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Long Y, Xia C, Zheng X, Feng J, Li W, Ma Y, Sun Y, Zeng X, Liu C. Functional alterations in colonic CD4+T and regulatory T cells drive immune imbalance in ulcerative colitis. Immunol Lett 2025; 275:107010. [PMID: 40187693 DOI: 10.1016/j.imlet.2025.107010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 04/01/2025] [Accepted: 04/02/2025] [Indexed: 04/07/2025]
Abstract
Immune imbalance plays a key role in the pathogenesis of ulcerative colitis (UC). The changes in CD4+ T cells and regulatory T cells (Tregs) in colonic T cells have an important relationship with UC. It is of great significance to elucidate the functional characteristics of CD4+ cells andTregs in UC patients. This study aimed to inquire into changes in functional markers of CD4+T cells and Tregs, including Helios, Bcl6, CTLA-4, CD226, TIGIT, PD-1 and ICOS. DSS-induced colitis was established in Balb/c mice and lymphocytes from spleen, mesenteric lymph nodes (MLNs), peripheral blood, and colon tissue were obtained. CD4+T cells and Tregs were analyzed by flow cytometry. We found that Helios+ and Bcl-6+ proportions were increased in colonic CD4+T cells of DSS-induced colitis mice. CD4+FoxP3+CXCR5-Tregs were significantly elevated in the colon of colitis mice, with CTLA-4+ percentages increased. Naïve subsets in colonic CD4+T and Tregs were significantly reduced, while effector T-cell subsets were increased in colitis mice. TIGIT+ and CD226+ percentages were significantly increased in both colonic CD4+T cells and Tregs of colitis mice. Both PD-1+ and ICOS+ percentages in colonic CD4+T cells and the ICOS+ percentage in colonic Tregs were significantly increased in colitis mice. In conclusion, functional molecules related to CD4+T cells and Tregs in colonic T cells are altered in UC, often adopting an activated phenotype. These changes may be associated with the pathogenesis of UC and could potentially serve as clinical therapeutic targets.
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Affiliation(s)
- Yan Long
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China.
| | - Changsheng Xia
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Xiaoyi Zheng
- School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Jinghong Feng
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Wenyi Li
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Yinting Ma
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Yuanyuan Sun
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Xingyue Zeng
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Chen Liu
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China.
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Patra S, Chaudhary S, Samal SC, Ayyanar P, Padhi S, Nayak HK, Satapathy AK, Nayak S, Sahu A, Parida T, Shahin M. FoxP3-positive T regulatory cells and its effector mechanisms in Crohn's disease: an immunohistochemical and image morphometric analysis on endoscopic mucosal biopsies. Eur J Gastroenterol Hepatol 2025:00042737-990000000-00509. [PMID: 40207496 DOI: 10.1097/meg.0000000000002971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/11/2025]
Abstract
OBJECTIVE Crohn's disease (CD) is an immune inflammatory disorder of the gastrointestinal tract arising from a complex interplay of genetic, environmental, microbiome, and immune factors. Regulatory T cells (Tregs), characterized by FoxP3 expression, are crucial for maintaining immune homeostasis through PD-1/PD-L1 interaction, interleukin (IL)-10 release, and granzyme (GrB) production. This study aimed to elucidate the role of FoxP3 positive (+) Tregs in CD. METHODS Segmental colonoscopic biopsies from 46 treatment-naive CD cases (34 adults and 12 children) categorized into noninflamed [n = 32; Nancy histologic index (NHI) 0, 1] and inflamed (n = 100; NHI 2-4) mucosae using NHI. CD4, FoxP3, PD-1, IL-10, and GrB immunoexpression were analyzed by eyeballing and image morphometry. Findings were correlated with activity, granulomas, and skip lesions; and compared with site-matched non-inflammatory bowel disease (IBD) controls (n = 30). RESULTS FoxP3+ Tregs, IL-10, PD-1, and GrB expressions were significantly higher in NHI 3-4 mucosae than in NHI 0-1 and controls (P < 0.05). No significant differences were observed between adults and children, whereas those with granulomas had increased expression (P = 0.045). The FoxP3 : CD4 ratio positively correlated with IL-10 (Spearman, r = 0.307, P = 0.002), GrB (r = 0.302, P = 0.002), but not with PD-1 (r = 0.98, P = 0.33). CONCLUSIONS Our findings point to the possibility of a qualitative defect in FoxP3+ Tregs in CD. The functional arms of Tregs in CD need to be elucidated further in larger prospective cohorts to validate our observations and pave the way for future immunotherapy.
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Affiliation(s)
| | | | | | | | | | | | | | - Saurav Nayak
- Department of Biochemistry, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
| | - Ajit Sahu
- Department of Pathology and Laboratory Medicine
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Shim JV, Rehberg M, Wagenhuber B, van der Graaf PH, Chung DW. Combining mechanistic modeling with machine learning as a strategy to predict inflammatory bowel disease clinical scores. Front Pharmacol 2025; 16:1479666. [PMID: 40070575 PMCID: PMC11893853 DOI: 10.3389/fphar.2025.1479666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 01/27/2025] [Indexed: 03/14/2025] Open
Abstract
Disease activity scores are efficacy endpoints in clinical trials of inflammatory bowel disease (IBD) therapies. Crohn's disease activity index (CDAI), Mayo endoscopic score (MES) and Mayo score are frequently used in clinical trials. They rely on either the physician's observation of the inflammatory state of the patient's gastrointestinal tissue alone or combined with the patient's subjective evaluation of general wellbeing. Given the importance of these scores in evaluating the efficacy of drug treatment and disease severity, there has been interest in developing a computational approach to reliably predict these scores. A promising approach is using mechanistic models such as quantitative systems pharmacology (QSP) which simulate the mechanisms of the disease and its modulation by the drug pharmacology. However, extending QSP model simulations to clinical score predictions has been challenging due to the limited availability of gut biopsy measurements and the subjective nature of some of the evaluation criteria for these scores that cannot be described using mechanistic relationships. In this perspective, we examine details of IBD disease activity scores and current progress in building predictive models for these scores (such as biomarkers for disease activity). Then, we propose a method to leverage simulated markers of inflammation from a QSP model to predict IBD clinical scores using a machine learning algorithm. We will demonstrate how this combined approach can be used to (1) explore mechanistic insights underlying clinical observations; and (2) simulate novel therapeutic strategies that could potentially improve clinical outcomes.
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Affiliation(s)
- Jaehee V. Shim
- Certara Applied BioSimulation, Sheffield, United Kingdom
| | - Markus Rehberg
- Sanofi R&D, Translational Disease Modeling, Frankfurt amMain, Germany
| | - Britta Wagenhuber
- Sanofi R&D, Translational Disease Modeling, Frankfurt amMain, Germany
| | - Piet H. van der Graaf
- Certara Applied BioSimulation, Sheffield, United Kingdom
- Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
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Jiang Y, Meng H, Zhang X, Yang J, Sun C, Wang X. Identification of subtypes and biomarkers associated with disulfidptosis-related ferroptosis in ulcerative colitis. Hereditas 2025; 162:27. [PMID: 39987439 PMCID: PMC11846262 DOI: 10.1186/s41065-025-00390-y] [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: 12/13/2024] [Accepted: 02/14/2025] [Indexed: 02/24/2025] Open
Abstract
BACKGROUND Disulfidptosis and ferroptosis are different programmed cell death modes, which are closely related to the development of a variety of diseases, but the relationship between them and ulcerative colitis (UC) is still unclear. Therefore, our study aimed to explore the molecular subtypes and biomarkers associated with disulfidptosis-related ferroptosis (DRF) in UC. METHODS We used Pearson analysis to identify DRF genes. Then, we classified 140 UC samples into different subtypes based on the DRF genes and explored the biological and clinical characteristics between them. Next, the hub genes were identified by differential analysis and WGCNA algorithms, and three machine learning algorithms were used to screen biomarkers for UC from hub genes. In addition, we analyzed the relationship between biomarkers of immune cells and transcription factors and predicted natural compounds that might be used to treat UC. Finally, we further verified the reliability of the markers by RT-qPCR experiments. RESULTS 118 DRF genes were identified using Pearson analysis. Based on the expression level of the DRF genes, we classified UC patients into C1 and C2 subtypes, with significant differences in the abundance of immune infiltration and disease activity between the two subtypes. The machine learning algorithms identified three biomarkers, including XBP1, FH, and MAP3K5. Further analyses revealed that the three biomarkers were closely associated with a variety of immune cells and transcription factors. In addition, six natural compounds corresponding to the biomarkers were predicted, which may contribute to the effective treatment of UC. Finally, the expression trends of XBP1, FH, and MAP3K5 in animal experiments were consistent with the results of bioinformatics analysis. CONCLUSION In this study, we systematically elucidated the role of DRF genes in the development of UC, and identified three potential biomarkers, providing a new idea for the diagnosis and treatment of UC.
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Affiliation(s)
- Yinghao Jiang
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Hongyan Meng
- Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Xin Zhang
- Department of Gastroenterology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Jinguang Yang
- Staff Hospital of JIER MACHINE-TOOL GROUP CO.,LTD, Jinan, China
| | - Chengxin Sun
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Xiaoyan Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China.
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Zhu H, Pan J. Effects of immune cells in mediating the relationship between inflammatory bowel disease and pyoderma gangrenosum: a two-sample, two-step mendelian randomization study. Arch Dermatol Res 2025; 317:176. [PMID: 39760889 DOI: 10.1007/s00403-024-03736-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 07/31/2024] [Accepted: 12/20/2024] [Indexed: 01/07/2025]
Abstract
BACKGROUND Although the precise cause of the co-occurrence of pyoderma gangrenosum (PG) and inflammatory bowel disease (IBD) is still unknown, prior research has shown that the two conditions coexist. Moreover, it is currently unknown how immune cells function in influencing the relationship between IBD and PG. METHODS In order to choose independent single nucleotide polymorphism (SNP) as instrumental variables, we were provided with genome-wide association study (GWAS) summary data of European populations from the IEU OpenGWAS project (for IBD) and a the FinnGen database (for PG) publically available. For the MR analysis, a range of analytical techniques were employed to peer into the possible causative relationship between PG and IBD. The two-step MR analysis was used to investigate the mediating role of immune cells between IBD and PG. The chief method utilized was the inverse variance weighted (IVW) approach. Using the Cochran's Q test and the MR-Egger intercept, respectively, heterogeneity or pleiotropy was evaluated to support the findings. MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) were used to identify the outlier SNP. RESULTS IBD was found to raise the incidence of PG (IVW-FE: OR = 1.604, 95%CI = 1.308-1.966, p = 5.58 × 10- 6), according to MR findings. Moreover, UC or CD were strongly correlated with a greater risk of PG (OR = 1.339, 95%CI = 1.041-1.723, p = 0.023 for UC; OR = 1.339, 95%CI = 1.107-1.621, p = 0.003 for CD). The results of the reverse MR study did not suggest a connection between PG and IBD. CD4+ regulatory T cell is the mediator that particularly stood out in the interaction between UC and PG. There was evidence of neither heterogeneity nor horizontal pleiotropy. And the validity of these conclusions was verified. CONCLUSION In the European population, PG risk may be genetically elevated by IBD, including CD and UC, according to the current study. The effect of UC on PG may have been causally mediated by CD4+ regulatory T cells.
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Affiliation(s)
- Haoqi Zhu
- Department of Gastroenterology, Wenzhou Central Hospital, The Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China
| | - Jingyi Pan
- Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
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Hurtado-Lorenzo A, Swantek JL. The landscape of new therapeutic opportunities for IBD. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2024; 101:1-83. [PMID: 39521596 DOI: 10.1016/bs.apha.2024.10.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
This chapter presents an overview of the emerging strategies to address the unmet needs in the management of inflammatory bowel diseases (IBD). IBD poses significant challenges, as over half of patients experience disease progression despite interventions, leading to irreversible complications, and a substantial proportion do not respond to existing therapies, such as biologics. To overcome these limitations, we describe a diverse array of novel therapeutic approaches. In the area of immune homeostasis restoration, the focus is on targeting cytokine networks, leukocyte trafficking, novel immune pathways, and cell therapies involving regulatory T cells and mesenchymal stem cells (MSC). Recognizing the critical role of impaired intestinal barrier integrity in IBD, we highlight therapies aimed at restoring barrier function and promoting mucosal healing, such as those targeting cell proliferation, tight junctions, and lipid mediators. Addressing the challenges posed by fibrosis and fistulas, we describe emerging targets for reversing fibrosis like kinase and cytokine inhibitors and nuclear receptor agonists, as well as the potential of MSC for fistulas. The restoration of a healthy gut microbiome, through strategies like fecal microbiota transplantation, rationally defined bacterial consortia, and targeted antimicrobials, is also highlighted. We also describe innovative approaches to gut-targeted drug delivery to enhance efficacy and minimize side effects. Reinforcing these advancements is the critical role of precision medicine, which emphasizes the use of multiomics analysis for the discovery of biomarkers to enable personalized IBD care. Overall, the emerging landscape of therapeutic opportunities for IBD holds great potential to surpass the therapeutic ceiling of current treatments.
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Affiliation(s)
- Andrés Hurtado-Lorenzo
- Translational Research & IBD Ventures, Research Department, Crohn's & Colitis Foundation, New York, NY, United States.
| | - Jennifer L Swantek
- Translational Research & IBD Ventures, Research Department, Crohn's & Colitis Foundation, New York, NY, United States
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Liang Y, Li Y, Lee C, Yu Z, Chen C, Liang C. Ulcerative colitis: molecular insights and intervention therapy. MOLECULAR BIOMEDICINE 2024; 5:42. [PMID: 39384730 PMCID: PMC11464740 DOI: 10.1186/s43556-024-00207-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 09/13/2024] [Indexed: 10/11/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by abdominal pain, diarrhea, rectal bleeding, and weight loss. The pathogenesis and treatment of UC remain key areas of research interest. Various factors, including genetic predisposition, immune dysregulation, and alterations in the gut microbiota, are believed to contribute to the pathogenesis of UC. Current treatments for UC include 5-aminosalicylic acids, corticosteroids, immunosuppressants, and biologics. However, study reported that the one-year clinical remission rate is only around 40%. It is necessary to prompt the exploration of new treatment modalities. Biologic therapies, such as anti-TNF-α monoclonal antibody and JAK inhibitor, primarily consist of small molecules targeting specific pathways, effectively inducing and maintaining remission. Given the significant role of the gut microbiota, research into intestinal microecologics, such as probiotics and prebiotics, and fecal microbiota transplantation (FMT) shows promising potential in UC treatment. Additionally, medicinal herbs, such as chili pepper and turmeric, used in complementary therapy have shown promising results in UC management. This article reviews recent findings on the mechanisms of UC, including genetic susceptibility, immune cell dynamics and cytokine regulation, and gut microbiota alterations. It also discusses current applications of biologic therapy, herbal therapy, microecologics, and FMT, along with their prospects and challenges.
