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Menghini P, Buttó LF, Gomez-Nguyen A, Aladyshkina N, Buela KA, Osme A, Chan R, Wargo HL, De Santis S, Bamias G, Pizarro T, Cominelli F. Tumor Necrosis Factor-Like Ligand 1A/Death Receptor 3 Signaling Regulates the Generation of Pathogenic T Helper 9 Cells in Experimental Crohn's Disease. Gastroenterology 2025:S0016-5085(25)00606-7. [PMID: 40204100 DOI: 10.1053/j.gastro.2025.03.035] [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] [Received: 03/21/2024] [Revised: 02/13/2025] [Accepted: 03/03/2025] [Indexed: 04/11/2025]
Abstract
BACKGROUND & AIMS Death receptor 3 (DR3) and its ligand, tumor necrosis factor-like ligand 1A (TL1A), regulate the balance between effector and regulatory T cells in inflammatory bowel disease (IBD). Although interleukin 9 (IL9)-secreting T helper 9 (Th9) cells are linked to ulcerative colitis, their role in Crohn's disease (CD) is unclear. We investigated the role of DR3 signaling in Th9 cell differentiation in mouse models of CD-like ileitis and colitis. METHODS Polarized Th9 cells with functional DR3 and DR3-deficient Th9 cells from SAMP wild-type (Th9WT) and DR3-/-×SAMP knockout (Th9KO) mice, respectively, were characterized and adoptively transferred into Rag2-/- and SAMP×Rag2-/- recipients. Expression of Th9-associated molecules from experimental mice and IBD patients/controls was compared. RESULTS Th9WT possess a proinflammatory profile compared with Th9KO cells; conversely, ablation of DR3 signaling generates anti-inflammatory responses, as reflected by increased IL10-producing cells in DR3-/-×SAMP mice. RNA sequencing and phosphoproteomic analyses show that inflammatory pathways are robustly activated in Th9WT compared with Th9KO cells, whereas Th9 cells are detected in SAMP mice in vivo, and Th9-related genes display the same expression patterns in both experimental ileitis and IBD patients. Finally, in the T-cell adoptive transfer model, Th9KO cells are less colitogenic than Th9WT, whereas IL9 blockade diminishes the severity of intestinal inflammation, indicating a crucial role of functional DR3 receptor in the pathogenicity of Th9 cells. CONCLUSIONS We demonstrate that the functional DR3 receptor is essential for Th9 cell pathogenicity, revealing a new mechanism by which TL1A/DR3 signaling drives experimental CD-like ileitis. The TL1A/DR3/Th9 proinflammatory pathway may offer a novel therapeutic target for patients with CD.
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Affiliation(s)
- Paola Menghini
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio; Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Ludovica F Buttó
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio; Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Adrian Gomez-Nguyen
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio; Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Natalia Aladyshkina
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio; Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Kristine-Ann Buela
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Abdullah Osme
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Ricky Chan
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
| | - Hannah L Wargo
- Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Stefania De Santis
- Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Giorgos Bamias
- Gastrointestinal Unit, Third Academic Department of Internal Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, Athens, Greece
| | - Theresa Pizarro
- Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Fabio Cominelli
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio; Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio.
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Deng Y, Fu T, Gao D, Zhou J, Nie X, Wang F, Yu Q. Systemic Immune-Inflammation Index: A Promising, Non-Invasive Biomarker for Crohn's Disease Activity and Severity Assessment. Int J Gen Med 2025; 18:483-496. [PMID: 39901979 PMCID: PMC11789774 DOI: 10.2147/ijgm.s495692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 01/18/2025] [Indexed: 02/05/2025] Open
Abstract
Purpose Crohn's disease (CD) is a chronic inflammatory disorder with periods of exacerbation and remission. We aim to evaluate the systemic immune-inflammation index (SII) as a prognostic biomarker in CD and its utility in predicting disease activity and severity. Patients and Methods This retrospective study analyzed CD patients using the Harvey-Bradshaw index (HBI) for disease stratification and the Simple Endoscopic Score for Crohn's Disease (SES-CD) for post-treatment evaluation. Data analysis was conducted using R software. Serological indices underwent predictive analysis through the receiver operating characteristic (ROC) curve. The least absolute shrinkage and selection operator (LASSO) regression and multivariate logistic regression identified independent prognostic factors to construct nomograms. Model validation was performed using the Concordance index (C-index), calibration analysis and decision curve analysis (DCA). Results In this study, 254 patients with Crohn's disease (CD) were enrolled, including 171 males and 83 females, with ages ranging from 13 to 74. SII was significantly elevated in active CD (p<0.001), correlating with disease severity (p<0.001). Although SII decreased in patients with mucosal healing (p<0.001), its prognostic accuracy (AUC=0.719) was lower than other biomarkers. However, SII emerged as an independent predictor for CD activity and severity with higher efficacy (AUC=0.774 and 0.807). The CD activity and severity prediction nomograms showed high C-indices (0.8038 and 0.8208), indicating strong predictive performance. Conclusion SII is a valuable biomarker for assessing CD severity and monitoring mucosal healing post-treatment. The SII-based nomograms offer a reliable model for evaluating CD progression, aiding in personalized treatment approaches and enhancing clinical decision-making. We recommend randomized controlled trials (RCTs) or studies with larger sample sizes to improve the model.
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Affiliation(s)
- Yu’en Deng
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, People’s Republic of China
- Huankui Academy, Jiangxi Medical College, Nanchang University, Nanchang, 330031, People’s Republic of China
| | - Ting Fu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, People’s Republic of China
| | - Dian Gao
- Department of Pathogen Biology and Immunology, Jiangxi Medical College, Nanchang University, Nanchang, 330006, People’s Republic of China
| | - Jianming Zhou
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, People’s Republic of China
| | - Xinhua Nie
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, People’s Republic of China
| | - Fenfen Wang
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, People’s Republic of China
| | - Qiongfang Yu
- Department of Gastroenterology and Hepatology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, People’s Republic of China
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Yue N, Hu P, Tian C, Kong C, Zhao H, Zhang Y, Yao J, Wei Y, Li D, Wang L. Dissecting Innate and Adaptive Immunity in Inflammatory Bowel Disease: Immune Compartmentalization, Microbiota Crosstalk, and Emerging Therapies. J Inflamm Res 2024; 17:9987-10014. [PMID: 39634289 PMCID: PMC11615095 DOI: 10.2147/jir.s492079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 11/12/2024] [Indexed: 12/07/2024] Open
Abstract
The intestinal immune system is the largest immune organ in the human body. Excessive immune response to intestinal cavity induced by harmful stimuli including pathogens, foreign substances and food antigens is an important cause of inflammatory diseases such as celiac disease and inflammatory bowel disease (IBD). Although great progress has been made in the treatment of IBD by some immune-related biotherapeutic products, yet a considerable proportion of IBD patients remain unresponsive or immune tolerant to immunotherapeutic strategy. Therefore, it is necessary to further understand the mechanism of immune cell populations involved in enteritis, including dendritic cells, macrophages and natural lymphocytes, in the steady-state immune tolerance of IBD, in order to find effective IBD therapy. In this review, we discussed the important role of innate and adaptive immunity in the development of IBD. And the relationship between intestinal immune system disorders and microflora crosstalk were also presented. We also focus on the new findings in the field of T cell immunity, which might identify novel cytokines, chemokines or anti-cytokine antibodies as new approaches for the treatment of IBD.
