. Intestinal macrophages and dendritic cells act in a synergistic fashion with intestinal epithelial cells and microbiota to initiate the triad that governs the intestinal immune responses (whether inflammatory or regulatory). In this review, we will discuss the interplay of intestinal epithelial cells, bacteria and the innate immune component. Moreover, whether or not genetic intervention of probiotic bacteria is a valid approach for attenuating/mitigating exaggerated inflammation and IBD will also be discussed.
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Affiliation(s)
- Mohammad W Khan
- The Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
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38
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Monteleone G, Pallone F, MacDonald TT. Emerging immunological targets in inflammatory bowel disease. Curr Opin Pharmacol 2011; 11:640-5. [PMID: 22000933 DOI: 10.1016/j.coph.2011.09.013] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2011] [Revised: 09/27/2011] [Accepted: 09/27/2011] [Indexed: 01/09/2023]
Abstract
Crohn's disease (CD) and ulcerative colitis (UC) are the major forms of inflammatory bowel diseases (IBD) in man. They are caused by damage to the lining of the intestine and deeper layers, due to an excessive immune response directed against components of the gut microflora and poorly controlled by counter-regulatory mechanisms. CD and UC are however immunologically distinct. CD-related inflammation is characterized by a marked mucosal infiltration of T lymphocytes secreting T helper type (Th) 1 and Th17 cytokines. In UC, the local immune response is less polarized but may show enhanced production of IL-5, IL-13 and Th17 cytokines. Downstream however CD and UC share important end-stage effector pathways of intestinal injury, mediated by an active cross-talk between immune and non-immune cells. The clarification of the complex networks of immune-inflammatory mediators operating in the gut of IBD patients has led to the identification of new targets that should facilitate the development of novel biological therapies.
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Affiliation(s)
- Giovanni Monteleone
- Department of Internal Medicine, University Tor Vergata of Rome, Rome, Italy.
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Strober W, Fuss IJ. Proinflammatory cytokines in the pathogenesis of inflammatory bowel diseases. Gastroenterology 2011; 140:1756-1767. [PMID: 21530742 PMCID: PMC3773507 DOI: 10.1053/j.gastro.2011.02.016] [Citation(s) in RCA: 850] [Impact Index Per Article: 60.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2010] [Revised: 02/04/2011] [Accepted: 02/08/2011] [Indexed: 02/07/2023]
Abstract
The cytokine responses characterizing the inflammatory bowel diseases are the key pathophysiologic elements that govern the initiation, evolution, and, ultimately, the resolution of these forms of inflammation. Studies during the last 2 decades now provide a detailed (but not yet complete) picture of the nature of these responses. The first tier of cytokine responses are governed by the T-cell differentiation patterns dominating the disease. In Crohn's disease, the major cytokines arise from T-helper cell (Th) 1 and Th17 CD4(+) T-cell differentiation and consist of interferon-γ and interleukin (IL)-17/IL-22 generated by these types of differentiation. The relative importance of these cytokines to Crohn's inflammation is still unclear, although evidence is mounting that interferon-γ is primus inter pare (first among equals). In contrast, in ulcerative colitis, a Th2-like differentiation process is paramount, which results in expansion of natural killer T cells producing IL-13 (and perhaps IL-5). These disease-specific cytokine patterns give rise to a second tier of cytokines that span the Th1/Th17-Th2 divide and act as upstream facilitators and downstream mediators of inflammation. These cytokines include the well-known tumor necrosis factor-α, IL-1β, IL-6 triumphirate, as well as a more recently studied cytokine known as TL1A (tumor necrosis factor-like ligand). In this review, we will explore this cytokine landscape with the view of providing an understanding of how recent and future anticytokine therapies actually function.
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Affiliation(s)
- Warren Strober
- Mucosal Immunity Section Laboratory of Host Defenses NIAID, NIH
| | - Ivan J Fuss
- Mucosal Immunity Section Laboratory of Host Defenses NIAID, NIH
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40
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Monteleone I, Pallone F, Monteleone G. Th17-cytokine blockers as a new approach for treating inflammatory bowel disease. Ann Med 2011; 43:172-8. [PMID: 21114459 DOI: 10.3109/07853890.2010.531758] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Anti-cytokine therapies, including the anti-TNF-α antibody-based therapies, have largely transformed the management of patients with inflammatory bowel diseases (IBD). However, benefit is seen in nearly 50% of patients, and response can wane with time. Moreover, patients treated with anti-TNF-α antibodies can develop severe side-effects and new immune-mediated diseases. Therefore enormous effort has been made by the research community to elucidate new inflammatory networks in the IBD tissue and to develop novel anti-cytokine compounds, which may act in patients who do not respond to or cannot receive anti-TNF-α therapies. In this article we review the available data supporting the pathogenic role of Th17 cytokines in IBD, and discuss whether and how inhibitors of these inflammatory mediators may enter into the therapeutic armamentarium of IBD.