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Affiliation(s)
- Yuqing Liang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
- Department of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Yang Li
- Department of Respiratory, Sichuan Integrative Medicine Hospital, Chengdu, 610042, China
| | - Chehao Lee
- Department of Traditional Chinese Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, China
| | - Ziwei Yu
- State Key Laboratory of Southwestern Chinese Medicine Resources, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Chongli Chen
- Department of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
| | - Chao Liang
- Department of Geriatrics, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China.
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Tubau-Juni N, Hontecillas R, Leber AJ, Alva SS, Bassaganya-Riera J. Treating Autoimmune Diseases With LANCL2 Therapeutics: A Novel Immunoregulatory Mechanism for Patients With Ulcerative Colitis and Crohn's Disease. Inflamm Bowel Dis 2024; 30:671-680. [PMID: 37934790 DOI: 10.1093/ibd/izad258] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Indexed: 11/09/2023]
Abstract
Lanthionine synthetase C-like 2 (LANCL2) therapeutics have gained increasing recognition as a novel treatment modality for a wide range of autoimmune diseases. Genetic ablation of LANCL2 in mice results in severe inflammatory phenotypes in inflammatory bowel disease (IBD) and lupus. Pharmacological activation of LANCL2 provides therapeutic efficacy in mouse models of intestinal inflammation, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and psoriasis. Mechanistically, LANCL2 activation enhances regulatory CD4 + T cell (Treg) responses and downregulates effector responses in the gut. The stability and suppressive capacities of Treg cells are enhanced by LANCL2 activation through engagement of immunoregulatory mechanisms that favor mitochondrial metabolism and amplify IL-2/CD25 signaling. Omilancor, the most advanced LANCL2 immunoregulatory therapeutic in late-stage clinical development, is a phase 3 ready, first-in-class, gut-restricted, oral, once-daily, small-molecule therapeutic in clinical development for the treatment of UC and CD. In this review, we discuss this novel mechanism of mucosal immunoregulation and how LANCL2-targeting therapeutics could help address the unmet clinical needs of patients with autoimmune diseases, starting with IBD.
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Ben-Mustapha Y, Rekik R, Ben-Fradj MK, Serghini M, Sanhaji H, Ben-Ahmed M, Boubaker J, Feki M. Abnormal expression of oxylipins and related synthesizing/signaling pathways in inflammatory bowel diseases. Prostaglandins Leukot Essent Fatty Acids 2024; 202:102628. [PMID: 38991597 DOI: 10.1016/j.plefa.2024.102628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 06/11/2024] [Accepted: 06/30/2024] [Indexed: 07/13/2024]
Abstract
We investigated selected oxylipins and related synthesizing/signaling pathways in 28 patients with Crohn's disease (CD), 19 patients with ulcerative colitis (UC), and 39 controls. Plasma and mucosal PUFA/oxylipin profiles were analyzed by LC-MS/MS. mRNA expression of 5, 12 and 15-lipooxygenases, FPR2/ALXR, FFAR4/GPR120, annexin A1, and interleukin-10 were analyzed by qRT-PCR. Oxylipin profile and related metabolic pathways were altered in both CD and UC patients. The patterns were characterized by increased prostaglandins, leukotrienes, and lipoxins and overexpression of 5-lipoxygenase, FPR2/ALXR, annexin A1, and interleukin-10 genes, but decreased n-3 PUFAs and 18-hydroxyeisapentaenoic acid. The gene of 15-lipoxygenase was under-expressed mainly in UC patients. CD and UC are associated with unbalanced n-6 and n-3 derivatives and pro-inflammatory and anti-inflammatory/pro-resolving mediators favoring the former compounds. The findings suggest that oxylipins engage in the pathophysiology of the diseases. Targeting oxylipin's metabolic pathways would be a promising therapy for inflammatory bowel diseases.
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Affiliation(s)
- Yamina Ben-Mustapha
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis 1007, Tunisia; Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis 2092, Tunisia; Laboratory of Biochemistry & LR99ES11, Rabta Hospital, Tunis 1007, Tunisia
| | - Raja Rekik
- Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis 2092, Tunisia; Institute Pasteur of Tunis, Laboratory of Clinical Immunology, Tunis 1002, Tunisia
| | - Mohamed K Ben-Fradj
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis 1007, Tunisia; Laboratory of Biochemistry & LR99ES11, Rabta Hospital, Tunis 1007, Tunisia
| | - Meriem Serghini
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis 1007, Tunisia; Rabta Hospital, Service of Gastroenterology A, Tunis 1007, Tunisia
| | - Haifa Sanhaji
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis 1007, Tunisia; Laboratory of Biochemistry & LR99ES11, Rabta Hospital, Tunis 1007, Tunisia
| | - Melika Ben-Ahmed
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis 1007, Tunisia; Institute Pasteur of Tunis, Laboratory of Clinical Immunology, Tunis 1002, Tunisia
| | - Jalel Boubaker
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis 1007, Tunisia; Rabta Hospital, Service of Gastroenterology A, Tunis 1007, Tunisia
| | - Moncef Feki
- Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis 1007, Tunisia; Laboratory of Biochemistry & LR99ES11, Rabta Hospital, Tunis 1007, Tunisia.
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Mennillo E, Kim YJ, Lee G, Rusu I, Patel RK, Dorman LC, Flynn E, Li S, Bain JL, Andersen C, Rao A, Tamaki S, Tsui J, Shen A, Lotstein ML, Rahim M, Naser M, Bernard-Vazquez F, Eckalbar W, Cho SJ, Beck K, El-Nachef N, Lewin S, Selvig DR, Terdiman JP, Mahadevan U, Oh DY, Fragiadakis GK, Pisco A, Combes AJ, Kattah MG. Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis. Nat Commun 2024; 15:1493. [PMID: 38374043 PMCID: PMC10876948 DOI: 10.1038/s41467-024-45665-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 01/30/2024] [Indexed: 02/21/2024] Open
Abstract
Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we perform single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.
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Affiliation(s)
- Elvira Mennillo
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | | | - Gyehyun Lee
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Iulia Rusu
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Ravi K Patel
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | | | - Emily Flynn
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | - Stephanie Li
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Jared L Bain
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Christopher Andersen
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | - Arjun Rao
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | - Stanley Tamaki
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | - Jessica Tsui
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Alan Shen
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Madison L Lotstein
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | - Maha Rahim
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Mohammad Naser
- Biological Imaging Development CoLab, University of California San Francisco, San Francisco, CA, USA
| | | | - Walter Eckalbar
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | - Soo-Jin Cho
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Kendall Beck
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Najwa El-Nachef
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Sara Lewin
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Daniel R Selvig
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Jonathan P Terdiman
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Uma Mahadevan
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - David Y Oh
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Gabriela K Fragiadakis
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
| | | | - Alexis J Combes
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
- CoLabs, University of California San Francisco, San Francisco, CA, USA
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Michael G Kattah
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
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Mennillo E, Kim YJ, Lee G, Rusu I, Patel RK, Dorman LC, Flynn E, Li S, Bain JL, Andersen C, Rao A, Tamaki S, Tsui J, Shen A, Lotstein ML, Rahim M, Naser M, Bernard-Vazquez F, Eckalbar W, Cho SJ, Beck K, El-Nachef N, Lewin S, Selvig DR, Terdiman JP, Mahadevan U, Oh DY, Fragiadakis GK, Pisco A, Combes AJ, Kattah MG. Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.01.21.525036. [PMID: 36711576 PMCID: PMC9882264 DOI: 10.1101/2023.01.21.525036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we performed single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.
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12
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Harjacek M. Role of regulatory T cells in pathogenesis and therapeutics of spondyloarthritis. REGULATORY T CELLS AND AUTOIMMUNE DISEASES 2024:165-196. [DOI: 10.1016/b978-0-443-13947-5.00042-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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13
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Zhang H, Cai W, Xu D, Liu J, Zhao Q, Shao S. Effects of mesenchymal stem cells on Treg cells in rats with colitis. Clin Exp Immunol 2023; 214:296-303. [PMID: 37417713 PMCID: PMC10719214 DOI: 10.1093/cei/uxad072] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 05/28/2023] [Accepted: 07/06/2023] [Indexed: 07/08/2023] Open
Abstract
The aim was to investigate the therapeutic effect of bone marrow mesenchymal stem cells (BM-MSC) on dextran sulfate sodium (DSS) induced colitis in rats and its effect on regulatory T cells (Treg). A model of DSS-induced colitis was established. BM-MSC was isolated and cultured to observe the efficacy of BM-MSC on colitis, including general vital signs, weight changes, colonic length changes, colonic histopathological changes, and colonic tissue MPO activity. The expression of inflammatory factors (IFN-γ, IL-4, IL-17, TGF-β) in colonic tissues was measured by real-time PCR. The amount of CD4 + CD25 + Treg was detected by flow cytometry. Real-time PCR was used to detect Foxp3+mRNA in CD4 + CD25 + Treg, western to detect Foxp3+protein expression in CD4 + CD25 + Treg, and ELISA was used to detect IL-35 and IL-10 cytokines in CD4 + CD25 + Treg culture supernatant. Results show that intravenous injection of BM-MSC significantly improved the clinical manifestations and histopathological changes in rats with experimental DSS colitis; significantly down-regulated the expression of inflammatory factors IFN-γ, IL-4, and IL-17 and up-regulated the expression of TGF-β in colon tissues; BM-MSC also increased the number of CD4+CD25+Foxp3+Treg and enhanced the function of CD4+CD25+Foxp3+Treg in colon tissues, and up-regulated the expression of IL-35. In conclusion, BM-MSC has a certain therapeutic effect on DSS-induced colitis. It can improve the general signs of colitis rats and reduce intestinal injury and inflammatory response. The immunoregulatory effect of BM-MSC is achieved by enhancing the function of CD4+CD25+Foxp3+Treg and up-regulating the secretion of immunosuppressive inflammatory factors.
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Affiliation(s)
- Heng Zhang
- Department of Gastroenterology, The Central Hospital of Wuhan, Wuhan, China
| | - Wei Cai
- Department of Gastrointestinal Surgery, The Central Hospital of Wuhan, Wuhan, China
| | - Dan Xu
- Department of Gastroenterology, The Central Hospital of Wuhan, Wuhan, China
| | - Jing Liu
- Department of Gastroenterology, The Central Hospital of Wuhan, Wuhan, China
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Su’E Shao
- Department of Gastroenterology, The Central Hospital of Wuhan, Wuhan, China
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14
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Shao TY, Jiang TT, Stevens J, Russi AE, Troutman TD, Bernieh A, Pham G, Erickson JJ, Eshleman EM, Alenghat T, Jameson SC, Hogquist KA, Weaver CT, Haslam DB, Deshmukh H, Way SS. Kruppel-like factor 2+ CD4 T cells avert microbiota-induced intestinal inflammation. Cell Rep 2023; 42:113323. [PMID: 37889750 PMCID: PMC10822050 DOI: 10.1016/j.celrep.2023.113323] [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: 12/12/2022] [Revised: 09/05/2023] [Accepted: 10/06/2023] [Indexed: 10/29/2023] Open
Abstract
Intestinal colonization by antigenically foreign microbes necessitates expanded peripheral immune tolerance. Here we show commensal microbiota prime expansion of CD4 T cells unified by the Kruppel-like factor 2 (KLF2) transcriptional regulator and an essential role for KLF2+ CD4 cells in averting microbiota-driven intestinal inflammation. CD4 cells with commensal specificity in secondary lymphoid organs and intestinal tissues are enriched for KLF2 expression, and distinct from FOXP3+ regulatory T cells or other differentiation lineages. Mice with conditional KLF2 deficiency in T cells develop spontaneous rectal prolapse and intestinal inflammation, phenotypes overturned by eliminating microbiota or reconstituting with donor KLF2+ cells. Activated KLF2+ cells selectively produce IL-10, and eliminating IL-10 overrides their suppressive function in vitro and protection against intestinal inflammation in vivo. Together with reduced KLF2+ CD4 cell accumulation in Crohn's disease, a necessity for the KLF2+ subpopulation of T regulatory type 1 (Tr1) cells in sustaining commensal tolerance is demonstrated.
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Affiliation(s)
- Tzu-Yu Shao
- Division of Infectious Diseases, Center for Inflammation and Tolerance, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Tony T Jiang
- Division of Infectious Diseases, Center for Inflammation and Tolerance, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Joseph Stevens
- Division of Neonatology and Pulmonary Biology, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Abigail E Russi
- Division of Gastroenterology, Hepatology and Advanced Nutrition, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Ty D Troutman
- Division of Allergy and Immunology, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Anas Bernieh
- Division of Pathology, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Giang Pham
- Division of Infectious Diseases, Center for Inflammation and Tolerance, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - John J Erickson
- Division of Neonatology and Pulmonary Biology, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Emily M Eshleman
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Theresa Alenghat
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Stephen C Jameson
- Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Kristin A Hogquist
- Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN 55455, USA
| | - Casey T Weaver
- Program in Immunology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL 35233, USA
| | - David B Haslam
- Division of Infectious Diseases, Center for Inflammation and Tolerance, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Hitesh Deshmukh
- Division of Neonatology and Pulmonary Biology, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA
| | - Sing Sing Way
- Division of Infectious Diseases, Center for Inflammation and Tolerance, University of Cincinnati School of Medicine, Cincinnati, OH 45229, USA.