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Affiliation(s)
- Ningning Yue
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Peng Hu
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, People’s Republic of China
| | - Chengmei Tian
- Department of Emergency, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Chen Kong
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Hailan Zhao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Yuan Zhang
- Department of Medical Administration, Huizhou Institute of Occupational Diseases Control and Prevention, Huizhou, People’s Republic of China
| | - Jun Yao
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Yuqi Wei
- Department of Rehabilitation, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Defeng Li
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
| | - Lisheng Wang
- Department of Gastroenterology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, People’s Republic of China
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Fan Y, Wu J, Huang W, Li S, Zeng Q, Gesang Z, Silang Y, Zhang C, Fu G. Immunomodulatory effect of tibetan medicine compound extracts against ORFV in vitro by metabolomics. BMC Vet Res 2024; 20:366. [PMID: 39143608 PMCID: PMC11325804 DOI: 10.1186/s12917-024-04204-7] [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: 08/15/2023] [Accepted: 07/23/2024] [Indexed: 08/16/2024] Open
Abstract
Ovine contagious pustular dermatitis (ORF) is one of the main diseases of sheep and is a zoonotic disease caused by Ovine contagious pustular dermatitis virus (ORFV) infection, posing a significant constraint on sheep breeding industry and human health. The Tibetan medical formulation composed of Polygonum leucoides, Polygonum xanthoxylum and Acanthophora rotunda significantly regulated lymphocyte immune function following ORFV stimulation, although the mechanism remains unclear. In order to study the immunomodulatory effects and mechanism of three Tibetan medicinal extracts (Polygonum leucoides, Polygonum xanthoxylum, and Acanthophora rotunda) against ORFV in vitro, sheep peripheral blood lymphocytes were isolated in vitro and treated with different concentrations of Tibetan medicine compound extract solution after ORFV infection. The cytokine expression levels in lymphocytes were measured at 4 h, 8 h and 12 h. Additionally endogenous metabolites in lymphocytes at 0 h, 4 h, 8 h and 12 h were quantified by untargeted metabolomics method. The results showed that, the extracts could regulate the lymphocyte immune factors altered by ORFV, and regulate the lymphocyte immune function through cysteine and methionine metabolic pathways as well as the pyrimidine metabolic pathways, potentially alleviating the immune evasion induced by ORFV.
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Affiliation(s)
- Yueyuan Fan
- College of Veterinary Medicine, Yunnan Agricultural University, Kunming, 650201, China
| | - Jiao Wu
- College of Veterinary Medicine, Yunnan Agricultural University, Kunming, 650201, China
| | - Wei Huang
- College of Agronomy and Life Sciences, Kunming University, Kunming, 650214, China
| | - Saiju Li
- College of Veterinary Medicine, Yunnan Agricultural University, Kunming, 650201, China
| | - Qin Zeng
- College of Veterinary Medicine, Yunnan Agricultural University, Kunming, 650201, China
| | - Zhuoga Gesang
- Institute of Animal Science, Tibet Academy of Agricultural and Animal Husbandry Sciences, Lhasa, 850000, China
| | - Yuzhen Silang
- Institute of Animal Science, Tibet Academy of Agricultural and Animal Husbandry Sciences, Lhasa, 850000, China.
| | - Chong Zhang
- Kunming Customs Technology Center, Kunming, 650228, China.
| | - Guowen Fu
- College of Veterinary Medicine, Yunnan Agricultural University, Kunming, 650201, China.
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Liao HX, Mao X, Wang L, Wang N, Ocansey DKW, Wang B, Mao F. The role of mesenchymal stem cells in attenuating inflammatory bowel disease through ubiquitination. Front Immunol 2024; 15:1423069. [PMID: 39185411 PMCID: PMC11341407 DOI: 10.3389/fimmu.2024.1423069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 07/22/2024] [Indexed: 08/27/2024] Open
Abstract
Inflammatory bowel disease (IBD), a condition of the digestive tract and one of the autoimmune diseases, is becoming a disease of significant global public health concern and substantial clinical burden. Various signaling pathways have been documented to modulate IBD, but the exact activation and regulatory mechanisms have not been fully clarified; thus, a need for constant exploration of the molecules and pathways that play key roles in the development of IBD. In recent years, several protein post-translational modification pathways, such as ubiquitination, phosphorylation, methylation, acetylation, and glycolysis, have been implicated in IBD. An aberrant ubiquitination in IBD is often associated with dysregulated immune responses and inflammation. Mesenchymal stem cells (MSCs) play a crucial role in regulating ubiquitination modifications through the ubiquitin-proteasome system, a cellular machinery responsible for protein degradation. Specifically, MSCs have been shown to influence the ubiquitination of key signaling molecules involved in inflammatory pathways. This paper reviews the recent research progress in MSC-regulated ubiquitination in IBD, highlighting their therapeutic potential in treating IBD and offering a promising avenue for developing targeted interventions to modulate the immune system and alleviate inflammatory conditions.