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Affiliation(s)
- Ivan Monteleone
- Department of Internal Medicine, University 'Tor Vergata' of Rome, Rome, Italy
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41
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Guan Q, Ma Y, Hillman CL, Qing G, Ma AG, Weiss CR, Zhou G, Bai A, Warrington RJ, Bernstein CN, Peng Z. Targeting IL-12/IL-23 by employing a p40 peptide-based vaccine ameliorates TNBS-induced acute and chronic murine colitis. Mol Med 2011; 17:646-56. [PMID: 21424108 DOI: 10.2119/molmed.2010.00252] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2010] [Accepted: 03/10/2011] [Indexed: 12/17/2022] Open
Abstract
Interleukin (IL)-12 and IL-23 both share the p40 subunit and are key cytokines in the pathogenesis of Crohn's disease. Previously, we have developed and identified three mouse p40 peptide-based and virus-like particle vaccines. Here, we evaluated the effects and immune mechanisms of the optimal vaccine in downregulating intestinal inflammation in murine acute and chronic colitis, induced by intrarectal administrations of trinitrobenzene sulfonic acid (TNBS). Mice were injected subcutaneously with vaccine, vaccine carrier or saline three times, and then intrarectally administered TNBS weekly for 2 wks (acute colitis) or 7 wks (chronic colitis). The severity of colitis was evaluated by body weight, histology and collagen and cytokine levels in colon tissue. Th1 and Th17 cells in mesenteric lymph nodes (MLN) were determined. Our results showed the vaccine induced high level and long-lasting specific IgG antibodies to p40, IL-12 and IL-23. After administrations of TNBS, vaccinated mice had significantly less body weight loss and a significant decrease of inflammatory scores, collagen deposition and expression of p40, IL-12, IL-23, IL-17, TNF, iNOS and Bcl-2 in colon tissues, compared with carrier and saline groups. Moreover, vaccinated mice exhibited a trend to lower percentages of Th1 cells in acute colitis and of Th17 cells in chronic colitis in MLN than in controls. In summary, administration of the vaccine induced specific antibodies to IL-12 and IL-23, which was associated with improvement of intestinal inflammation and fibrosis. This suggests that the vaccine may provide a potential approach for the long-term treatment of Crohn's disease.
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Affiliation(s)
- Qingdong Guan
- Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada
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Diaz-Gallo LM, Palomino-Morales RJ, Gómez-García M, Cardeña C, Rodrigo L, Nieto A, Alcain G, Cueto I, López-Nevot MA, Martin J. STAT4 gene influences genetic predisposition to ulcerative colitis but not Crohn's disease in the Spanish population: a replication study. Hum Immunol 2010; 71:515-519. [PMID: 20153791 DOI: 10.1016/j.humimm.2010.02.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2009] [Revised: 01/21/2010] [Accepted: 02/01/2010] [Indexed: 12/12/2022]
Abstract
Recently, the signal transducer and activator of transcription 4 (STAT4) gene has been associated with multiple autoimmune diseases. Interestingly, a recent work showed that the T allele of the rs7574865 STAT4 SNP was associated with inflammatory bowel disease (IBD) in a Spanish population. The aim of the present study was to reevaluate the role of the STAT4 rs7574865 polymorphism on IBD. The present case-control study included 498 Crohn's disease (CD) patients, 402 ulcerative colitis (UC) patients, and 1296 healthy matched controls. Genotyping was performed using a PCR system with a pre-developed TaqMan allelic discrimination assay for the rs7574865 STAT4 SNP. Moreover, a meta-analysis was performed with the previous work in a Spanish population and the current study, including a final sample size of 1574 IBD patients (820 with CD and 754 with UC) and 2012 healthy controls. No evidence of association was found for the current case-control study (CD: p = 0.23, OR = 0.9, 95% CI = 0.75-1.1; UC: p = 0.17, OR = 1.14, 95% CI = 0.95-1.38). However, the meta-analysis showed that the STAT4 rs7574865 T allele was significantly associated with susceptibility to UC (p = 0.012 pooled; OR = 1.20, 95% CI = 1.04-1.39) but not CD (p = 0.71 pooled; OR = 0.93, 95% CI = 0.65-1.34). Our data suggest that the rs7574865 STAT4 SNP is a genetic susceptibility variant for UC but not CD in the Spanish population.