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15
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Hu C, Liao S, Lv L, Li C, Mei Z. Intestinal Immune Imbalance is an Alarm in the Development of IBD. Mediators Inflamm 2023; 2023:1073984. [PMID: 37554552 PMCID: PMC10406561 DOI: 10.1155/2023/1073984] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 07/06/2023] [Accepted: 07/08/2023] [Indexed: 08/10/2023] Open
Abstract
Immune regulation plays a crucial role in human health and disease. Inflammatory bowel disease (IBD) is a chronic relapse bowel disease with an increasing incidence worldwide. Clinical treatments for IBD are limited and inefficient. However, the pathogenesis of immune-mediated IBD remains unclear. This review describes the activation of innate and adaptive immune functions by intestinal immune cells to regulate intestinal immune balance and maintain intestinal mucosal integrity. Changes in susceptible genes, autophagy, energy metabolism, and other factors interact in a complex manner with the immune system, eventually leading to intestinal immune imbalance and the onset of IBD. These events indicate that intestinal immune imbalance is an alarm for IBD development, further opening new possibilities for the unprecedented development of immunotherapy for IBD.
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Affiliation(s)
- Chunli Hu
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Shengtao Liao
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Lin Lv
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Chuanfei Li
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Zhechuan Mei
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
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Chauhan SK, Bartolomé Casado R, Landsverk OJB, Johannessen H, Phung D, Nilsen HR, Sætre F, Jahnsen J, Horneland R, Yaqub S, Aandahl EM, Lundin KEA, Bækkevold ES, Jahnsen FL. Human small intestine contains 2 functionally distinct regulatory T-cell subsets. J Allergy Clin Immunol 2023; 152:278-289.e6. [PMID: 36893861 DOI: 10.1016/j.jaci.2023.02.030] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 02/17/2023] [Accepted: 02/23/2023] [Indexed: 03/09/2023]
Abstract
BACKGROUND Regulatory T (Treg) CD4 cells in mouse gut are mainly specific for intestinal antigens and play an important role in the suppression of immune responses against harmless dietary antigens and members of the microbiota. However, information about the phenotype and function of Treg cells in the human gut is limited. OBJECTIVE We performed a detailed characterization of Foxp3+ CD4 Treg cells in human normal small intestine (SI) as well as from transplanted duodenum and celiac disease lesions. METHODS Treg cells and conventional CD4 T cells derived from SI were subjected to extensive immunophenotyping and their suppressive activity and ability to produce cytokines assessed. RESULTS SI Foxp3+ CD4 T cells were CD45RA-CD127-CTLA-4+ and suppressed proliferation of autologous T cells. Approximately 60% of Treg cells expressed the transcription factor Helios. When stimulated, Helios-negative Treg cells produced IL-17, IFN-γ, and IL-10, whereas Helios-positive Treg cells produced very low levels of these cytokines. By sampling mucosal tissue from transplanted human duodenum, we demonstrated that donor Helios-negative Treg cells persisted for at least 1 year after transplantation. In normal SI, Foxp3+ Treg cells constituted only 2% of all CD4 T cells, while in active celiac disease, both Helios-negative and Helios-positive subsets expanded 5- to 10-fold. CONCLUSION The SI contains 2 subsets of Treg cells with different phenotypes and functional capacities. Both subsets are scarce in healthy gut but increase dramatically in active celiac disease.
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Affiliation(s)
- Sudhir Kumar Chauhan
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
| | - Raquel Bartolomé Casado
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Ole J B Landsverk
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Hanna Johannessen
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway; Department of Gastrointestinal and Pediatric Surgery, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Danh Phung
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Hogne Røed Nilsen
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Frank Sætre
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Jørgen Jahnsen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Gastroenterology, Akershus University Hospital, Lørenskog, Norway
| | - Rune Horneland
- Department of Transplantation Medicine, Section for Transplant Surgery, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Sheraz Yaqub
- Department of Gastrointestinal Surgery, Oslo University Hospital-Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Einar Martin Aandahl
- Department of Transplantation Medicine, Section for Transplant Surgery, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Knut E A Lundin
- Department of Gastroenterology, Oslo University Hospital-Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Espen S Bækkevold
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Frode L Jahnsen
- Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
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17
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Zhou X, Gu Y, Wang H, Zhou W, Zou L, Li S, Hua C, Gao S. From bench to bedside: targeting lymphocyte activation gene 3 as a therapeutic strategy for autoimmune diseases. Inflamm Res 2023:10.1007/s00011-023-01742-y. [PMID: 37314518 DOI: 10.1007/s00011-023-01742-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 01/12/2023] [Accepted: 05/12/2023] [Indexed: 06/15/2023] Open
Abstract
BACKGROUND Immune checkpoints negatively regulate immune response, thereby playing an important role in maintaining immune homeostasis. Substantial studies have confirmed that blockade or deficiency of immune checkpoint pathways contributes to the deterioration of autoimmune diseases. In this context, focusing on immune checkpoints might provide alternative strategies for the treatment of autoimmunity. Lymphocyte activation gene 3 (LAG3), as a member of immune checkpoint, is critical in regulating immune responses as manifested in multiple preclinical studies and clinical trials. Recent success of dual-blockade of LAG3 and programmed death-1 in melanoma also supports the notion that LAG3 is a crucial regulator in immune tolerance. METHODS We wrote this review article by searching the PubMed, Web of Science and Google Scholar databases. CONCLUSION In this review, we summarize the molecular structure and the action mechanisms of LAG3. Additionally, we highlight its roles in diverse autoimmune diseases and discuss how the manipulation of the LAG3 pathway can serve as a promising therapeutic strategy as well as its specific mechanism with the aim of filling the gaps from bench to bedside.
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Affiliation(s)
- Xueyin Zhou
- School of the 2nd Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yiming Gu
- School of the 2nd Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Huihong Wang
- School of the 2nd Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Wei Zhou
- School of the 2nd Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Lei Zou
- School of the 2nd Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Shuting Li
- School of the 2nd Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Chunyan Hua
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
| | - Sheng Gao
- Laboratory Animal Center, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
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18
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Cheru N, Hafler DA, Sumida TS. Regulatory T cells in peripheral tissue tolerance and diseases. Front Immunol 2023; 14:1154575. [PMID: 37197653 PMCID: PMC10183596 DOI: 10.3389/fimmu.2023.1154575] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 04/13/2023] [Indexed: 05/19/2023] Open
Abstract
Maintenance of peripheral tolerance by CD4+Foxp3+ regulatory T cells (Tregs) is essential for regulating autoreactive T cells. The loss of function of Foxp3 leads to autoimmune disease in both animals and humans. An example is the rare, X-linked recessive disorder known as IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy X-linked) syndrome. In more common human autoimmune diseases, defects in Treg function are accompanied with aberrant effector cytokines such as IFNγ. It has recently become appreciated that Tregs plays an important role in not only maintaining immune homeostasis but also in establishing the tissue microenvironment and homeostasis of non-lymphoid tissues. Tissue resident Tregs show profiles that are unique to their local environments which are composed of both immune and non-immune cells. Core tissue-residence gene signatures are shared across different tissue Tregs and are crucial to homeostatic regulation and maintaining the tissue Treg pool in a steady state. Through interaction with immunocytes and non-immunocytes, tissue Tregs exert a suppressive function via conventional ways involving contact dependent and independent processes. In addition, tissue resident Tregs communicate with other tissue resident cells which allows Tregs to adopt to their local microenvironment. These bidirectional interactions are dependent on the specific tissue environment. Here, we summarize the recent advancements of tissue Treg studies in both human and mice, and discuss the molecular mechanisms that maintain tissue homeostasis and prevent pathogenesis.
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Affiliation(s)
- Nardos Cheru
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, United States
| | - David A. Hafler
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, United States
- Department of Neurology, Yale School of Medicine, New Haven, CT, United States
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
| | - Tomokazu S. Sumida
- Department of Neurology, Yale School of Medicine, New Haven, CT, United States
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19
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Laukova M, Glatman Zaretsky A. Regulatory T cells as a therapeutic approach for inflammatory bowel disease. Eur J Immunol 2023; 53:e2250007. [PMID: 36562391 PMCID: PMC10107179 DOI: 10.1002/eji.202250007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/20/2022] [Accepted: 12/22/2022] [Indexed: 12/24/2022]
Abstract
Foxp3+ T regulatory (Treg) cells suppress inflammation and are essential for maintaining tissue homeostasis. A growing appreciation of tissue-specific Treg functions has built interest in leveraging the endogenous suppressive mechanisms of these cells into cellular therapeutics in organ-specific diseases. Notably, Treg cells play a critical role in maintaining the intestinal environment. As a barrier site, the gut requires Treg cells to mediate interactions with the microbiota, support barrier integrity, and regulate the immune system. Without fully functional Treg cells, intestinal inflammation and microbial dysbiosis ensue. Thus, there is a particular interest in developing Treg cellular therapies for intestinal inflammatory disease, such as inflammatory bowel disease (IBD). This article reviews some of the critical pathways that are dysregulated in IBD, Treg cell mechanisms of suppression, and the efforts and approaches in the field to develop these cells as a cellular therapy for IBD.
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20
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Aggeletopoulou I, Tsounis EP, Triantos C. Molecular Mechanisms Underlying IL-33-Mediated Inflammation in Inflammatory Bowel Disease. Int J Mol Sci 2022; 24:ijms24010623. [PMID: 36614065 PMCID: PMC9820409 DOI: 10.3390/ijms24010623] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 12/20/2022] [Accepted: 12/28/2022] [Indexed: 12/31/2022] Open
Abstract
Interleukin-33 (IL-33) is a cytokine defined by its pleiotropic function, acting either as a typical extracellular cytokine or as a nuclear transcription factor. IL-33 and its receptor, suppression of tumorigenicity 2 (ST2), interact with both innate and adaptive immunity and are considered critical regulators of inflammatory disorders. The IL-33/ST2 axis is involved in the maintenance of intestinal homeostasis; on the basis of their role as pro- or anti-inflammatory mediators of first-line innate immunity, their expression is of great importance in regard to mucosal defenses. Mucosal immunity commonly presents an imbalance in inflammatory bowel disease (IBD). This review summarizes the main cellular and molecular aspects of IL-33 and ST2, mainly focusing on the current evidence of the pro- and anti-inflammatory effects of the IL-33/ST2 axis in the course of ulcerative colitis and Crohn's disease, as well as the molecular mechanisms underlying the association of IL-33/ST2 signaling in IBD pathogenesis. Although IL-33 modulates and impacts the development, course, and recurrence of the inflammatory response, the exact role of this molecule is elusive, and it seems to be associated with the subtype of the disease or the disease stage. Unraveling of IL-33/ST2-mediated mechanisms involved in IBD pathology shows great potential for clinical application as therapeutic targets in IBD treatment.
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21
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Hone Lopez S, Jalving M, Fehrmann RS, Nagengast WB, de Vries EG, de Haan JJ. The gut wall’s potential as a partner for precision oncology in immune checkpoint treatment. Cancer Treat Rev 2022; 107:102406. [DOI: 10.1016/j.ctrv.2022.102406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/29/2022] [Accepted: 05/01/2022] [Indexed: 11/02/2022]
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22
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Burrello C, Strati F, Lattanzi G, Diaz-Basabe A, Mileti E, Giuffrè MR, Lopez G, Cribiù FM, Trombetta E, Kallikourdis M, Cremonesi M, Conforti F, Botti F, Porretti L, Rescigno M, Vecchi M, Fantini MC, Caprioli F, Facciotti F. IL10 Secretion Endows Intestinal Human iNKT Cells with Regulatory Functions Towards Pathogenic T Lymphocytes. J Crohns Colitis 2022; 16:1461-1474. [PMID: 35358301 PMCID: PMC9455792 DOI: 10.1093/ecco-jcc/jjac049] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Invariant natural killer T [iNKT] cells perform pleiotropic functions in different tissues by secreting a vast array of pro-inflammatory and cytotoxic molecules. However, the presence and function of human intestinal iNKT cells capable of secreting immunomodulatory molecules such as IL-10 has never been reported so far. Here we describe for the first time the presence of IL10-producing iNKT cells [NKT10 cells] in the intestinal lamina propria of healthy individuals and of Crohn's disease [CD] patients. METHODS Frequency and phenotype of NKT10 cells were analysed ex vivo from intestinal specimens of Crohn's disease [n = 17] and controls [n = 7]. Stable CD-derived intestinal NKT10 cell lines were used to perform in vitro suppression assays and co-cultures with patient-derived mucosa-associated microbiota. Experimental colitis models were performed by adoptive cell transfer of splenic naïve CD4+ T cells in the presence or absence of IL10-sufficient or -deficient iNKT cells. In vivo induction of NKT10 cells was performed by administration of short chain fatty acids [SCFA] by oral gavage. RESULTS Patient-derived intestinal NKT10 cells demonstrated suppressive capabilities towards pathogenic CD4+ T cells. The presence of increased proportions of mucosal NKT10 cells associated with better clinical outcomes in CD patients. Moreover, an intestinal microbial community enriched in SCFA-producing bacteria sustained the production of IL10 by iNKT cells. Finally, IL10-deficient iNKT cells failed to control the pathogenic activity of adoptively transferred CD4+ T cells in an experimental colitis model. CONCLUSIONS These results describe an unprecedentd IL10-mediated immunoregulatory role of intestinal iNKT cells in controlling the pathogenic functions of mucosal T helper subsets and in maintaining the intestinal immune homeostasis.