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Affiliation(s)
- Hong Xi Liao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
- Department of Laboratory Medicine, Lianyungang Clinical College, Jiangsu University, Lianyungang, Jiangsu, China
| | - Xiaojun Mao
- The People’s Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Zhenjiang, Jiangsu, China
| | - Lan Wang
- Department of Laboratory Medicine, Danyang Blood Station, Zhenjiang, Jiangsu, China
| | - Naijian Wang
- Department of Laboratory Medicine, Lianyungang Clinical College, Jiangsu University, Lianyungang, Jiangsu, China
| | - Dickson Kofi Wiredu Ocansey
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Bo Wang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
- Department of Laboratory Medicine, Lianyungang Clinical College, Jiangsu University, Lianyungang, Jiangsu, China
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He L, Deng T, Huang Y, Yang W, Yang J, Song G. Association between 23 drugs and inflammatory bowel disease: a two-sample Mendelian randomization study. Front Med (Lausanne) 2024; 11:1371362. [PMID: 38835788 PMCID: PMC11149542 DOI: 10.3389/fmed.2024.1371362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 05/07/2024] [Indexed: 06/06/2024] Open
Abstract
Background Inflammatory bowel disease (IBD) is a group of diseases characterized by chronic and recurrent inflammation of the gastrointestinal tract. The etiology of IBD remains multifaceted and poorly understood, resulting in limited treatment options that primarily target disease induction and remission maintenance. Thus, the exploration of novel therapeutic options for IBD among existing medications is advantageous. Mendelian randomization analysis (MR) serves as a valuable tool in investigating the relationship between drugs and diseases. In this study, MR analysis was employed to investigate the potential causal relationship between 23 approved drugs for the treatment of various diseases and IBD. Method We performed a two-sample MR analysis using publicly available genome-wide association study (GWAS) statistics. The inverse variance weighting (IVW) method was used as the main analysis method, supplemented by the remaining four methods (weighted median, MR Egger regression, simple and weighted models), and Meta-analysis was performed to expand the sample size to obtain a more reliable composite causal effect. Finally, Cochran's Q statistic and the MR-Egger test for directed pleiotropy were applied to determine whether significant heterogeneity or directed pleiotropy existed. Results In the main MR analysis (IVW), drugs with a negative causal association with the risk of IBD were immunosuppressant {OR (95% CI) = 0.7389 [0.6311-0.8651], p = 0.0046} and diabetes drugs {OR (95% CI) = 0.9266 [0.8876-0.9674], p = 0.0058}. A positive causal association with the risk of IBD was found for salicylic acid and derivatives {OR (95% CI) = 1.2737 [1.0778-1.5053], p = 0.0345}. Negative causal associations with UC risk were identified for immunosuppressants {OR (95% CI) = 0.6660 [0.5133-0.8640], p = 0.0169} and diabetes medications {OR (95% CI) = 0.9020 [0.8508-0.9551], p = 0.0046}; positive causal associations with UC risk were found for β-receptor blockers {OR (95% CI) = 1.1893 [1.0823-1.3070], p = 0.0046}. A negative causal association with the risk of CD was found for immunosuppressants {OR (95% CI) = 0.6957 [0.5803-0.8341], p = 0.0023}. There was no statistically significant association between the remaining 19 drugs and IBD and subtypes. Conclusion This MR study provides evidence suggesting that immunosuppressants have a mitigating effect on the risk of IBD and demonstrate consistent efficacy in subtypes of ulcerative colitis (UC) and Crohn's disease (CD). Additionally, diabetes medications show potential in reducing the risk of IBD, particularly in cases of UC, while β-blockers may elevate the risk of UC. Conversely, salicylic acid and its derivatives may increase the risk of IBD, although this effect is not consistently observed in the subtypes of the disease. These findings offer new insights into the prevention and management of IBD.
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Affiliation(s)
- Lei He
- Department of Gastroenterology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Tuo Deng
- Department of Gastroenterology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Yurong Huang
- Department of Gastroenterology, Liupanshui People's Hospital, Liupanshui, Guizhou, China
| | - Wangliu Yang
- Department of Gastroenterology, Liupanshui People's Hospital, Liupanshui, Guizhou, China
| | - Jie Yang
- Department of Gastroenterology, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Gengqing Song
- Department of Gastroenterology and Hepatology, Metrohealth Medical Center, Case Western Reserve University, Cleveland, OH, United States
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Wen C, Chen D, Zhong R, Peng X. Animal models of inflammatory bowel disease: category and evaluation indexes. Gastroenterol Rep (Oxf) 2024; 12:goae021. [PMID: 38634007 PMCID: PMC11021814 DOI: 10.1093/gastro/goae021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 02/12/2024] [Accepted: 02/29/2024] [Indexed: 04/19/2024] Open
Abstract
Inflammatory bowel disease (IBD) research often relies on animal models to study the etiology, pathophysiology, and management of IBD. Among these models, rats and mice are frequently employed due to their practicality and genetic manipulability. However, for studies aiming to closely mimic human pathology, non-human primates such as monkeys and dogs offer valuable physiological parallels. Guinea pigs, while less commonly used, present unique advantages for investigating the intricate interplay between neurological and immunological factors in IBD. Additionally, New Zealand rabbits excel in endoscopic biopsy techniques, providing insights into mucosal inflammation and healing processes. Pigs, with their physiological similarities to humans, serve as ideal models for exploring the complex relationships between nutrition, metabolism, and immunity in IBD. Beyond mammals, non-mammalian organisms including zebrafish, Drosophila melanogaster, and nematodes offer specialized insights into specific aspects of IBD pathology, highlighting the diverse array of model systems available for advancing our understanding of this multifaceted disease. In this review, we conduct a thorough analysis of various animal models employed in IBD research, detailing their applications and essential experimental parameters. These include clinical observation, Disease Activity Index score, pathological assessment, intestinal barrier integrity, fibrosis, inflammatory markers, intestinal microbiome, and other critical parameters that are crucial for evaluating modeling success and drug efficacy in experimental mammalian studies. Overall, this review will serve as a valuable resource for researchers in the field of IBD, offering insights into the diverse array of animal models available and their respective applications in studying IBD.