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Tan DBA, Fernandez S, French M, Price P. Could natural killer cells compensate for impaired CD4+ T-cell responses to CMV in HIV patients responding to antiretroviral therapy? Clin Immunol 2009; 132:63-70. [DOI: 10.1016/j.clim.2009.03.518] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2009] [Revised: 03/17/2009] [Accepted: 03/18/2009] [Indexed: 11/25/2022]
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Caruso R, Sarra M, Stolfi C, Rizzo A, Fina D, Fantini MC, Pallone F, MacDonald TT, Monteleone G. Interleukin-25 inhibits interleukin-12 production and Th1 cell-driven inflammation in the gut. Gastroenterology 2009; 136:2270-9. [PMID: 19505427 DOI: 10.1053/j.gastro.2009.02.049] [Citation(s) in RCA: 108] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2008] [Revised: 02/02/2009] [Accepted: 02/06/2009] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS During the pathogenesis of Crohn's disease (CD), interleukin (IL)-12, a cytokine produced by mucosal CD14+ monocyte-like cells, promotes tissue-damaging T helper cell (Th) 1-mediated inflammation through mechanisms that are not fully understood. IL-25 promotes Th2 cell responses by activating major histocompatibility complex class II-positive non-T and non-B cells. Because Th1 and Th2 cells, and the cytokines they release, are often mutually antagonistic, we examined whether IL-25 affects IL-12 production or Th1 cell-mediated inflammation in the gut. METHODS Studies were performed using colonic samples from patients and mice with peptidoglycan (PGN)-, 2,4,6-trinitrobenzenesulphonic acid (TNBS)-, or oxazolone-induced colitis. IL-25 receptor (IL-25R) levels were evaluated in intestinal lamina propria mononuclear cells by flow cytometry, and IL-25 levels were measured by real-time polymerase chain reaction, immunoblotting, and immunohistochemistry. Mucosal CD14+ cells from patients with CD were incubated with IL-25 and/or lipopolysaccharide or PGN. Mice were injected with IL-25, and some mice first received injections of an IL-13 blocking antibody. Cytokines were quantified by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS CD14+ cells from the mucosa of CD patients expressed IL-25R and responded to IL-25 by decreasing the synthesis of IL-12 and IL-23. IL-25 prevented PGN-induced colitis in mice. IL-25 induced IL-13 production in the colon, but IL-13 was not required for suppression of PGN colitis. IL-25 ameliorated TNBS- and oxazolone-colitis. Patients with CD or ulcerative colitis produced significantly less IL-25 compared with controls. CONCLUSIONS IL-25 inhibits CD14+ cell-derived cytokines and experimental colitis. IL-25 could be a useful treatment of CD and ulcerative colitis.
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Affiliation(s)
- Roberta Caruso
- Department of Internal Medicine and Centre of Excellence for Genomic Risk Assessment in Multifactorial and Complex Diseases, University "Tor Vergata" of Rome, Rome, Italy
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O’Malley JT, Eri RD, Stritesky GL, Mathur AN, Chang HC, HogenEsch H, Srinivasan M, Kaplan MH. STAT4 isoforms differentially regulate Th1 cytokine production and the severity of inflammatory bowel disease. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2008; 181:5062-70. [PMID: 18802110 PMCID: PMC2596939 DOI: 10.4049/jimmunol.181.7.5062] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
STAT4, a critical regulator of inflammation in vivo, can be expressed as two alternative splice forms, a full-length STAT4alpha, and a STAT4beta isoform lacking a C-terminal transactivation domain. Each isoform is sufficient to program Th1 development through both common and distinct subsets of target genes. However, the ability of these isoforms to mediate inflammation in vivo has not been examined. Using a model of colitis that develops following transfer of CD4(+) CD45RB(high) T cells expressing either the STAT4alpha or STAT4beta isoform into SCID mice, we determined that although both isoforms mediate inflammation and weight loss, STAT4beta promotes greater colonic inflammation and tissue destruction. This correlates with STAT4 isoform-dependent expression of TNF-alpha and GM-CSF in vitro and in vivo, but not Th1 expression of IFN-gamma or Th17 expression of IL-17, which were similar in STAT4alpha- and STAT4beta-expressing T cells. Thus, higher expression of a subset of inflammatory cytokines from STAT4beta-expressing T cells correlates with the ability of STAT4beta-expressing T cells to mediate more severe inflammatory disease.