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Affiliation(s)
- Claudia Burrello
- Current address: Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | | | | | | | - Erika Mileti
- Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy
| | - Maria Rita Giuffrè
- Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy
| | - Gianluca Lopez
- Pathology Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Fulvia Milena Cribiù
- Pathology Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Elena Trombetta
- Clinical Chemistry and Microbiology Laboratory Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Marinos Kallikourdis
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Laboratory of Adaptive Immunity, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Marco Cremonesi
- Laboratory of Adaptive Immunity, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Francesco Conforti
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Fiorenzo Botti
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
- General and Emergency Surgery Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
| | - Laura Porretti
- Clinical Chemistry and Microbiology Laboratory Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Maria Rescigno
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Maurizio Vecchi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Massimo C Fantini
- Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy
| | - Flavio Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Federica Facciotti
- Corresponding author: Dr Federica Facciotti, Department of Experimental Oncology, European Institute of Oncology IRCCS, Via Adamello 16, 20135, Milan, Italy.
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Lu Q, Yang MF, Liang YJ, Xu J, Xu HM, Nie YQ, Wang LS, Yao J, Li DF. Immunology of Inflammatory Bowel Disease: Molecular Mechanisms and Therapeutics. J Inflamm Res 2022; 15:1825-1844. [PMID: 35310454 PMCID: PMC8928114 DOI: 10.2147/jir.s353038] [Citation(s) in RCA: 96] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/26/2022] [Indexed: 12/12/2022] Open
Abstract
As a main digestive organ and an important immune organ, the intestine plays a vital role in resisting the invasion of potential pathogens into the body. Intestinal immune dysfunction remains important pathogenesis of inflammatory bowel disease (IBD). In this review, we explained the interactions among symbiotic flora, intestinal epithelial cells, and the immune system, clarified the operating mechanism of the intestinal immune system, and highlighted the immunological pathogenesis of IBD, with a focus on the development of immunotherapy for IBD. In addition, intestinal fibrosis is a significant complication in patients with long-term IBD, and we reviewed the immunological pathogenesis involved in the development of intestinal fibrogenesis and provided novel antifibrotic immunotherapies for IBD.
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Affiliation(s)
- Quan Lu
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, People’s Republic of China
- Department of Gastroenterology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Mei-feng Yang
- Department of Hematology, Yantian District People’s Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - Yu-jie Liang
- Department of Child and Adolescent Psychiatry, Shenzhen Kangning Hospital, Shenzhen, Guangdong, People’s Republic of China
| | - Jing Xu
- Department of Gastroenterology and Hepatology, Guangzhou First People’s Hospital (School of Medicine of South China University of Technology), Guangzhou, Guangdong, People’s Republic of China
| | - Hao-ming Xu
- Department of Gastroenterology and Hepatology, Guangzhou First People’s Hospital (School of Medicine of South China University of Technology), Guangzhou, Guangdong, People’s Republic of China
| | - Yu-qiang Nie
- Department of Gastroenterology and Hepatology, Guangzhou First People’s Hospital (School of Medicine of South China University of Technology), Guangzhou, Guangdong, People’s Republic of China
| | - Li-sheng Wang
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, People’s Republic of China
- Department of Gastroenterology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, People’s Republic of China
- Department of Gastroenterology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
| | - De-feng Li
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, Guangdong, People’s Republic of China
- Department of Gastroenterology, Shenzhen People’s Hospital (The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China
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24
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Voskens CJ, Stoica D, Roessner S, Vitali F, Zundler S, Rosenberg M, Wiesinger M, Wunder J, Siegmund B, Schuler-Thurner B, Schuler G, Berking C, Atreya R, Neurath MF. Safety and tolerability of a single infusion of autologous ex vivo expanded regulatory T cells in adults with ulcerative colitis (ER-TREG 01): protocol of a phase 1, open-label, fast-track dose-escalation clinical trial. BMJ Open 2021; 11:e049208. [PMID: 34880013 PMCID: PMC8655533 DOI: 10.1136/bmjopen-2021-049208] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Accumulating evidence suggests that the adoptive transfer of ex vivo expanded regulatory T cells (Treg) may overcome colitogenic immune responses in patients with inflammatory bowel diseases. The objective of the ER-TREG 01 trial is to assess safety and tolerability of a single infusion of autologous ex vivo expanded Treg in adults with ulcerative colitis. METHODS AND ANALYSIS The study is designed as a single-arm, fast-track dose-escalation trial. The study will include 10 patients with ulcerative colitis. The study intervention consists of (1) a baseline visit; (2) a second visit that includes a leukapheresis to generate the investigational medicinal product, (3) a third visit to infuse the investigational medicinal product and (4) five subsequent follow-up visits within the next 26 weeks to assess safety and tolerability. Patients will intravenously receive a single dose of 0.5×106, 1×106, 2×106, 5×106 or 10×106 autologous Treg/kg body weight. The primary objective is to define the maximum tolerable dose of a single infusion of autologous ex vivo expanded Treg. Secondary objectives include the evaluation of safety of one single infusion of autologous ex vivo expanded Treg, efficacy assessment and accompanying immunomonitoring to measure Treg function in the peripheral blood and intestinal mucosa. ETHICS AND DISSEMINATION The study protocol was approved by the Ethics Committee of the Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany (number 417_19 Az). In addition, the study was approved by the Paul-Ehrlich Institute, Federal Institute for Vaccines and Biomedicines, Langen, Germany (number 3652/01). The study is funded by the German Research Foundation (DFG, KFO 257 project 08 and SFB/TransRegio 241 project C04). The trial will be conducted in compliance with this study protocol, the Declaration of Helsinki, Good Clinical Practice and Good Manufacturing Practice. The results will be published in peer-reviewed scientific journals and disseminated in scientific conferences and media. TRIAL REGISTRATION NUMBER NCT04691232.
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Affiliation(s)
- Caroline J Voskens
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Diane Stoica
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Susanne Roessner
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Francesco Vitali
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Sebastian Zundler
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Marita Rosenberg
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Manuel Wiesinger
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Jutta Wunder
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Britta Siegmund
- Department of Medicine (Gastroenterology, Infectiology, Rheumatology), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Benjamin Franklin, Berlin, Germany
| | - Beatrice Schuler-Thurner
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Gerold Schuler
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Carola Berking
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Raja Atreya
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
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25
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Ostner J, Carcy S, Müller CL. tascCODA: Bayesian Tree-Aggregated Analysis of Compositional Amplicon and Single-Cell Data. Front Genet 2021; 12:766405. [PMID: 34950190 PMCID: PMC8689185 DOI: 10.3389/fgene.2021.766405] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 11/01/2021] [Indexed: 12/11/2022] Open
Abstract
Accurate generative statistical modeling of count data is of critical relevance for the analysis of biological datasets from high-throughput sequencing technologies. Important instances include the modeling of microbiome compositions from amplicon sequencing surveys and the analysis of cell type compositions derived from single-cell RNA sequencing. Microbial and cell type abundance data share remarkably similar statistical features, including their inherent compositionality and a natural hierarchical ordering of the individual components from taxonomic or cell lineage tree information, respectively. To this end, we introduce a Bayesian model for tree-aggregated amplicon and single-cell compositional data analysis (tascCODA) that seamlessly integrates hierarchical information and experimental covariate data into the generative modeling of compositional count data. By combining latent parameters based on the tree structure with spike-and-slab Lasso penalization, tascCODA can determine covariate effects across different levels of the population hierarchy in a data-driven parsimonious way. In the context of differential abundance testing, we validate tascCODA's excellent performance on a comprehensive set of synthetic benchmark scenarios. Our analyses on human single-cell RNA-seq data from ulcerative colitis patients and amplicon data from patients with irritable bowel syndrome, respectively, identified aggregated cell type and taxon compositional changes that were more predictive and parsimonious than those proposed by other schemes. We posit that tascCODA constitutes a valuable addition to the growing statistical toolbox for generative modeling and analysis of compositional changes in microbial or cell population data.
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Affiliation(s)
- Johannes Ostner
- Department of Statistics, Ludwig-Maximilians-Universität München, Munich, Germany
- Institute of Computational Biology, Helmholtz Zentrum München, Munich, Germany
| | - Salomé Carcy
- Institute of Computational Biology, Helmholtz Zentrum München, Munich, Germany
- Department of Biology, École Normale Supérieure, PSL University, Paris, France
| | - Christian L. Müller
- Department of Statistics, Ludwig-Maximilians-Universität München, Munich, Germany
- Institute of Computational Biology, Helmholtz Zentrum München, Munich, Germany
- Center for Computational Mathematics, Flatiron Institute, New York, NY, United States
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26
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Büttner M, Ostner J, Müller CL, Theis FJ, Schubert B. scCODA is a Bayesian model for compositional single-cell data analysis. Nat Commun 2021; 12:6876. [PMID: 34824236 PMCID: PMC8616929 DOI: 10.1038/s41467-021-27150-6] [Citation(s) in RCA: 159] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 11/01/2021] [Indexed: 12/19/2022] Open
Abstract
Compositional changes of cell types are main drivers of biological processes. Their detection through single-cell experiments is difficult due to the compositionality of the data and low sample sizes. We introduce scCODA ( https://github.com/theislab/scCODA ), a Bayesian model addressing these issues enabling the study of complex cell type effects in disease, and other stimuli. scCODA demonstrated excellent detection performance, while reliably controlling for false discoveries, and identified experimentally verified cell type changes that were missed in original analyses.
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Affiliation(s)
- M Büttner
- Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - J Ostner
- Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Department of Statistics, Ludwig-Maximilians-Universität München, München, Germany
| | - C L Müller
- Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
- Department of Statistics, Ludwig-Maximilians-Universität München, München, Germany.
- Center for Computational Mathematics, Flatiron Institute, New York, NY, USA.
| | - F J Theis
- Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Department of Mathematics, Technische Universität München, Garching bei München, Germany
- TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - B Schubert
- Institute of Computational Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
- Department of Mathematics, Technische Universität München, Garching bei München, Germany.
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27
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Abstract
Current practice in IBD is to classify patients based on clinical signs and symptoms and provide treatments accordingly. However, the response of IBD patients to available treatments is highly variable, highlighting clinically significant heterogeneity among patients. Thus, more accurate patient stratification is urgently needed to more effectively target therapeutic interventions to specific patients. Here we review the degree of heterogeneity in IBD, discussing how the microbiota, genetics, and immune system may contribute to the variation among patients. We highlight how molecular heterogeneity may relate to clinical phenotype, but in other situations may be independent of clinical phenotype, encouraging future studies to fill the gaps. Finally, we discuss novel stratification methodologies as a foundation for precision medicine, in particular a novel stratification strategy based on conserved genes across species. All of these dimensions of heterogeneity have potential to provide strategies for patient stratification and move IBD practice towards personalised medicine.
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Affiliation(s)
- Katja A Selin
- Division of Immunology and Allergy, Department of Medicine, Solna, Karolinska Institutet and University Hospital, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Gastroenterology Unit, Patient Area Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine, Solna, Division of Clinical Medicine, Karolinska Institutet, Solna, Sweden
| | - Charlotte R H Hedin
- Gastroenterology Unit, Patient Area Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine, Solna, Division of Clinical Medicine, Karolinska Institutet, Solna, Sweden
| | - Eduardo J Villablanca
- Division of Immunology and Allergy, Department of Medicine, Solna, Karolinska Institutet and University Hospital, Stockholm, Sweden
- Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Medicine, Solna, Division of Clinical Medicine, Karolinska Institutet, Solna, Sweden
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28
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Daferera N, Escudero-Hernández C, Nyström S, Jenmalm MC, Hjortswang H, Ignatova S, Ström M, Münch A. Collagenous Colitis Mucosa Is Characterized by an Expansion of Nonsuppressive FoxP3+ T Helper Cells. Inflamm Bowel Dis 2021; 27:1482-1490. [PMID: 33319252 DOI: 10.1093/ibd/izaa322] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Increased frequencies of T regulatory (Treg) cells, key players in immune regulation, have been reported in inflammatory bowel diseases, including collagenous colitis (CC). However, traditional Treg identification techniques might have misinterpreted the frequencies of Treg cells in CC. Thus, we investigated the presence of genuine Treg cells in CC. METHODS Treg cells were analyzed in mucosal and peripheral blood samples of CC patients before and during treatment with the corticosteroid drug budesonide and in healthy controls. Samples were analyzed by flow cytometry by classifying CD3+CD4+ cells as activated FoxP3highCD45RA- Treg cells, resting FoxP3dimCD45RA+ Treg cells, and nonsuppressive FoxP3dimCD45RA- T helper cells. Traditional gating strategies that classified Treg cells as CD25highCD127low, FoxP3+CD127low, and CD4+CD25+FoxP3+ were also used to facilitate comparison with previous studies. RESULTS Activated and resting Treg cell frequencies did not change in active CC mucosa or peripheral blood and were not affected by budesonide treatment. Instead, nonsuppressive FoxP3dimCD45RA- T helper cells were increased in active CC mucosa, and budesonide helped restore them to normal levels. In contrast, traditional Treg cell gating strategies resulted in increased Treg cell frequencies in active CC mucosa. No alterations were found in peripheral blood samples, independently of patient treatment or gating techniques. CONCLUSION Previously reported increase of Treg cells is a result of incomplete Treg phenotyping, which included nonsuppressive FoxP3dimCD45RA- T helper cells. Because budesonide did not affect Treg percentage, its therapeutic effect in CC might involve alternative mechanisms.