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Affiliation(s)
- Changlin Wen
- Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, Sichuan, P. R. China
| | - Dan Chen
- Acupuncture and Moxibustion School of Teaching, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, P. R. China
| | - Rao Zhong
- Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, Sichuan, P. R. China
| | - Xi Peng
- Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, Sichuan, P. R. China
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Liu T, Qin Z, Yang Z, Feng X. Predictive Value of MHR and NLR for Ulcerative Colitis Disease Activity. Int J Gen Med 2024; 17:685-692. [PMID: 38435113 PMCID: PMC10908246 DOI: 10.2147/ijgm.s446723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 01/18/2024] [Indexed: 03/05/2024] Open
Abstract
Background Numerous non-invasive serologic tests are available to diagnose and monitor ulcerative colitis (UC), but their accuracy levels are limited. Thus, there is a pressing need for a serologic biomarker with higher precision for clinical practice. This study aims to evaluate the predictive capacity of monocyte/HDL ratio (MHR) and neutrophil/lymphocyte ratio (NLR) for UC disease activity. Patients and Methods We conducted a retrospective analysis of 81 UC patients and 77 age- and sex-matched healthy controls. UC patients were categorized into active and inactive groups based on the Mayo score. The Mayo endoscopic subscore classified them into mild-to-moderate and severe UC groups. Results The optimal cut-off values for diagnosing UC were 0.34 for MHR (85.7% sensitivity, 76.0% specificity, 88.9% positive predictive value, 70.4% negative predictive value) and 2.49 for NLR (66.1% sensitivity, 88.0% specificity, 92.5% positive predictive value, 53.7% negative predictive value). The optimal MHR and NLR cut-off values to differentiate between mild-to-moderate UC and severe UC were 0.38 (92.9% sensitivity, 56.6% specificity, 53.1% positive predictive value, 93.7% negative predictive value) and 3.46 (71.4% sensitivity, 88.7% specificity, 76.9% positive predictive value, 85.5% negative predictive value), respectively. Conclusion NLR and MHR are simple yet effective biological predictors of disease activity in UC patients.
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Affiliation(s)
- Tian Liu
- Division of General Practice, The Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China
| | - Zhenkun Qin
- Division of General Practice, The Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China
| | - Zhiyue Yang
- Division of General Practice, The Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China
| | - Xiaoling Feng
- Division of General Practice, The Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi, People’s Republic of China
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9
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Shrinivasan R, Wyatt-Johnson SK, Brutkiewicz RR. The MR1/MAIT cell axis in CNS diseases. Brain Behav Immun 2024; 116:321-328. [PMID: 38157945 PMCID: PMC10842441 DOI: 10.1016/j.bbi.2023.12.029] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 12/14/2023] [Accepted: 12/21/2023] [Indexed: 01/03/2024] Open
Abstract
Mucosal-associated invariant T (MAIT) cells are a subpopulation of innate-like T cells that can be found throughout the body, predominantly in mucosal sites, the lungs and in the peripheral blood. MAIT cells recognize microbial-derived vitamin B (e.g., riboflavin) metabolite antigens that are presented by the major histocompatibility complex class I-like protein, MR1, found on a variety of cell types in the periphery and the CNS. Since their original discovery, MAIT cells have been studied predominantly in their roles in diseases in the periphery; however, it was not until the early 2000s that these cells were first examined for their contributions to disorders of the CNS, with the bulk of the work being done within the past few years. Currently, the MR1/MAIT cell axis has been investigated in only a few neurological diseases including, multiple sclerosis and experimental autoimmune encephalomyelitis, brain cancer/tumors, ischemia, cerebral palsy, general aging and, most recently, Alzheimer's disease. Each of these diseases demonstrates a role for this under-studied innate immune axis in its neuropathology. Together, they highlight the importance of studying the MR1/MAIT cell axis in CNS disorders. Here, we review the contributions of the MR1/MAIT cell axis in the progression or remission of these neurological diseases. This work has shed some light in terms of potentially exploiting the MR1/MAIT cell axis in novel therapeutic applications.
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Affiliation(s)
- Rashmi Shrinivasan
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Season K Wyatt-Johnson
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Randy R Brutkiewicz
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
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10
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Pei J, Wang G, Li Y, Li L, Li C, Wu Y, Liu J, Tian G. Utility of four machine learning approaches for identifying ulcerative colitis and Crohn's disease. Heliyon 2024; 10:e23439. [PMID: 38148824 PMCID: PMC10750181 DOI: 10.1016/j.heliyon.2023.e23439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 12/04/2023] [Accepted: 12/04/2023] [Indexed: 12/28/2023] Open
Abstract
Objective Peripheral blood routine parameters (PBRPs) are simple and easily acquired markers to identify ulcerative colitis (UC) and Crohn's disease (CD) and reveal the severity, whereas the diagnostic performance of individual PBRP is limited. We, therefore used four machine learning (ML) models to evaluate the diagnostic and predictive values of PBRPs for UC and CD. Methods A retrospective study was conducted by collecting the PBRPs of 414 inflammatory bowel disease (IBD) patients, 423 healthy controls (HCs), and 344 non-IBD intestinal diseases (non-IBD) patients. We used approximately 70 % of the PBRPs data from both patients and HCs for training, 30 % for testing, and another group for external verification. The area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnosis and prediction performance of these four ML models. Results Multi-layer perceptron artificial neural network model (MLP-ANN) yielded the highest diagnostic performance than the other three models in six subgroups in the training set, which is helpful for discriminating IBD and HCs, UC and CD, active CD and remissive CD, active UC and remissive UC, non-IBD and HCs, and IBD and non-IBD with the AUC of 1.00, 0.988, 0.942, 1.00, 0.986, and 0.97 in the testing set, as well as the AUC of 1.00, 1.00, 0.773, 0.904, 1.00 and 0.992 in the external validation set. Conclusion PBRPs-based MLP-ANN model exhibited good performance in discriminating between UC and CD and revealing the disease activity; however, a larger sample size and more models need to be considered for further research.
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Affiliation(s)
- Jingwen Pei
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Sichuan 646000, China
| | - Guobing Wang
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Sichuan 646000, China
| | - Yi Li
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Sichuan 646000, China
| | - Lan Li
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Sichuan 646000, China
| | - Chang Li
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Sichuan 646000, China
| | - Yu Wu
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Sichuan 646000, China
| | - Jinbo Liu
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Sichuan 646000, China
| | - Gang Tian
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Sichuan 646000, China
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Wei L, Chen Z, Lv Q. Mucosal-associated invariant T cells display both pathogenic and protective roles in patients with inflammatory bowel diseases. Amino Acids 2023; 55:1819-1827. [PMID: 37819474 DOI: 10.1007/s00726-023-03344-8] [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: 08/21/2023] [Accepted: 09/26/2023] [Indexed: 10/13/2023]
Abstract
An important subtype of the innate-like T lymphocytes is mucosal-associated invariant T (MAIT) cells expressing a semi-invariant T cell receptor α (TCR-α) chain. MAIT cells could be activated mainly by TCR engagement or cytokines. They have been found to have essential roles in various immune mediated. There have been growing preclinical and clinical findings that show an association between MAIT cells and the physiopathology of inflammatory bowel diseases (IBD). Of note, published reports demonstrate contradictory findings regarding the role of MAIT cells in IBD patients. A number of reports suggests a protective effect, whereas others show a pathogenic impact. The present review article aimed to explore and discuss the findings of experimental and clinical investigations evaluating the effects of MAIT cells in IBD subjects and animal models. Findings indicate that MAIT cells could exert opposite effects in the course of IBD, including an anti-inflammatory protective effect of blood circulating MAIT cells and an effector pathogenic effect of colonic MAIT cells. Another important finding is that blood levels of MAIT cells can be considered as a potential biomarker in IBD patients.