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Affiliation(s)
- John T. O’Malley
- Departments of Pediatrics, HB Wells Center for Pediatric Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Rajaraman D. Eri
- Department of Oral Pathology, Medicine and Radiology, School of Dentistry, Indiana University Purdue University at Indianapolis, Indianapolis, IN 46205
| | - Gretta L. Stritesky
- Departments of Pediatrics, HB Wells Center for Pediatric Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Anubhav N. Mathur
- Departments of Pediatrics, HB Wells Center for Pediatric Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Hua-Chen Chang
- Departments of Pediatrics, HB Wells Center for Pediatric Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Harm HogenEsch
- Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907
| | - Mythily Srinivasan
- Department of Oral Pathology, Medicine and Radiology, School of Dentistry, Indiana University Purdue University at Indianapolis, Indianapolis, IN 46205
| | - Mark H. Kaplan
- Departments of Pediatrics, HB Wells Center for Pediatric Research and Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
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Affiliation(s)
- Ivan J Fuss
- Mucosal Immunity Section, National Institutes of Health, Maryland, USA
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Weigmann B, Lehr HA, Yancopoulos G, Valenzuela D, Murphy A, Stevens S, Schmidt J, Galle PR, Rose-John S, Neurath MF. The transcription factor NFATc2 controls IL-6-dependent T cell activation in experimental colitis. ACTA ACUST UNITED AC 2008; 205:2099-110. [PMID: 18710929 PMCID: PMC2526204 DOI: 10.1084/jem.20072484] [Citation(s) in RCA: 114] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
The nuclear factor of activated T cells (NFAT) family of transcription factors controls calcium signaling in T lymphocytes. In this study, we have identified a crucial regulatory role of the transcription factor NFATc2 in T cell–dependent experimental colitis. Similar to ulcerative colitis in humans, the expression of NFATc2 was up-regulated in oxazolone-induced chronic intestinal inflammation. Furthermore, NFATc2 deficiency suppressed colitis induced by oxazolone administration. This finding was associated with enhanced T cell apoptosis in the lamina propria and strikingly reduced production of IL-6, -13, and -17 by mucosal T lymphocytes. Further studies using knockout mice showed that IL-6, rather than IL-23 and -17, are essential for oxazolone colitis induction. Administration of hyper-IL-6 blocked the protective effects of NFATc2 deficiency in experimental colitis, suggesting that IL-6 signal transduction plays a major pathogenic role in vivo. Finally, adoptive transfer of IL-6 and wild-type T cells demonstrated that oxazolone colitis is critically dependent on IL-6 production by T cells. Collectively, these results define a unique regulatory role for NFATc2 in colitis by controlling mucosal T cell activation in an IL-6–dependent manner. NFATc2 in T cells thus emerges as a potentially new therapeutic target for inflammatory bowel diseases.
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Affiliation(s)
- Benno Weigmann
- Institute of Molecular Medicine, Johanes Gutenberg Univeristy, 55131 Mainz, Germany
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Qian BF, Tonkonogy SL, Sartor RB. Reduced responsiveness of HLA-B27 transgenic rat cells to TGF-beta and IL-10-mediated regulation of IFN-gamma production. Inflamm Bowel Dis 2008; 14:921-30. [PMID: 18340648 DOI: 10.1002/ibd.20415] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND We have reported that commensal luminal bacterial components induce an active in vitro IFN-gamma response in mesenteric lymph node (MLN) and intestinal cells from specific pathogen-free (SPF) HLA-B27 transgenic (TG) rats with chronic colitis but not in cells from non-diseased SPF non-TG, germ-free (GF) non-TG or GF TG rats. METHODS The study examined IL-12 stimulation of MLN IFN-gamma responses to luminal bacteria and regulation of these responses by suppressive cytokines. RESULTS Exogenous IL-12 significantly increased the bacterial lysate-induced IFN-gamma response in SPF TG MLN cells, while bacterial lysate and IL-12 synergistically induced IFN-gamma from low baseline levels in cells obtained from both SPF and GF non-TG rats, and in GF TG cells. TGF-beta fully counteracted the effects of IL-12 and bacterial lysate on non-TG cells by almost completely inhibiting IFN-gamma production. In contrast, TG cells were less responsive to TGF-beta-mediated downregulation with a substantial residual IFN-gamma response to IL-12 plus bacterial lysate. Further experiments showed that CD4+/CD25+ cells had no inhibitory effect on the IFN-gamma production and were not required for TGF-beta-mediated suppression. Addition of exogenous IL-10 also partially inhibited IFN-gamma production by non-TG cells but did not affect TG cells. Conversely, exogenous IL-12 preferentially suppressed bacterial lysate-induced TGF-beta and IL-10 production in TG rat cells. CONCLUSIONS An attenuated response to regulatory signals leads to uncontrolled potentiated induction of effector IFN-gamma responses to commensal bacteria in HLA-B27 TG rats that spontaneously develop chronic intestinal inflammation.