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Affiliation(s)
- Niki Daferera
- Division of Gastroenterology and Hepatology, Department of Biomedical and Clinical Sciences (BKV), Faculty of Health Science, Linköping University, Linköping, Sweden
| | - Celia Escudero-Hernández
- Institute of Clinical Molecular Biology, Christian-Albrecht's-University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Sofia Nyström
- Department of Biomedical and Clinical Sciences (BKV), Linköping University, Linköping, Sweden
| | - Maria C Jenmalm
- Department of Biomedical and Clinical Sciences (BKV), Linköping University, Linköping, Sweden
| | - Henrik Hjortswang
- Division of Gastroenterology and Hepatology, Department of Biomedical and Clinical Sciences (BKV), Faculty of Health Science, Linköping University, Linköping, Sweden
| | - Simone Ignatova
- Department of Pathology, Linköping University, Linköping, Sweden
| | - Magnus Ström
- Division of Gastroenterology and Hepatology, Department of Biomedical and Clinical Sciences (BKV), Faculty of Health Science, Linköping University, Linköping, Sweden
| | - Andreas Münch
- Division of Gastroenterology and Hepatology, Department of Biomedical and Clinical Sciences (BKV), Faculty of Health Science, Linköping University, Linköping, Sweden
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29
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Jacobse J, Li J, Rings EHHM, Samsom JN, Goettel JA. Intestinal Regulatory T Cells as Specialized Tissue-Restricted Immune Cells in Intestinal Immune Homeostasis and Disease. Front Immunol 2021; 12:716499. [PMID: 34421921 PMCID: PMC8371910 DOI: 10.3389/fimmu.2021.716499] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/16/2021] [Indexed: 12/28/2022] Open
Abstract
FOXP3+ regulatory T cells (Treg cells) are a specialized population of CD4+ T cells that restrict immune activation and are essential to prevent systemic autoimmunity. In the intestine, the major function of Treg cells is to regulate inflammation as shown by a wide array of mechanistic studies in mice. While Treg cells originating from the thymus can home to the intestine, the majority of Treg cells residing in the intestine are induced from FOXP3neg conventional CD4+ T cells to elicit tolerogenic responses to microbiota and food antigens. This process largely takes place in the gut draining lymph nodes via interaction with antigen-presenting cells that convert circulating naïve T cells into Treg cells. Notably, dysregulation of Treg cells leads to a number of chronic inflammatory disorders, including inflammatory bowel disease. Thus, understanding intestinal Treg cell biology in settings of inflammation and homeostasis has the potential to improve therapeutic options for patients with inflammatory bowel disease. Here, the induction, maintenance, trafficking, and function of intestinal Treg cells is reviewed in the context of intestinal inflammation and inflammatory bowel disease. In this review we propose intestinal Treg cells do not compose fixed Treg cell subsets, but rather (like T helper cells), are plastic and can adopt different programs depending on microenvironmental cues.
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Affiliation(s)
- Justin Jacobse
- Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Jing Li
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
| | - Edmond H. H. M. Rings
- Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands
- Department of Pediatrics, Sophia Children’s Hospital, Erasmus University, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Janneke N. Samsom
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Jeremy A. Goettel
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States
- Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, United States
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, United States
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30
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Negi S, Saini S, Tandel N, Sahu K, Mishra RP, Tyagi RK. Translating Treg Therapy for Inflammatory Bowel Disease in Humanized Mice. Cells 2021; 10:1847. [PMID: 34440615 PMCID: PMC8393385 DOI: 10.3390/cells10081847] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 02/07/2023] Open
Abstract
Crohn's disease and ulcerative colitis, two major forms of inflammatory bowel disease (IBD) in humans, afflicted in genetically predisposed individuals due to dysregulated immune response directed against constituents of gut flora. The defective immune responses mounted against the regulatory mechanisms amplify and maintain the IBD-induced mucosal inflammation. Therefore, restoring the balance between inflammatory and anti-inflammatory immunepathways in the gut may contribute to halting the IBD-associated tissue-damaging immune response. Phenotypic and functional characterization of various immune-suppressive T cells (regulatory T cells; Tregs) over the last decade has been used to optimize the procedures for in vitro expansion of these cells for developing therapeutic interventional strategies. In this paper, we review the mechanisms of action and functional importance of Tregs during the pathogenesis of IBD and modulating the disease induced inflammation as well as role of mouse models including humanized mice repopulated with the human immune system (HIS) to study the IBD. "Humanized" mouse models provide new tools to analyze human Treg ontogeny, immunobiology, and therapy and the role of Tregs in developing interventional strategies against IBD. Overall, humanized mouse models replicate the human conditions and prove a viable tool to study molecular functions of human Tregs to harness their therapeutic potential.
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MESH Headings
- Adoptive Transfer
- Animals
- Colitis, Ulcerative/genetics
- Colitis, Ulcerative/immunology
- Colitis, Ulcerative/metabolism
- Colitis, Ulcerative/therapy
- Crohn Disease/genetics
- Crohn Disease/immunology
- Crohn Disease/metabolism
- Crohn Disease/therapy
- Disease Models, Animal
- Hematopoietic Stem Cell Transplantation
- Humans
- Mice, Transgenic
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/transplantation
- Transplantation, Heterologous
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Affiliation(s)
- Sushmita Negi
- Biomedical Parasitology and Nano-Immunology Lab, Division of Cell Biology and Immunology, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh 160036, India; (S.N.); (S.S.); (K.S.)
- BERPDC Department, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh 160036, India
| | - Sheetal Saini
- Biomedical Parasitology and Nano-Immunology Lab, Division of Cell Biology and Immunology, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh 160036, India; (S.N.); (S.S.); (K.S.)
| | - Nikunj Tandel
- Institute of Science, Nirma University, Ahmedabad, Gujarat 382481, India;
| | - Kiran Sahu
- Biomedical Parasitology and Nano-Immunology Lab, Division of Cell Biology and Immunology, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh 160036, India; (S.N.); (S.S.); (K.S.)
| | - Ravi P.N. Mishra
- BERPDC Department, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh 160036, India
| | - Rajeev K. Tyagi
- Biomedical Parasitology and Nano-Immunology Lab, Division of Cell Biology and Immunology, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh 160036, India; (S.N.); (S.S.); (K.S.)
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31
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Fernandez-Perez R, Lopez-Santalla M, Sánchez-Domínguez R, Alberquilla O, Gutiérrez-Cañas I, Juarranz Y, Bueren JA, Garin MI. Enhanced Susceptibility of Galectin-1 Deficient Mice to Experimental Colitis. Front Immunol 2021; 12:687443. [PMID: 34262567 PMCID: PMC8273429 DOI: 10.3389/fimmu.2021.687443] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/07/2021] [Indexed: 12/17/2022] Open
Abstract
Galectin-1 is a β-galactoside-binding lectin, ubiquitously expressed in stromal, epithelial, and different subsets of immune cells. Galectin-1 is the prototype member of the galectin family which shares specificity with β-galactoside containing proteins and lipids. Immunomodulatory functions have been ascribed to endogenous galectin-1 due to its induction of T cell apoptosis, inhibitory effects of neutrophils and T cell trafficking. Several studies have demonstrated that administration of recombinant galectin-1 suppressed experimental colitis by modulating adaptive immune responses altering the fate and phenotype of T cells. However, the role of endogenous galectin-1 in intestinal inflammation is poorly defined. In the present study, the well-characterized acute dextran sulfate sodium (DSS)-induced model of ulcerative colitis was used to study the function of endogenous galectin-1 during the development of intestinal inflammation. We found that galectin-1 deficient mice (Lgals1-/- mice) displayed a more severe intestinal inflammation, characterized by significantly elevated clinical scores, than their wild type counterparts. The mechanisms underlying the enhanced inflammatory response in colitic Lgals1-/- mice involved an altered Th17/Th1 profile of effector CD4+ T cells. Furthermore, increased frequencies of Foxp3+CD4+ regulatory T cells in colon lamina propria in Lgals1-/- mice were found. Strikingly, the exacerbated intestinal inflammatory response observed in Lgals1-/- mice was alleviated by adoptive transfer of wild type Foxp3+CD4+ regulatory T cells at induction of colitis. Altogether, these data highlight the importance of endogenous galectin-1 as a novel determinant in regulating T cell reactivity during the development of intestinal inflammation.
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MESH Headings
- Adoptive Transfer
- Animals
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- CD4-Positive T-Lymphocytes/transplantation
- Colitis, Ulcerative/chemically induced
- Colitis, Ulcerative/immunology
- Colitis, Ulcerative/metabolism
- Colitis, Ulcerative/pathology
- Colon/immunology
- Colon/metabolism
- Colon/pathology
- Dextran Sulfate
- Disease Models, Animal
- Galectin 1/deficiency
- Galectin 1/genetics
- Mice, Inbred C57BL
- Mice, Knockout
- Phenotype
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/transplantation
- Th1 Cells/immunology
- Th1 Cells/metabolism
- Th17 Cells/immunology
- Th17 Cells/metabolism
- Mice
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Affiliation(s)
- Raquel Fernandez-Perez
- Division of Hematopoietic Innovative Therapies, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Madrid, Spain
- Advanced Therapy Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD/UAM), Madrid, Spain
| | - Mercedes Lopez-Santalla
- Division of Hematopoietic Innovative Therapies, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Madrid, Spain
- Advanced Therapy Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD/UAM), Madrid, Spain
| | - Rebeca Sánchez-Domínguez
- Division of Hematopoietic Innovative Therapies, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Madrid, Spain
- Advanced Therapy Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD/UAM), Madrid, Spain
| | - Omaira Alberquilla
- Division of Hematopoietic Innovative Therapies, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Madrid, Spain
- Advanced Therapy Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD/UAM), Madrid, Spain
| | - Irene Gutiérrez-Cañas
- Departamento de Biología Celular, Facultad de Biología y Medicina, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Universidad Complutense de Madrid, Madrid, Spain
| | - Yasmina Juarranz
- Departamento de Biología Celular, Facultad de Biología y Medicina, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Universidad Complutense de Madrid, Madrid, Spain
| | - Juan A. Bueren
- Division of Hematopoietic Innovative Therapies, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Madrid, Spain
- Advanced Therapy Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD/UAM), Madrid, Spain
| | - Marina I. Garin
- Division of Hematopoietic Innovative Therapies, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER), Madrid, Spain
- Advanced Therapy Unit, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD/UAM), Madrid, Spain
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Abstract
Mucosal surfaces are distinctive sites exposed to environmental, dietary, and microbial antigens. Particularly in the gut, the host continuously actively adapts via complex interactions between the microbiota and dietary compounds and immune and other tissue cells. Regulatory T cells (Tregs) are critical for tuning the intestinal immune response to self- and non-self-antigens in the intestine. Its importance in intestinal homeostasis is illustrated by the onset of overt inflammation caused by deficiency in Treg generation, function, or stability in the gut. A substantial imbalance in Tregs has been observed in intestinal tissue during pathogenic conditions, when a tightly regulated and equilibrated system becomes dysregulated and leads to unimpeded and chronic immune responses. In this chapter, we compile and critically discuss the current knowledge on the key factors that promote Treg-mediated tolerance in the gut, such as those involved in intestinal Treg differentiation, specificity and suppressive function, and their immunophenotype during health and disease. We also discuss the current state of knowledge on Treg dysregulation in human intestine during pathological states such as inflammatory bowel disease (IBD), necrotizing enterocolitis (NEC), graft-versus-host disease (GVHD), and colorectal cancer (CRC), and how that knowledge is guiding development of Treg-targeted therapies to treat or prevent intestinal disorders.
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Sznurkowska K, Luty J, Bryl E, Witkowski JM, Hermann-Okoniewska B, Landowski P, Kosek M, Szlagatys-Sidorkiewicz A. Enhancement of Circulating and Intestinal T Regulatory Cells and Their Expression of Helios and Neuropilin-1 in Children with Inflammatory Bowel Disease. J Inflamm Res 2020; 13:995-1005. [PMID: 33273840 PMCID: PMC7705274 DOI: 10.2147/jir.s268484] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 10/20/2020] [Indexed: 12/17/2022] Open
Abstract
Background/Aims The proportions of intestinal and peripheral regulatory T cells (Tregs) in pediatric inflammatory bowel disease (IBD) were poorly investigated, as well as different subsets of these cells. Helios and Neuropilin-1 were proposed as markers differentiating between thymic and peripheral Tregs. Therefore, the aim of current work was to investigate the proportions of Tregs and expression of Helios and Neuropilin-1 in Tregs in peripheral blood and intestinal mucosa of children with inflammatory bowel disease. Materials and methods Fifteen patients newly diagnosed with inflammatory bowel disease: ulcerative colitis (n=7) and Crohn's disease (n=8) were included in the study. Nine children who presented with no abnormalities in colonoscopy served as a control group. Quantification of regulatory T cells of the CD4+CD25highFOXP3+ phenotype, as well as Helios+ and Neuropilin-1+ in peripheral blood and bowel mucosa was based on multicolor flow cytometry. Results The rates of circulating and intestinal Tregs were significantly higher in the studied group than in the control group. The rate of intestinal T regulatory lymphocytes was significantly higher than circulating Tregs in patients with IBD, but not in the control group. The median proportion of circulating FOXP3+Helios+ cells amounted to 24.83% in IBD patients and 15.93% in the controls. The median proportion of circulating FOXP3+Nrp-1+ cells was 34.23% in IBD and 21.01% in the control group. No statistically significant differences were noted for the circulating FOXP3+Helios+ cells and FOXP3+Nrp-1+ cells between the studied and the control group. Conclusion The rates of circulating and intestinal T regulatory cells are increased in naïve pediatric patients with IBD. The rate of Tregs is higher in intestinal mucosa than in peripheral blood in patients with IBD. Flow cytometry is a valuable method assessing the composition of infiltrates in inflamed tissue. Helios and Neuropilin-1 likely cannot serve as markers to differentiate between natural and adaptive Tregs.