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Affiliation(s)
- Lei Wei
- Department of General Surgery, Pudong New District Gongli Hospital of Shanghai, Shanghai, 200120, China
| | - Zhigang Chen
- Department of General Surgery, Pudong New District Gongli Hospital of Shanghai, Shanghai, 200120, China
| | - Qiang Lv
- Department of General Surgery, Pudong New District Gongli Hospital of Shanghai, Shanghai, 200120, China.
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12
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Gao S, Zheng H, Xu S, Kong J, Gao F, Wang Z, Li Y, Dai Z, Jiang X, Ding X, Lei H. Novel Natural Carrier-Free Self-Assembled Nanoparticles for Treatment of Ulcerative Colitis by Balancing Immune Microenvironment and Intestinal Barrier. Adv Healthc Mater 2023; 12:e2301826. [PMID: 37681364 DOI: 10.1002/adhm.202301826] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 09/05/2023] [Indexed: 09/09/2023]
Abstract
Ulcerative colitis (UC) is a chronic inflammatory illness affecting the colon and rectum, with current treatment methods being unable to meet the clinical needs of ulcerative colitis patients. Although nanomedicines are recognized as promising anti-inflammatory medicines, their clinical application is limited by their high cost and unpredictable safety risks. This study reveals that two natural phytochemicals, berberine (BBR) and hesperetin (HST), self-assemble directly to form binary carrier-free multi-functional spherical nanoparticles (BBR-HST NPs) through noncovalent bonds involving electrostatic interactions, π-π stacking, and hydrogen bonding. Because of their synergistic anti-inflammatory activity, berberine-hesperetin nanoparticles (BBR-HST NPs) exhibit significantly better therapeutic effects on UC and inhibitory effects on inflammation than BBR and HST at the same dose by regulating the immune microenvironment and repairing the damaged intestinal barrier. Furthermore, BBR-HST NPs exhibit good biocompatibility and biosafety. Thus, this study proves the potential of novel natural anti-inflammatory nanoparticles as therapeutic agents for UC, which could promote the progress of drug development for UC and eventually benefit patients who suffering from it.
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Affiliation(s)
- Shan Gao
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Haocheng Zheng
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Shujing Xu
- School of Life Science, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Jingwei Kong
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Feng Gao
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Zhijia Wang
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Yuan Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Ziqi Dai
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xinqi Jiang
- School of Life Science, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Xia Ding
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Haimin Lei
- School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing, 102488, China
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White Z, Cabrera I, Kapustka I, Sano T. Microbiota as key factors in inflammatory bowel disease. Front Microbiol 2023; 14:1155388. [PMID: 37901813 PMCID: PMC10611514 DOI: 10.3389/fmicb.2023.1155388] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 09/07/2023] [Indexed: 10/31/2023] Open
Abstract
Inflammatory Bowel Disease (IBD) is characterized by prolonged inflammation of the gastrointestinal tract, which is thought to occur due to dysregulation of the immune system allowing the host's cells to attack the GI tract and cause chronic inflammation. IBD can be caused by numerous factors such as genetics, gut microbiota, and environmental influences. In recent years, emphasis on commensal bacteria as a critical player in IBD has been at the forefront of new research. Each individual harbors a unique bacterial community that is influenced by diet, environment, and sanitary conditions. Importantly, it has been shown that there is a complex relationship among the microbiome, activation of the immune system, and autoimmune disorders. Studies have shown that not only does the microbiome possess pathogenic roles in the progression of IBD, but it can also play a protective role in mediating tissue damage. Therefore, to improve current IBD treatments, understanding not only the role of harmful bacteria but also the beneficial bacteria could lead to attractive new drug targets. Due to the considerable diversity of the microbiome, it has been challenging to characterize how particular microorganisms interact with the host and other microbiota. Fortunately, with the emergence of next-generation sequencing and the increased prevalence of germ-free animal models there has been significant advancement in microbiome studies. By utilizing human IBD studies and IBD mouse models focused on intraepithelial lymphocytes and innate lymphoid cells, this review will explore the multifaceted roles the microbiota plays in influencing the immune system in IBD.
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Affiliation(s)
| | | | | | - Teruyuki Sano
- Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States
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14
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Yen FS, Huang JY, Lin SY, Liao PL, Wei JCC. Maternal autoimmune disease associated with a higher risk of offspring with type 1 diabetes: A nationwide mother-child cohort study in Taiwan. DIABETES & METABOLISM 2023; 49:101443. [PMID: 36972847 DOI: 10.1016/j.diabet.2023.101443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 03/17/2023] [Accepted: 03/22/2023] [Indexed: 03/28/2023]
Abstract
AIM The incidence of type 1 diabetes continues to increase. However, the strategies to prevent or reduce its occurrence are inadequate. Therefore, we attempted to investigate if mothers with autoimmune disease were more likely to have children with type 1 diabetes. METHODS We identified 1,288,347 newborns from the Taiwan Maternal and Child Health Database between January 1, 2009, and December 31, 2016, and followed them up to December 31, 2019. We used a multivariable Cox regression model to compare the childhood-onset type 1 diabetes risk between children whose mother had or did not have an autoimmune disease. RESULTS The multivariable model demonstrated significantly higher risks of type 1 diabetes in the children with maternal autoimmune disease (aHR 1.55, 95% CI 1.16-2.08), type 1 diabetes (aHR 11.33, 95% CI 4.62-27.77), Hashimoto's thyroiditis (aHR 3.73, 95% CI 1.70-8.15), and inflammatory bowel diseases (aHR 2.00, 95% CI 1.07-3.76). CONCLUSION This nationwide mother and child cohort study showed a higher risk of type 1 diabetes in the children whose mothers had autoimmune disease, including Hashimoto's thyroiditis, and inflammatory bowel diseases.