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Affiliation(s)
- Bi-Feng Qian
- Center for Gastrointestinal Biology and Disease, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA
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Ebert EC, Jabri B. Massive interleukin-12-induced interferon-gamma production by interleukin-15-stimulated lamina propria lymphocytes followed by down-regulation of the interleukin-12 receptor. Immunology 2008; 124:453-60. [PMID: 18540964 DOI: 10.1111/j.1365-2567.2007.02796.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
The intestinal mucosal immune response must differentiate between harmless foreign antigens and pathogens, a distinction that may depend upon changes in the cytokine milieu. A key cytokine in the adaptive immune response is interleukin-12 (IL-12), secreted by antigen-presenting cells (APC) immediately after encounter with a pathogen. IL-12 is important in the priming and polarization of naïve T cells. Here, we show that IL-12 and IL-15 direct human intestinal lamina propria lymphocytes (LPL) in the absence of T-cell receptor engagement to secrete extremely high amounts of interferon-gamma (IFN-gamma), greater than with any other stimulus. The functional synergy of IL-12 with IL-15 surprisingly operates independently of signal transducer and activator of transcription 1 (STAT1), STAT3, STAT4, or STAT5 phosphorylation and occurs during transcription. Four-colour immunofluorescence showed that IL-12 receptor beta1 is found on the CD4+ T cells expressing intracytoplasmic IFN-gamma. Importantly, IL-12 receptors beta1 and beta2 are not up-regulated by IL-12, unlike findings using antigen-specific T cells, and are lost over time. This study demonstrates the early and massive IFN-gamma response of LPL to IL-12 and IL-15, providing the tools to deal with a pathogen. The down-regulation of IL-12 receptors may curtail any excess damaging inflammation.
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Affiliation(s)
- Ellen C Ebert
- UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA.
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Yoshimitsu M, Hayamizu K, Egi H, Okiyama J, Okajima M, Itamoto T, Asahara T. The neutrophil/Th1 lymphocyte balance and the therapeutic effect of granulocyte colony-stimulating factor in TNBS-induced colitis of rat strains. J Interferon Cytokine Res 2007; 26:291-300. [PMID: 16689657 DOI: 10.1089/jir.2006.26.291] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Intramucosal neutrophil infiltration is related to the activity of ulcerative colitis, and Th1 immunity is responsible for the onset of Crohn's disease. We examined the therapeutic effects of recombinant human granulocyte colony-stimulating factor (rHuG-CSF) in the two types of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis of five rat strains. SD and DA rats showed much lower mRNA expression levels of endogenous G-CSF in lipopolysaccharide (LPS)-stimulated splenocytes than did Lewis, F344, and BN rats. On day 7 after anal instillation of TNBS, SD and DA rats demonstrated massive lymphocyte infiltration with an interferon-gamma (IFN-gamma) mRNA upregulation, whereas Lewis, F344, and BN rats showed an intense submucosal neutrophil accumulation with high tumor necrosis factor-alpha (TNF-alpha) mRNA levels. A 5-day course of rHuG-CSF pretreatment (250 microg/kg/day, s.c.) reduced the elevated levels of both cytokines. The treatment improved the survival rate of DA and reduced the degree of body weight loss of SD, while not significantly influencing the wasting disease of other strains. Interleukin-10 (IL-10) mRNA levels were highly upregulated by rHuG-CSF treatment on day 1 in the neutrophil-dominant lesions of F344 but not in the Th1-type lesions of SD, and IL-12p35 mRNA levels were downregulated in both. A supply of G-CSF prevents the onset of Th1-type TNBS colitis and does not deteriorate neutrophil-dominant chronic colitis in hosts showing higher expression of endogenous G-CSF.
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Affiliation(s)
- Masanori Yoshimitsu
- Department of Surgery, Division of Frontier Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
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