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Affiliation(s)
- Katarzyna Sznurkowska
- Department of Pediatrics, Pediatric Gastroenterology, Allergology and Nutrition, Medical University of Gdańsk, Gdańsk, Poland
| | - Justyna Luty
- Department of Pathology and Experimental Rheumatology, Medical University of Gdańsk, Gdańsk, Poland
| | - Ewa Bryl
- Department of Pathology and Experimental Rheumatology, Medical University of Gdańsk, Gdańsk, Poland
| | - Jacek M Witkowski
- Department of Pathophysiology, Medical University of Gdańsk, Gdańsk, Poland
| | | | - Piotr Landowski
- Department of Pediatrics, Pediatric Gastroenterology, Allergology and Nutrition, Medical University of Gdańsk, Gdańsk, Poland
| | - Marta Kosek
- Department of Pediatrics, Pediatric Gastroenterology, Allergology and Nutrition, Medical University of Gdańsk, Gdańsk, Poland
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Libera J, Wittner M, Kantowski M, Woost R, Eberhard JM, de Heer J, Reher D, Huber S, Haag F, Schulze Zur Wiesch J. Decreased Frequency of Intestinal CD39 + γδ + T Cells With Tissue-Resident Memory Phenotype in Inflammatory Bowel Disease. Front Immunol 2020; 11:567472. [PMID: 33072107 PMCID: PMC7541837 DOI: 10.3389/fimmu.2020.567472] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 08/13/2020] [Indexed: 12/22/2022] Open
Abstract
The ectoenzymes CD39 and CD73 play a major role in controlling tissue inflammation by regulating the balance between adenosine triphosphate (ATP) and adenosine. Still, little is known about the role of these two enzymes and ATP and its metabolites in the pathophysiology of inflammatory bowel disease (IBD). We isolated mononuclear cells from peripheral blood and lamina propria of the large intestine of patients diagnosed with IBD and of healthy volunteers. We then comprehensively analyzed the CD39 and CD73 expression patterns together with markers of activation (HLA-DR, CD38), differentiation (CCR7, CD45RA) and tissue-residency (CD69, CD103, CD49a) on CD4+, CD8+, γδ+ T cells and mucosa-associated invariant T cells using flow cytometry. CD39 expression levels of γδ+ and CD8+ T cells in lamina propria lymphocytes (LPL) were much higher compared to peripheral blood mononuclear cells. Moreover, the frequency of CD39+ CD4+ and CD8+, but not γδ+ LPL positively correlated with T-cell activation. The frequency of CD39+ cells among tissue-resident memory LPL (Trm) was higher compared to non-Trm for all subsets, confirming that CD39 is a marker for the tissue-resident memory phenotype. γδ+ Trm also showed a distinct cytokine profile upon stimulation – the frequency of IFN-γ+ and IL-17A+ cells was significantly lower in γδ+ Trm compared to non-Trm. Interestingly, we observed a decreased frequency of CD39+ γδ+ T cells in IBD patients compared to healthy controls (p = 0.0049). Prospective studies need to elucidate the exact role of this novel CD39+ γδ+ T-cell population with tissue-resident memory phenotype and its possible contribution to the pathogenesis of IBD and other inflammatory disorders.
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Affiliation(s)
- Jana Libera
- I. Department of Medicine, Infectious Disease Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Melanie Wittner
- I. Department of Medicine, Infectious Disease Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg Lübeck Borstel Riems, Hamburg, Germany
| | - Marcus Kantowski
- Clinic and Polyclinic for Interdisciplinary Endoscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Robin Woost
- I. Department of Medicine, Infectious Disease Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg Lübeck Borstel Riems, Hamburg, Germany
| | - Johanna M Eberhard
- I. Department of Medicine, Infectious Disease Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg Lübeck Borstel Riems, Hamburg, Germany
| | - Jocelyn de Heer
- Clinic and Polyclinic for Interdisciplinary Endoscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Dominik Reher
- I. Department of Medicine, Infectious Disease Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Samuel Huber
- I. Department of Medicine, Infectious Disease Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Friedrich Haag
- Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Julian Schulze Zur Wiesch
- I. Department of Medicine, Infectious Disease Unit, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,German Center for Infection Research (DZIF), Partner Site Hamburg Lübeck Borstel Riems, Hamburg, Germany
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Fantini MC, Favale A, Onali S, Facciotti F. Tumor Infiltrating Regulatory T Cells in Sporadic and Colitis-Associated Colorectal Cancer: The Red Little Riding Hood and the Wolf. Int J Mol Sci 2020; 21:E6744. [PMID: 32937953 PMCID: PMC7555219 DOI: 10.3390/ijms21186744] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 09/11/2020] [Accepted: 09/11/2020] [Indexed: 02/07/2023] Open
Abstract
Regulatory T cells represent a class of specialized T lymphocytes that suppress unwanted immune responses and size the activation of the immune system whereby limiting collateral damages in tissues involved by inflammation. In cancer, the accumulation of Tregs is generally associated with poor prognosis. Many lines of evidence indicate that Tregs accumulation in the tumor microenvironment (TME) suppresses the immune response against tumor-associated antigens (TAA), thus promoting tumor progression in non-small cell lung carcinoma (NSLC), breast carcinoma and melanoma. In colorectal cancer (CRC) the effect of Tregs accumulation is debated. Some reports describe the association of high number of Tregs in CRC stroma with a better prognosis while others failed to find any association. These discordant results stem from the heterogeneity of the immune environment generated in CRC in which anticancer immune response may coexists with tumor promoting inflammation. Moreover, different subsets of Tregs have been identified that may exert different effects on cancer progression depending on tumor stage and their location within the tumor mass. Finally, Tregs phenotypic plasticity may be induced by cytokines released in the TME by dysplastic and other tumor-infiltrating cells thus affecting their functional role in the tumor. Here, we reviewed the recent literature about the role of Tregs in CRC and in colitis-associated colorectal cancer (CAC), where inflammation is the main driver of tumor initiation and progression. We tried to explain when and how Tregs can be considered to be the "good" or the "bad" in the colon carcinogenesis process on the basis of the available data concluding that the final effect of Tregs on sporadic CRC and CAC depends on their localization within the tumor, the subtype of Tregs involved and their phenotypic plasticity.
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Affiliation(s)
- Massimo Claudio Fantini
- Department of Medical Science and Public Health, University of Cagliari, 09042 Cagliari, Italy;
| | - Agnese Favale
- Department of Medical Science and Public Health, University of Cagliari, 09042 Cagliari, Italy;
| | - Sara Onali
- CEMAD-IBD UNIT-Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy;
| | - Federica Facciotti
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, 20139 Milan, Italy;
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Mitsialis V, Wall S, Liu P, Ordovas-Montanes J, Parmet T, Vukovic M, Spencer D, Field M, McCourt C, Toothaker J, Bousvaros A, BCH IBD Center, BWH Crohn’s and Colitis Center, Shalek AK, Kean L, Horwitz B, Goldsmith J, Tseng G, Snapper SB, Konnikova L. Single-Cell Analyses of Colon and Blood Reveal Distinct Immune Cell Signatures of Ulcerative Colitis and Crohn's Disease. Gastroenterology 2020; 159:591-608.e10. [PMID: 32428507 PMCID: PMC8166295 DOI: 10.1053/j.gastro.2020.04.074] [Citation(s) in RCA: 227] [Impact Index Per Article: 45.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 04/07/2020] [Accepted: 04/24/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Studies are needed to determine the mechanisms of mucosal dysregulation in patients with inflammatory bowel diseases (IBDs) and differences in inflammatory responses of patients with ulcerative colitis (UC) vs Crohn's disease (CD). We used mass cytometry (CyTOF) to characterize and compare immune cell populations in the mucosa and blood from patients with IBD and without IBD (controls) at single-cell resolution. METHODS We performed CyTOF analysis of colonic mucosa samples (n = 87) and peripheral blood mononuclear cells (n = 85) from patients with active or inactive UC or CD and controls. We also performed single-cell RNA sequencing, flow cytometry, and RNA in situ hybridization analyses to validate key findings. We used random forest modeling to identify differences in signatures across subject groups. RESULTS Compared with controls, colonic mucosa samples from patients with IBD had increased abundances of HLA-DR+CD38+ T cells, including T-regulatory cells that produce inflammatory cytokines; CXCR3+ plasmablasts; and IL1B+ macrophages and monocytes. Colonic mucosa samples from patients with UC were characterized by expansion of IL17A+ CD161+ effector memory T cells and IL17A+ T-regulatory cells; expansion of HLA-DR+CD56+ granulocytes; and reductions in type 3 innate lymphoid cells. Mucosal samples from patients with active CD were characterized by IL1B+HLA-DR+CD38+ T cells, IL1B+TNF+IFNG+ naïve B cells, IL1B+ dendritic cells (DCs), and IL1B+ plasmacytoid DCs. Peripheral blood mononuclear cells from patients with active CD differed from those of active UC in that the peripheral blood mononuclear cells from patients with CD had increased IL1B+ T-regulatory cells, IL1B+ DCs and IL1B+ plasmacytoid DCs, IL1B+ monocytes, and fewer group 1 innate lymphoid cells. Random forest modeling differentiated active UC from active CD in colonic mucosa and blood samples; top discriminating features included many of the cellular populations identified above. CONCLUSIONS We used single-cell technologies to identify immune cell populations specific to mucosa and blood samples from patients with active or inactive CD and UC and controls. This information might be used to develop therapies that target specific cell populations in patients with different types of IBD.
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Affiliation(s)
- Vanessa Mitsialis
- Division of Gastroenterology, Brigham and Women’s Hospital, Boston, MA 02115, USA,Division of Gastroenterology, Hepatology and Nutrition, Boston, MA 02115, USA
| | - Sarah Wall
- Division of Gastroenterology, Hepatology and Nutrition, Boston, MA 02115, USA
| | - Peng Liu
- Department of Biostatistics University of Pittsburgh, Pittsburgh, PA 15224, USA
| | - Jose Ordovas-Montanes
- Division of Gastroenterology, Hepatology and Nutrition, Boston, MA 02115, USA,Broad Institute of MIT and Harvard, Cambridge, MA, USA 02139 USA,Harvard Stem Cell Institute, Cambridge, MA, USA 02138 USA
| | - Tamar Parmet
- Division of Gastroenterology, Hepatology and Nutrition, Boston, MA 02115, USA
| | - Marko Vukovic
- Institute for Medical Engineering and Science (IMES), MIT, Cambridge, MA, 02139 USA,Broad Institute of MIT and Harvard, Cambridge, MA, USA 02139 USA,Harvard Stem Cell Institute, Cambridge, MA, USA 02138 USA,Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, 02139 USA,Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139 USA
| | - Dennis Spencer
- Division of Gastroenterology, Hepatology and Nutrition, Boston, MA 02115, USA
| | - Michael Field
- Division of Gastroenterology, Hepatology and Nutrition, Boston, MA 02115, USA
| | - Collin McCourt
- Broad Institute of MIT and Harvard, Cambridge, MA, USA 02139 USA
| | | | - Athos Bousvaros
- Division of Gastroenterology, Hepatology and Nutrition, Boston, MA 02115, USA
| | - BCH IBD Center
- BCH IBD Center: Sonia Ballal, MD, Silvana Bonilla, MD, MS, Rima Fawaz, MD, Laurie N. Fishman, MD, Alejandro Flores, MD, Victor Fox, MD, Amit S. Grover, MB, BCh BAO, Leslie Higuchi, MD, Susanna Huh, MD, Stacy Kahn, MD, Christine Lee, MD, Munir Mobassaleh, MD, Jodie Ouahed, MD, Randi G. Pleskow, MD, Brian Regan, DO, Paul A. Rufo, MD, MMSc, Sabina Sabharwal, MD, Jared Silverstein, MD, Menno Verhave, MD, Anne Wolf, MD, Lori Zimmerman, MD, Naamah Zitomersky, MD
| | - BWH Crohn’s and Colitis Center
- BWH Crohn’s and Colitis Center: Jessica R. Allegretti, MD, MPH, Punyanganie De Silva, MD, MPH, Sonia Friedman, MD, Matthew Hamilton, MD, Joshua Korzenik, MD, Frederick Makrauer, MD, Beth-Ann Norton, MS, RN, ANP-BC, Rachel W. Winter, MD, MPH
| | - Alex K. Shalek
- Institute for Medical Engineering and Science (IMES), MIT, Cambridge, MA, 02139 USA,Broad Institute of MIT and Harvard, Cambridge, MA, USA 02139 USA,Harvard Stem Cell Institute, Cambridge, MA, USA 02138 USA,Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, 02139 USA,Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, 02139 USA
| | - Leslie Kean
- Division of Hematology Oncology Boston Children’s Hospital, Boston, MA 02115, USA
| | - Bruce Horwitz
- Division of Gastroenterology, Hepatology and Nutrition, Boston, MA 02115, USA
| | | | - George Tseng
- Department of Biostatistics University of Pittsburgh, Pittsburgh, PA 15224, USA
| | - Scott B. Snapper
- Division of Gastroenterology, Brigham and Women’s Hospital, Boston, MA 02115, USA,Division of Gastroenterology, Hepatology and Nutrition, Boston, MA 02115, USA
| | - Liza Konnikova
- Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts; Department of Pediatrics, University of Pittsburgh Medical Center Children's Hospital, Pittsburgh, Pennsylvania; Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Developmental Biology University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.
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Tryptophan Metabolism, Regulatory T Cells, and Inflammatory Bowel Disease: A Mini Review. Mediators Inflamm 2020; 2020:9706140. [PMID: 32617076 PMCID: PMC7306093 DOI: 10.1155/2020/9706140] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 05/26/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract resulting from the homeostasis imbalance of intestinal microenvironment, immune dysfunction, environmental and genetic factors, and so on. This disease is associated with multiple immune cells including regulatory T cells (Tregs). Tregs are a subset of T cells regulating the function of various immune cells to induce immune tolerance and maintain intestinal immune homeostasis. Tregs are correlated with the initiation and progression of IBD; therefore, strategies that affect the differentiation and function of Tregs may be promising for the prevention of IBD-associated pathology. It is worth noting that tryptophan (Trp) metabolism is effective in inducing the differentiation of Tregs through microbiota-mediated degradation and kynurenine pathway (KP), which is important for maintaining the function of Tregs. Interestingly, patients with IBD show Trp metabolism disorder in the pathological process, including changes in the concentrations of Trp and its metabolites and alteration in the activities of related catalytic enzymes. Thus, manipulation of Treg differentiation through Trp metabolism may provide a potential target for prevention of IBD. The purpose of this review is to highlight the relationship between Trp metabolism and Treg differentiation and the role of this interaction in the pathogenesis of IBD.