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Affiliation(s)
- Fu-Shun Yen
- Dr. Yen's Clinic, No. 15, Shanying Road, Gueishan District, Taoyuan 33354, Taiwan
| | - Jing-Yang Huang
- Institute of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Rd., South District, Taichung 40201, Taiwan
| | - Shih-Yi Lin
- Center for Geriatrics and Gerontology, Taichung Veterans General Hospital, No. 1650 Taiwan Boulevard, Sect. 4, Taichung 40705, Taiwan; Department of Medicine, School of Medicine, National Yang Ming Chiao Tung University, No.155, Sec.2, Linong Street, Taipei 11221, Taiwan
| | - Pei-Lun Liao
- Institute of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Rd., South District, Taichung 40201, Taiwan
| | - James Cheng-Chung Wei
- Institute of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Rd., South District, Taichung 40201, Taiwan; Department of Medicine, Chung Shan Medical University Hospital, No. 110, Sec. 1, Jianguo N. Rd., South District, Taichung 40201, Taiwan; Graduate Institute of Integrated Medicine, China Medical University, No.91, Hsueh-Shih Road, Taichung 40402, Taiwan; Department of Medical Research, Taichung Veterans General Hospital, No. 1650 Taiwan Boulevard, Sect. 4, Taichung 40705, Taiwan.
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Räisänen LK, Kääriäinen SE, Sund R, Engberg E, Viljakainen HT, Kolho KL. Antibiotic exposures and the development of pediatric autoimmune diseases: a register-based case-control study. Pediatr Res 2023; 93:1096-1104. [PMID: 35854091 PMCID: PMC10033398 DOI: 10.1038/s41390-022-02188-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 05/27/2022] [Accepted: 06/22/2022] [Indexed: 11/09/2022]
Abstract
BACKGROUND Antibiotics have been associated with several individual autoimmune diseases (ADs). This study aims to discover whether pre-diagnostic antibiotics are associated with the onset of ADs in general. METHODS From a cohort of 11,407 children, 242 developed ADs (type 1 diabetes, autoimmune thyroiditis, juvenile idiopathic arthritis (JIA), or inflammatory bowel diseases) by a median age of 16 years. Antibiotic purchases from birth until the date of diagnosis (or respective date in the matched controls n = 708) were traced from national registers. RESULTS Total number of antibiotic purchases was not related to the onset of ADs when studied as a group. Of specific diagnoses, JIA was associated with the total number of antibiotics throughout the childhood and with broad-spectrum antibiotics before the age of 3 years. Intriguingly, recent and frequent antibiotic use (within 2 years before diagnosis and ≥3 purchases) was associated with the onset of ADs (OR 1.72, 95% CI 1.08-2.74). Regardless of frequent use in childhood (40% of all antibiotics), penicillin group antibiotics were not related to any ADs. CONCLUSIONS Use of antibiotics was relatively safe regarding the overall development of ADs. However, broad-spectrum antibiotics should be used considerately as they may associate with an increased likelihood of JIA. IMPACT Increasing numbers of antibiotic purchases before the age of 3 years or throughout childhood were not associated with the development of pediatric autoimmune diseases. Broad-spectrum antibiotics were related to the development of autoimmune diseases, especially juvenile idiopathic arthritis in children, while penicillin group antibiotics were not. The use of broad-spectrum antibiotics in children should be cautious as they may carry along a risk for autoimmune disease development.
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Affiliation(s)
- Laura K Räisänen
- Faculty of Medicine and Health Technology (MET), Tampere University, Tampere, Finland
- Folkhälsan Research Center, Helsinki, Finland
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland
| | | | - Reijo Sund
- Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Elina Engberg
- Folkhälsan Research Center, Helsinki, Finland
- Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Heli T Viljakainen
- Folkhälsan Research Center, Helsinki, Finland
- Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Kaija-Leena Kolho
- Faculty of Medicine and Health Technology (MET), Tampere University, Tampere, Finland.
- Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- Children's Hospital, Helsinki University Hospital, Helsinki, Finland.
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Khokhar M, Purohit P, Gadwal A, Tomo S, Bajpai NK, Shukla R. The Differentially Expressed Genes Responsible for the Development of T Helper 9 Cells From T Helper 2 Cells in Various Disease States: Immuno-Interactomics Study. JMIR BIOINFORMATICS AND BIOTECHNOLOGY 2023; 4:e42421. [PMID: 38935935 PMCID: PMC11135241 DOI: 10.2196/42421] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 01/18/2023] [Accepted: 01/25/2023] [Indexed: 06/29/2024]
Abstract
BACKGROUND T helper (Th) 9 cells are a novel subset of Th cells that develop independently from Th2 cells and are characterized by the secretion of interleukin (IL)-9. Studies have suggested the involvement of Th9 cells in variable diseases such as allergic and pulmonary diseases (eg, asthma, chronic obstructive airway disease, chronic rhinosinusitis, nasal polyps, and pulmonary hypoplasia), metabolic diseases (eg, acute leukemia, myelocytic leukemia, breast cancer, lung cancer, melanoma, pancreatic cancer), neuropsychiatric disorders (eg, Alzheimer disease), autoimmune diseases (eg, Graves disease, Crohn disease, colitis, psoriasis, systemic lupus erythematosus, systemic scleroderma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, atopic dermatitis, eczema), and infectious diseases (eg, tuberculosis, hepatitis). However, there is a dearth of information on its involvement in other metabolic, neuropsychiatric, and infectious diseases. OBJECTIVE This study aims to identify significant differentially altered genes in the conversion of Th2 to Th9 cells, and their regulating microRNAs (miRs) from publicly available Gene Expression Omnibus data sets of the mouse model using in silico analysis to unravel various pathogenic pathways involved in disease processes. METHODS Using differentially expressed genes (DEGs) identified from 2 publicly available data sets (GSE99166 and GSE123501) we performed functional enrichment and network analyses to identify pathways, protein-protein interactions, miR-messenger RNA associations, and disease-gene associations related to significant differentially altered genes implicated in the conversion of Th2 to Th9 cells. RESULTS We extracted 260 common downregulated, 236 common upregulated, and 634 common DEGs from the expression profiles of data sets GSE99166 and GSE123501. Codifferentially expressed ILs, cytokines, receptors, and transcription factors (TFs) were enriched in 7 crucial Kyoto Encyclopedia of Genes and Genomes pathways and Gene Ontology. We constructed the protein-protein interaction network and predicted the top regulatory miRs involved in the Th2 to Th9 differentiation pathways. We also identified various metabolic, allergic and pulmonary, neuropsychiatric, autoimmune, and infectious diseases as well as carcinomas where the differentiation of Th2 to Th9 may play a crucial role. CONCLUSIONS This study identified hitherto unexplored possible associations between Th9 and disease states. Some important ILs, including CCL1 (chemokine [C-C motif] ligand 1), CCL20 (chemokine [C-C motif] ligand 20), IL-13, IL-4, IL-12A, and IL-9; receptors, including IL-12RB1, IL-4RA (interleukin 9 receptor alpha), CD53 (cluster of differentiation 53), CD6 (cluster of differentiation 6), CD5 (cluster of differentiation 5), CD83 (cluster of differentiation 83), CD197 (cluster of differentiation 197), IL-1RL1 (interleukin 1 receptor-like 1), CD101 (cluster of differentiation 101), CD96 (cluster of differentiation 96), CD72 (cluster of differentiation 72), CD7 (cluster of differentiation 7), CD152 (cytotoxic T lymphocyte-associated protein 4), CD38 (cluster of differentiation 38), CX3CR1 (chemokine [C-X3-C motif] receptor 1), CTLA2A (cytotoxic T lymphocyte-associated protein 2 alpha), CTLA28, and CD196 (cluster of differentiation 196); and TFs, including FOXP3 (forkhead box P3), IRF8 (interferon regulatory factor 8), FOXP2 (forkhead box P2), RORA (RAR-related orphan receptor alpha), AHR (aryl-hydrocarbon receptor), MAF (avian musculoaponeurotic fibrosarcoma oncogene homolog), SMAD6 (SMAD family member 6), JUN (Jun proto-oncogene), JAK2 (Janus kinase 2), EP300 (E1A binding protein p300), ATF6 (activating transcription factor 6), BTAF1 (B-TFIID TATA-box binding protein associated factor 1), BAFT (basic leucine zipper transcription factor), NOTCH1 (neurogenic locus notch homolog protein 1), GATA3 (GATA binding protein 3), SATB1 (special AT-rich sequence binding protein 1), BMP7 (bone morphogenetic protein 7), and PPARG (peroxisome proliferator-activated receptor gamma, were able to identify significant differentially altered genes in the conversion of Th2 to Th9 cells. We identified some common miRs that could target the DEGs. The scarcity of studies on the role of Th9 in metabolic diseases highlights the lacunae in this field. Our study provides the rationale for exploring the role of Th9 in various metabolic disorders such as diabetes mellitus, diabetic nephropathy, hypertensive disease, ischemic stroke, steatohepatitis, liver fibrosis, obesity, adenocarcinoma, glioblastoma and glioma, malignant neoplasm of stomach, melanoma, neuroblastoma, osteosarcoma, pancreatic carcinoma, prostate carcinoma, and stomach carcinoma.
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Affiliation(s)
- Manoj Khokhar
- Department of Biochemistry, All India Institute of Medical Sciences Jodhpur, Jodhpur, India
| | - Purvi Purohit
- Department of Biochemistry, All India Institute of Medical Sciences Jodhpur, Jodhpur, India
| | - Ashita Gadwal
- Department of Biochemistry, All India Institute of Medical Sciences Jodhpur, Jodhpur, India
| | - Sojit Tomo
- Department of Biochemistry, All India Institute of Medical Sciences Jodhpur, Jodhpur, India
| | - Nitin Kumar Bajpai
- Department of Nephrology, All India Institute of Medical Sciences Jodhpur, Jodhpur, India
| | - Ravindra Shukla
- Department of Endocrinology and Metabolism, All India Institute of Medical Sciences Jodhpur, Jodhpur, India
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17
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Saez A, Herrero-Fernandez B, Gomez-Bris R, Sánchez-Martinez H, Gonzalez-Granado JM. Pathophysiology of Inflammatory Bowel Disease: Innate Immune System. Int J Mol Sci 2023; 24:ijms24021526. [PMID: 36675038 PMCID: PMC9863490 DOI: 10.3390/ijms24021526] [Citation(s) in RCA: 191] [Impact Index Per Article: 95.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 12/30/2022] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a heterogeneous state of chronic intestinal inflammation with no exact known cause. Intestinal innate immunity is enacted by neutrophils, monocytes, macrophages, and dendritic cells (DCs), and innate lymphoid cells and NK cells, characterized by their capacity to produce a rapid and nonspecific reaction as a first-line response. Innate immune cells (IIC) defend against pathogens and excessive entry of intestinal microorganisms, while preserving immune tolerance to resident intestinal microbiota. Changes to this equilibrium are linked to intestinal inflammation in the gut and IBD. IICs mediate host defense responses, inflammation, and tissue healing by producing cytokines and chemokines, activating the complement cascade and phagocytosis, or presenting antigens to activate the adaptive immune response. IICs exert important functions that promote or ameliorate the cellular and molecular mechanisms that underlie and sustain IBD. A comprehensive understanding of the mechanisms underlying these clinical manifestations will be important for developing therapies targeting the innate immune system in IBD patients. This review examines the complex roles of and interactions among IICs, and their interactions with other immune and non-immune cells in homeostasis and pathological conditions.