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Cho I, Lui PP, Ali N. Treg regulation of the epithelial stem cell lineage. JOURNAL OF IMMUNOLOGY AND REGENERATIVE MEDICINE 2020; 8:100028. [PMID: 32494759 PMCID: PMC7226844 DOI: 10.1016/j.regen.2020.100028] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 01/09/2020] [Accepted: 01/13/2020] [Indexed: 12/22/2022]
Abstract
Tissue repair and maintenance in adult organisms is dependent on the interactions between stem cells (SCs) and constituent cells of their microenvironment, or niche. Accumulating evidence suggests that immune cells, specifically Foxp3+ CD4+ Regulatory T cells (Tregs), play an important role as a regulator of the SC niche. Undisputedly, Tregs are the major immunosuppressive lineage of the CD4+ T cell compartment, and reside within numerous secondary lymphoid organs, where they exert their functions. These cells are also specialised in facilitating protective functions specific to their tissue of residence. In this review, we discuss the emerging concepts supporting the SC-regulatory functions of tissue-resident Tregs, during both the steady-state and SC-mediated regeneration. We highlight the skin, intestines, and lung as model organs which are subject to recurrent microinjury,exposure to microbiota, and constantly replenished by resident stem cell populations. An in-depth understanding of the biology of the Treg-SC axis will inform ongoing immunotherapeutic endeavours to target specific subpopulations of tissue-resident Tregs.
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Affiliation(s)
- Inchul Cho
- Centre for Stem Cells and Regenerative Medicine, School of Basic and Biomedical Sciences, King's College London, London, UK
| | - Prudence Pokwai Lui
- Centre for Stem Cells and Regenerative Medicine, School of Basic and Biomedical Sciences, King's College London, London, UK
| | - Niwa Ali
- Centre for Stem Cells and Regenerative Medicine, School of Basic and Biomedical Sciences, King's College London, London, UK
- The Francis Crick Institute, London, UK
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39
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Increased frequency of regulatory T cells in pediatric inflammatory bowel disease at diagnosis: a compensative role? Pediatr Res 2020; 87:853-861. [PMID: 31715619 DOI: 10.1038/s41390-019-0662-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 07/26/2019] [Accepted: 09/09/2019] [Indexed: 12/26/2022]
Abstract
BACKGROUND Regulatory T cells (Tregs) play a critical role in maintaining immune homeostasis. We investigated two main types of Tregs, the CD4+FOXP3+ and IL-10+ Tr1, in pediatric subjects with inflammatory bowel disease (IBD) both at diagnosis and after the clinical remission. METHODS Peripheral blood Tregs were analyzed in 16 children with Crohn's disease (CD), 19 with ulcerative colitis (UC), and 14 healthy controls (HC). Two cocktails of fluoresceinated antibodies were used to discriminate between CD4+FOXP3+ and Tr1. RESULTS We observed in both CD and UC groups a higher frequency of Tr1 at diagnosis compared to controls, which decreased at follow-up compared to diagnosis, in particular in UC. Similarly, in UC patients the percentage of CD4+FOXP3+ Tregs markedly decreased at follow-up compared to the same patients at diagnosis and compared to HC. The expression of CTLA-4 in CD4+FOXP3+ Tregs increased in both groups at clinical remission. CONCLUSION This study shows that IBD children present at diagnosis an increased frequency of circulating Tregs, probably as a compensative reaction to tissue inflammation. During the clinical remission, the Treg frequency diminishes, and concomitantly, their activation status increases. Notwithstanding, the high Treg density at diagnosis is not sufficient to counteract the inflammation in the childhood IBD.
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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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Iacomino G, Rotondi Aufiero V, Iannaccone N, Melina R, Giardullo N, De Chiara G, Venezia A, Taccone FS, Iaquinto G, Mazzarella G. IBD: Role of intestinal compartments in the mucosal immune response. Immunobiology 2020; 225:151849. [PMID: 31563276 DOI: 10.1016/j.imbio.2019.09.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 08/30/2019] [Accepted: 09/03/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Laser capture microdissection (LCM) is a powerful tool for the isolation of specific tissue compartments. We aimed to investigate the mucosal immune response that takes place in different intestinal compartments of IBD patients, dissected by LCM, analyzing cytokines expression profile and endoplasmic reticulum (ER) stress markers. METHODS Frozen sections of gut were obtained from patients with Crohn's disease (CD), ulcerative colitis (UC) and from controls. Using LCM, surface epithelium (SE) and lamina propria (LP) compartments were isolated and total RNA extracted. The relative expression of Th1, Th17 and Treg cytokines was evaluated by quantitative reverse transcriptase real-time PCR (qRT-PCR), in addition to the assessment of mRNA splicing of the transcription factor X-box binding protein-1 (XBP1). Human neutrophil elastase (HNE) and the transcription factor forkhead box P3 (Foxp3) were also analyzed by immunohistochemistry. RESULTS The increased expression of IL-17 was observed in both intestinal compartments of IBD patients when compared to controls. IFN- γ, TNF-α , IL-10, HNE and Foxp3 were overexpressed in the LP compartment of both IBD patients as compared to controls. An upregulation of IFN-γ and an infiltration of HNE+ cells was found in the SE of patients with UC. Splicing of XBP1 mRNA was recognized in both intestinal compartments of IBD patients when compared to controls. CONCLUSIONS In IBD patients, both intestinal compartments are involved in Th17 response, whereas, LP compartment plays a prominent role in Th1 and Treg immune responses. Nevertheless, high level of IFN- γ was found in the SE of UC patients, suggesting that this compartment is involved in the Th1 immune response. Our data also suggested that ER stress signalling is active in both LP and SE compartment of IBD patients, thus advocating that ER stress and immunity are intertwined.
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Affiliation(s)
| | | | | | - Raffaele Melina
- Department of Gastroenterology, San G. Moscati Hospital, Avellino, Italy
| | - Nicola Giardullo
- Department of Gastroenterology, San G. Moscati Hospital, Avellino, Italy
| | - Giovanni De Chiara
- Department of AnatomicPathology, San G. Moscati Hospital, Avellino, Italy
| | | | - Fabio Silvio Taccone
- Department of Intensive Care, Erasme Hospital, Universit e Libre de Bruxelles, Brussels, Belgium
| | - Gaetano Iaquinto
- Division of Gastroenterology, Santa Rita Hospital, Atripalda, Av, Italy
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42
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Zhou W, Deng J, Chen Q, Li R, Xu X, Guan Y, Li W, Xiong X, Li H, Li J, Cai X. Expression of CD4+CD25+CD127 Low regulatory T cells and cytokines in peripheral blood of patients with primary liver carcinoma. Int J Med Sci 2020; 17:712-719. [PMID: 32218692 PMCID: PMC7085268 DOI: 10.7150/ijms.44088] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 02/16/2020] [Indexed: 12/26/2022] Open
Abstract
Objective: To assess the clinical utility of the ratio of CD4+CD25+CD127low regulatory T cells (Tregs) in subjects at high risk of HCC, investigate the relationship between the percentage of Tregs and the expression of transforming growth factor (TGF)-β1 and interleukin (IL)-10 in patients with hepatocellular carcinoma before and after treatment. Methods: Peripheral venous blood was collected from patients with liver cancer before and after treatment. The proportion of CD4+CD25+CD127low Tregs was detected by flow cytometry. The levels of TGF-β1 and IL-10 in serum were detected by enzyme-linked immunosorbent assay, and were compared with healthy subjects as a control group. Results: The proportion of CD4+CD25+CD127low to CD4+T lymphocytes in patients with hepatocellular carcinoma was significantly higher than that in healthy controls (P<0.01). The proportion of CD4+CD25+CD127lowTregs, whose AUC of ROC curve was 0.917, could effectively separate the HCC patients from the healthy subjects with a diagnostic sensitivity of 90%, specificity of 80%. The proportion of CD4+CD25+CD127low to CD4+T lymphocytes and the levels of TGF-β1 and IL-10 in patients with hepatocellular carcinoma after the operation and chemotherapy were significantly lower than those before treatment (P<0.05).The proportion of CD4+CD25+CD127lowTregs was positively correlated with the concentrations of TGF-β1 and IL-10 before and after treatment of primary liver cancer (P<0.05). Conclusion: CD4+CD25+CD127lowTregs may be a significant predictor of HCC biopsy outcome and play an inhibitory role on effector T cells by regulating cytokines.
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Affiliation(s)
- Wenchao Zhou
- Clinical laboratory, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - Jianxin Deng
- Department of Endocrinology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center of Shenzhen University, Shenzhen 518035, People's Republic of China
| | - Qianmei Chen
- Clinical laboratory, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - Ruiying Li
- Clinical laboratory, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - Xiaosong Xu
- Clinical laboratory, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - Yubin Guan
- Clinical laboratory, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
| | - Wei Li
- Clinical laboratory, Guangzhou Military Area Inspection Center, the General Hospital of Guangzhou Military Region, Guangzhou 510010, China
| | - Xiaomin Xiong
- Clinical laboratory, the Hospital of Dongguan Renkang, Dongguan 523952, China
| | - Hongwei Li
- Institute of Biotherapy, Southern Medical University Guangzhou 510515, China
| | - Jianpei Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Department of Clinical Laboratory Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
- ✉ Corresponding authors: Jianpei Li, or Xiangsheng Cai,
| | - Xiangsheng Cai
- Clinical laboratory, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China
- ✉ Corresponding authors: Jianpei Li, or Xiangsheng Cai,
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Di Giovangiulio M, Rizzo A, Franzè E, Caprioli F, Facciotti F, Onali S, Favale A, Stolfi C, Fehling HJ, Monteleone G, Fantini MC. Tbet Expression in Regulatory T Cells Is Required to Initiate Th1-Mediated Colitis. Front Immunol 2019; 10:2158. [PMID: 31572375 PMCID: PMC6749075 DOI: 10.3389/fimmu.2019.02158] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 08/28/2019] [Indexed: 12/22/2022] Open
Abstract
In normal conditions gut homeostasis is maintained by the suppressive activity of regulatory T cells (Tregs), characterized by the expression of the transcription factor FoxP3. In human inflammatory bowel disease, which is believed to be the consequence of the loss of tolerance toward antigens normally contained in the gut lumen, Tregs have been found to be increased and functionally active, thus pointing against their possible role in the pathogenesis of this immune-mediated disease. Though, in inflammatory conditions, Tregs have been shown to upregulate the T helper (Th) type 1-related transcription factor Tbet and to express the pro-inflammatory cytokine IFNγ, thus suggesting that at a certain point of the inflammatory process, Tregs might contribute to inflammation rather than suppress it. Starting from the observation that Tregs isolated from the lamina propria of active but not inactive IBD patients or uninflamed controls express Tbet and IFNγ, we investigated the functional role of Th1-like Tregs in the dextran sulfate model of colitis. As observed in human IBD, Th1-like Tregs were upregulated in the inflamed lamina propria of treated mice and the expression of Tbet and IFNγ in Tregs preceded the accumulation of conventional Th1 cells. By using a Treg-specific Tbet conditional knockout, we demonstrated that Tbet expression in Tregs is required for the development of colitis. Indeed, Tbet knockout mice developed milder colitis and showed an impaired Th1 immune response. In these mice not only the Tbet deficient Tregs but also the Tbet proficient conventional T cells showed reduced IFNγ expression. However, Tbet deficiency did not affect the Tregs suppressive capacity in vitro and in vivo in the adoptive transfer model of colitis. In conclusion here we show that Tbet expression by Tregs sustains the early phase of the Th1-mediated inflammatory response in the gut.
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Affiliation(s)
| | - Angelamaria Rizzo
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Eleonora Franzè
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Flavio Caprioli
- Gastroenterology and Endoscopy Unit, IRCCS Cà Granda Fundation, Ospedale Maggiore Policlinico, Milan, Italy
| | - Federica Facciotti
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy
| | - Sara Onali
- Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy
| | - Agnese Favale
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Carmine Stolfi
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | | | - Giovanni Monteleone
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Massimo C Fantini
- Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy
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44
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Preventative delivery of IL-35 by Lactococcus lactis ameliorates DSS-induced colitis in mice. Appl Microbiol Biotechnol 2019; 103:7931-7941. [PMID: 31456001 DOI: 10.1007/s00253-019-10094-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 06/04/2019] [Accepted: 08/08/2019] [Indexed: 02/06/2023]
Abstract
Ulcerative colitis (UC) is one of the two major forms of inflammatory bowel disease (IBD) characterized by superficial mucosal inflammation, rectal bleeding, diarrhea, and abdominal pain. Anti-inflammatory and immunosuppressive drugs have been used in the therapy of human UC. Interleukin (IL)-35, which functions as an anti-inflammatory cytokine, has been shown to play a potential therapeutic role in a UC-like mouse colitis induced by dextran sodium sulfate (DSS). However, the contribution of IL-35 via oral administration to colitis prevention has not been determined. In order to explore its preventative potentiality, a dairy Lactococcus lactis NZ9000 strain was engineered to express murine IL-35 (NZ9000/IL-35), and this recombinant bacteria was applied to prevent and limit the development of DSS-induced mouse colitis. We found that oral administration of NZ9000/IL-35 induced the accumulation of IL-35 in the gut lumen of normal mice. When administrated preventatively, NZ9000/IL-35-gavaged mice exhibited decreased weight loss, DAI score, colon shortening as well as colitis-associated histopathological changes in colon, indicating that the oral administration of NZ9000/35 contributed to the suppression of DSS-induced colitis progression. Moreover, much less Th17 cells and higher level of Treg cells in lamina propria, as well as increased colon and serum levels of IL-10 with a concomitant reduced pro-inflammatory cytokines, IL-6, IL-17A, IFN-γ, and TNF-α were apparently regulated by NZ9000/IL-35 in colitis mice. Together, we put forward direct evidence pinpointing the effectiveness of NZ9000/IL-35 in preventing UC-like mouse colitis, implying a potential candidate of this recombinant Lactococcus lactis that prevent the progression of IBD.
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Smillie CS, Biton M, Ordovas-Montanes J, Sullivan KM, Burgin G, Graham DB, Herbst RH, Rogel N, Slyper M, Waldman J, Sud M, Andrews E, Velonias G, Haber AL, Jagadeesh K, Vickovic S, Yao J, Stevens C, Dionne D, Nguyen LT, Villani AC, Hofree M, Creasey EA, Huang H, Rozenblatt-Rosen O, Garber JJ, Khalili H, Desch AN, Daly MJ, Ananthakrishnan AN, Shalek AK, Xavier RJ, Regev A. Intra- and Inter-cellular Rewiring of the Human Colon during Ulcerative Colitis. Cell 2019; 178:714-730.e22. [PMID: 31348891 PMCID: PMC6662628 DOI: 10.1016/j.cell.2019.06.029] [Citation(s) in RCA: 836] [Impact Index Per Article: 139.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 03/25/2019] [Accepted: 06/18/2019] [Indexed: 11/29/2022]
Abstract
Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4+ enterocytes, microfold-like cells, and IL13RA2+IL11+ inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and co-regulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.
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Affiliation(s)
| | - Moshe Biton
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Department of Molecular Biology, MGH, Boston, MA, USA
| | - Jose Ordovas-Montanes
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Institute for Medical Engineering and Science (IMES), MIT, Cambridge, MA, USA; Department of Chemistry, MIT, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA; Division of Infectious Diseases and Division of Gastroenterology, Boston Children's Hospital, Boston, MA, USA
| | - Keri M Sullivan
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA
| | - Grace Burgin
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Daniel B Graham
- Department of Molecular Biology, MGH, Boston, MA, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA; Broad Institute, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, MA, USA
| | - Rebecca H Herbst
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA
| | - Noga Rogel
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Michal Slyper
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Julia Waldman
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Malika Sud
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Elizabeth Andrews
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA
| | - Gabriella Velonias
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA
| | - Adam L Haber
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | | | - Sanja Vickovic
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Junmei Yao
- Center for Computational and Integrative Biology, MGH, Boston, MA, USA
| | | | - Danielle Dionne
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Lan T Nguyen
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | - Alexandra-Chloé Villani
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Center for Immunology and Inflammatory Diseases, Department of Medicine, MGH, Boston, MA, USA
| | - Matan Hofree
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA
| | | | - Hailiang Huang
- Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Analytical and Translational Genetics Unit, MGH, Boston, MA, USA
| | | | - John J Garber
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA
| | - Hamed Khalili
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA
| | - A Nicole Desch
- Broad Institute, Cambridge, MA, USA; Center for Computational and Integrative Biology, MGH, Boston, MA, USA
| | - Mark J Daly
- Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Analytical and Translational Genetics Unit, MGH, Boston, MA, USA; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
| | - Ashwin N Ananthakrishnan
- Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA.
| | - Alex K Shalek
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Institute for Medical Engineering and Science (IMES), MIT, Cambridge, MA, USA; Department of Chemistry, MIT, Cambridge, MA, USA; Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
| | - Ramnik J Xavier
- Department of Molecular Biology, MGH, Boston, MA, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, MGH, Boston, MA, USA; Broad Institute, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, MA, USA; Center for Computational and Integrative Biology, MGH, Boston, MA, USA.
| | - Aviv Regev
- Klarman Cell Observatory, Broad Institute, Cambridge, MA, USA; Howard Hughes Medical Institute and Koch Institute for Integrative Cancer Research, Department of Biology, MIT, Cambridge, MA, USA.
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Barnig C, Bezema T, Calder PC, Charloux A, Frossard N, Garssen J, Haworth O, Dilevskaya K, Levi-Schaffer F, Lonsdorfer E, Wauben M, Kraneveld AD, Te Velde AA. Activation of Resolution Pathways to Prevent and Fight Chronic Inflammation: Lessons From Asthma and Inflammatory Bowel Disease. Front Immunol 2019; 10:1699. [PMID: 31396220 PMCID: PMC6664683 DOI: 10.3389/fimmu.2019.01699] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 07/08/2019] [Indexed: 12/15/2022] Open
Abstract
Formerly considered as a passive process, the resolution of acute inflammation is now recognized as an active host response, with a cascade of coordinated cellular and molecular events that promotes termination of the inflammatory response and initiates tissue repair and healing. In a state of immune fitness, the resolution of inflammation is contained in time and space enabling the restoration of tissue homeostasis. There is increasing evidence that poor and/or inappropriate resolution of inflammation participates in the pathogenesis of chronic inflammatory diseases, extending in time the actions of pro-inflammatory mechanisms, and responsible in the long run for excessive tissue damage and pathology. In this review, we will focus on how resolution can be the target for therapy in "Th1/Th17 cell-driven" immune diseases and "Th2 cell-driven" immune diseases, with inflammatory bowel diseases (IBD) and asthma, as relevant examples. We describe the main cells and mediators stimulating the resolution of inflammation and discuss how pharmacological and dietary interventions but also life style factors, physical and psychological conditions, might influence the resolution phase. A better understanding of the impact of endogenous and exogenous factors on the resolution of inflammation might open a whole area in the development of personalized therapies in non-resolving chronic inflammatory diseases.
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Affiliation(s)
- Cindy Barnig
- Department of Chest Disease, Strasbourg University Hospital, Strasbourg, France.,Equipe d'accueil 3072, University of Strasbourg, Strasbourg, France
| | | | - Philip C Calder
- Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.,National Institute for Health Research Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, United Kingdom
| | - Anne Charloux
- Department of Chest Disease, Strasbourg University Hospital, Strasbourg, France.,Equipe d'accueil 3072, University of Strasbourg, Strasbourg, France
| | - Nelly Frossard
- UMR 7200 CNRS/Université de Strasbourg, Laboratoire d'Innovation Thérapeutique and LabEx MEDALIS, Faculté de Pharmacie, Strasbourg, France
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands.,Nutricia Research, Utrecht, Netherlands
| | - Oliver Haworth
- Biochemical Pharmacology, William Harvey Research Institute, Bart's School of Medicine and Queen Mary University of London, London, United Kingdom
| | - Ksenia Dilevskaya
- Division of Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
| | - Francesca Levi-Schaffer
- Pharmacology and Experimental Therapeutics Unit, Faculty of Medicine, School of Pharmacy, Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Evelyne Lonsdorfer
- Department of Chest Disease, Strasbourg University Hospital, Strasbourg, France.,Equipe d'accueil 3072, University of Strasbourg, Strasbourg, France
| | - Marca Wauben
- Department of Biochemistry & Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Aletta D Kraneveld
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands.,Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - Anje A Te Velde
- Amsterdam UMC, Tytgat Institute for Liver and Intestinal Research, University of Amsterdam, AGEM, Amsterdam, Netherlands
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Creyns B, Cremer J, Hoshino T, Geboes K, de Hertogh G, Ferrante M, Vermeire S, Ceuppens JL, Van Assche G, Breynaert C. Fibrogenesis in Chronic DSS Colitis is Not Influenced by Neutralisation of Regulatory T Cells, of Major T Helper Cytokines or Absence of IL-13. Sci Rep 2019; 9:10064. [PMID: 31296924 PMCID: PMC6624199 DOI: 10.1038/s41598-019-46472-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 06/28/2019] [Indexed: 02/06/2023] Open
Abstract
Mechanisms underlying fibrogenesis in chronic colitis are largely unknown. There is an urgent need for clinical markers and identification of targets to prevent, treat and limit intestinal fibrosis. This study investigated the contribution of major T cell cytokines and T regulatory cells (Tregs) to inflammation and fibrosis induced in a model of experimental colitis by oral intake of dextran sodium sulphate (DSS) in wild type and IL-13 knock-out C57Bl/6 mice. Inflammation and fibrosis were scored by macroscopic and histological examination and fibrosis was quantified by hydroxyproline. Numbers of Tregs and IFN-γ+, IL-13+ and IL-17A+ CD4+ T helper (Th) cells in mesenteric lymph nodes increased during chronic DSS administration and mRNA for IFN-γ and IL-17 in the inflamed colon tissue was upregulated. However, antibody-mediated neutralisation of IFN-γ or IL-17A/F in a therapeutic setting had no effect on chronic intestinal inflammation and fibrosis. Antibody-mediated depletion of Tregs did not enhance fibrosis, nor did IL-13 deficiency have an effect on the fibrotic disease. These data argue against an important contribution of Tregs and of the cytokines IFN-γ, IL-13, IL-17A, IL-17F in the induction and/or control of fibrosis in this Crohn's disease like murine model.
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Affiliation(s)
- Brecht Creyns
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, Leuven, Belgium.,KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Jonathan Cremer
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, Leuven, Belgium.,KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Tomoaki Hoshino
- Division of Respirology, Neurology and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Karel Geboes
- KU Leuven, Department of Imaging and Pathology, Translational Cell & Tissue Research, Leuven, Belgium
| | - Gert de Hertogh
- KU Leuven, Department of Imaging and Pathology, Translational Cell & Tissue Research, Leuven, Belgium
| | - Marc Ferrante
- KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium.,University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium
| | - Séverine Vermeire
- KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium.,University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium
| | - Jan L Ceuppens
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, Leuven, Belgium
| | - Gert Van Assche
- KU Leuven, Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium.,University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium
| | - Christine Breynaert
- KU Leuven, Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, Leuven, Belgium. .,University Hospitals Leuven, Department of General Internal Medicine, Leuven, Belgium.
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Onali S, Favale A, Fantini MC. The Resolution of Intestinal Inflammation: The Peace-Keeper's Perspective. Cells 2019; 8:cells8040344. [PMID: 30979024 PMCID: PMC6523641 DOI: 10.3390/cells8040344] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/08/2019] [Accepted: 04/10/2019] [Indexed: 02/06/2023] Open
Abstract
The uncontrolled activation of the immune system toward antigens contained in the gut lumen in genetically predisposed subjects is believed to be the leading cause of inflammatory bowel disease (IBD). Two not mutually exclusive hypotheses can explain the pathogenic process leading to IBD. The first and mostly explored hypothesis states that the loss of tolerance toward gut microbiota antigens generates an aberrant inflammatory response that is perpetuated by continuous and unavoidable exposure to the triggering antigens. However, the discovery that the resolution of inflammation is not the mere consequence of clearing inflammatory triggers and diluting pro-inflammatory factors, but rather an active process in which molecular and cellular elements are involved, implies that a defect in the pro-resolving mechanisms might cause chronic inflammation in different immune-mediated diseases, including IBD. Here we review data on pro-resolving and counter-regulatory mechanisms involved in the resolution of inflammation, aiming to identify their possible involvement in the pathogenesis of IBD.
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Affiliation(s)
- Sara Onali
- Dep. of Biomedicine and Prevention, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.
| | - Agnese Favale
- Dep. of Systems Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.
| | - Massimo C Fantini
- Dep. of Systems Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy.
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49
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Kitz A, Singer E, Hafler D. Regulatory T Cells: From Discovery to Autoimmunity. Cold Spring Harb Perspect Med 2018; 8:cshperspect.a029041. [PMID: 29311129 DOI: 10.1101/cshperspect.a029041] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Multiple sclerosis (MS) is a genetically mediated autoimmune disease of the central nervous system. Allelic variants lead to lower thresholds of T-cell activation resulting in activation of autoreactive T cells. Environmental factors, including, among others, diet, vitamin D, and smoking, in combination with genetic predispositions, play a substantial role in disease development and activation of autoreactive T cells. FoxP3+ regulatory T cells (Tregs) have emerged as central in the control of autoreactive T cells. A consistent finding in patients with MS is defects in Treg cell function with reduced suppression of effector T cells and production of proinflammatory cytokines. Emerging data suggests that functional Tregs become effector-like T cells with loss of function associated with T-bet expression and interferon γ (IFN-γ) secretion.
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Affiliation(s)
- Alexandra Kitz
- Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, Connecticut 06520
| | - Emily Singer
- Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, Connecticut 06520
| | - David Hafler
- Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, Connecticut 06520
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Gui X, Li J, Ueno A, Iacucci M, Qian J, Ghosh S. Histopathological Features of Inflammatory Bowel Disease are Associated With Different CD4+ T Cell Subsets in Colonic Mucosal Lamina Propria. J Crohns Colitis 2018; 12:1448-1458. [PMID: 30137280 DOI: 10.1093/ecco-jcc/jjy116] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Inflammatory bowel disease [IBD] results particularly from an aberrance of CD4+ helper and regulatory T cells and comprises histopathologically chronic active enterocolitis with features reflecting both activity and chronicity of mucosal inflammation. The exact immunological-histological correlation in IBD is not understood. METHODS We studied the correlation between colonic mucosal CD4+ T cell subsets [Th1, Th2, Th17, Th22 and Treg] and mucosal histological changes in ulcerative colitis [UC] and Crohn's disease [CD]. CD4+ T cell subtyping and enumeration were achieved by flow cytometry. Histological features were categorized and assessed semi-quantitatively using three validated histological scoring schemes [ECAP, RHI and D'Haens]. Correlations between prevalence [%] of CD4+ T cell subsets and histological scores were analysed. RESULTS Treg cells were correlated with ECAP category A [activity] as well as RHI scores. Treg cell were increased particularly in mucosa with severe neutrophilic infiltration in the cryptal/surface epithelium and in lamina propria, and with basal plasmacytosis. Th17 cells were also increased in cases with extensive neutrophil infiltrate in lamina propria, whereas RORc+ cells were increased in cases with severe lymphoplasmacytic infiltration in lamina propria. In both UC and CD, mucosa with marked crypt architectural alteration had increased IL-22+ and Th22 cells. UC with Paneth cell metaplasia had higher Th17 cells. CD with granuloma had increased IL-22+ and IL-22+IFN-γ+ cells. CONCLUSIONS The Treg subset appears to be associated with the overall severity of IBD histopathology, particularly with active inflammation. Th17 is also associated with activity. By contrast, IL-22+ cells are associated with chronicity and granuloma formation in CD.
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Affiliation(s)
- Xianyong Gui
- Department of Pathology and Laboratory Medicine, University of Calgary, and Calgary Laboratory Services, Calgary, Alberta, Canada
| | - Ji Li
- Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada.,Department of Gastroenterology, Peking Union Medical College Hospital, Beijing, China
| | - Aito Ueno
- Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada
| | - Marietta Iacucci
- Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada.,Institute of Translational Medicine, University of Birmingham, Birmingham, UK
| | - Jiaming Qian
- Department of Gastroenterology, Peking Union Medical College Hospital, Beijing, China
| | - Subrata Ghosh
- Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada.,Institute of Translational Medicine, University of Birmingham, Birmingham, UK
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