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Affiliation(s)
- Angela Saez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria (UFV), 28223 Pozuelo de Alarcón, Spain
| | - Beatriz Herrero-Fernandez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
| | - Raquel Gomez-Bris
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
| | - Hector Sánchez-Martinez
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
| | - Jose M. Gonzalez-Granado
- LamImSys Lab, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain
- Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain
- CIBER de Enfermedades Cardiovasculares (CIBERCV), 28029 Madrid, Spain
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-913908766
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18
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Al-Rshaidat MMD, Al-Sharif S, Refaei AA, Shewaikani N, Alsayed AR, Rayyan YM. Evaluating the clinical application of the immune cells' ratios and inflammatory markers in the diagnosis of inflammatory bowel disease. Pharm Pract (Granada) 2023; 21:2755. [PMID: 37090461 PMCID: PMC10117338 DOI: 10.18549/pharmpract.2023.1.2755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 10/20/2022] [Indexed: 04/25/2023] Open
Abstract
Objective Inflammatory Bowel Diseases (IBDs) are chronic inflammatory conditions of the gastrointestinal tract, including Crohn's disease (CD) and ulcerative colitis (UC). Developing methods for effective screening and diagnosis is extremely needed. Accordingly, this study aims to evaluate the potential of immune cells ratios in the diagnosis of IBD. Methods This case-control study includes data from Jordan University Hospital (JUH) medical records for IBD patients with age- and gender-matched healthy controls. Results This study included 46 participants, of which 56.52% had IBD, 54.35% were males, with insignificant differences in sex, age, and body mass index (BMI) between IBD patients and controls (p>0.05). In the CD group, the variables with the highest sensitivity and specificity (HSS) were neutrophil-to-lymphocyte (NLR) (75%, 80%) and platelet-to-lymphocytes (PLR) (75%, 90%), in UC group; mean corpuscular hemoglobin (MCH) (80%, 80%). In CD group, the combinations giving the HSS were PLR+NLR (76%, 90.9%), C-reactive protein (CRP)+PLR (76%, 90.9%), and CRP+NLR (73.07%, 90%). In UC group, the combinations giving the HSS were erythrocyte sedimentation rate (ESR)+PLR (76.9%, 100%), PLR+MCH (74.07%, 100%), PLR+CRP (71.42%, 100%), and PLR+NLR (71.42%, 100%). Regression analysis identified five different combinations of significance in the diagnosis of CD and UC. Higher Youden's index was used and defined the most beneficial clinical combinations as NLR+PLR and CRP+PLR for CD, whereas ESR+PLR for UC. Conclusion Implications to our study include the clinical application of immune cell ratios, inflammatory markers, and their different combinations along with patients' history and physical examination findings for easier, faster, and more cost-effective diagnosis of IBDs.
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Affiliation(s)
- Mamoon M D Al-Rshaidat
- Department of Biological, Sciences, Laboratory for Molecular & Microbial Ecology (LaMME), School of Sciences, The University of Jordan, Amman 11942, Jordan.
| | - Shaima Al-Sharif
- Department of Biological, Sciences, School of Sciences, The University of Jordan, Amman 11942, Jordan.
| | - Assem Al Refaei
- School of Medicine, The University of Jordan, Amman 11942, Jordan.
| | - Nour Shewaikani
- School of Medicine, The University of Jordan, Amman 11942, Jordan.
| | - Ahmad R Alsayed
- Department of Clinical Pharmacy and Therapeutics, Faculty of Pharmacy, Applied Science Private University, Amman 11931-166, Jordan.
| | - Yaser M Rayyan
- School of Medicine, The University of Jordan, Amman 11942, Jordan.
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Räisänen L, Viljakainen H, Kolho KL. Exposure to proton pump inhibitors is associated with the development of pediatric autoimmune diseases. Front Pediatr 2023; 11:1157547. [PMID: 37051434 PMCID: PMC10083351 DOI: 10.3389/fped.2023.1157547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 03/08/2023] [Indexed: 04/14/2023] Open
Abstract
Proton pump inhibitors (PPIs) have been associated with decreased gut microbiota diversity. Disrupted gut microbiota composition has been reported in several autoimmune diseases (ADs), such as type 1 diabetes mellitus (DM), autoimmune thyroiditis (AIT), juvenile idiopathic arthritis (JIA), and inflammatory bowel diseases (IBD). We investigated whether PPIs are associated with the development of ADs in children and concluded that PPI exposures could be related to the onset of ADs, especially IBD and potentially AIT as well.
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Affiliation(s)
- Laura Räisänen
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland
- Correspondence: Laura Räisänen Kaija-Leena Kolho
| | - Heli Viljakainen
- Public Health Research Program, Folkhälsan Research Center, Helsinki, Finland
- Children’s Hospital, University of Helsinki and HUS, Helsinki, Finland
| | - Kaija-Leena Kolho
- Children’s Hospital, University of Helsinki and HUS, Helsinki, Finland
- Faculty of Medicine and Medical Technology, Tampere University, Tampere, Finland
- Correspondence: Laura Räisänen Kaija-Leena Kolho
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20
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Hammoudi N, Hamoudi S, Bonnereau J, Bottois H, Pérez K, Bezault M, Hassid D, Chardiny V, Grand C, Gergaud B, Bonnet J, Chedouba L, Tran Minh ML, Gornet JM, Baudry C, Corte H, Maggiori L, Toubert A, McBride J, Brochier C, Neighbors M, Le Bourhis L, Allez M. Autologous organoid co-culture model reveals T cell-driven epithelial cell death in Crohn's Disease. Front Immunol 2022; 13:1008456. [PMID: 36439157 PMCID: PMC9685428 DOI: 10.3389/fimmu.2022.1008456] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 10/24/2022] [Indexed: 09/15/2023] Open
Abstract
Lympho-epithelial interactions between intestinal T resident memory cells (Trm) and the epithelium have been associated with inflammatory bowel disease (IBD) activity. We developed ex vivo autologous organoid-mucosal T cell cocultures to functionally assess lymphoepithelial interactions in Crohn's Disease (CD) patients compared to controls. We demonstrate the direct epithelial cell death induced by autologous mucosal T cells in CD patients but not in controls. These findings were positively correlated with T cell infiltration of the organoids. This potential was inhibited by limiting lympho-epithelial interactions through CD103 and NKG2D blocking antibodies. These data directly demonstrate for the first time the direct deleterious effect of mucosal T cells on the epithelium of CD patients. Such ex-vivo models are promising techniques to unravel the pathophysiology of these diseases and the potential mode of action of current and future therapies.
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Affiliation(s)
- Nassim Hammoudi
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
- Gastroenterology Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
| | - Sarah Hamoudi
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
| | - Julie Bonnereau
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
| | - Hugo Bottois
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
| | - Kevin Pérez
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
| | - Madeleine Bezault
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
| | - Déborah Hassid
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
- Gastroenterology Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
| | - Victor Chardiny
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
| | - Céline Grand
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
| | - Brice Gergaud
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
| | - Joëlle Bonnet
- Gastroenterology Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
| | - Leila Chedouba
- Gastroenterology Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
| | - My-Linh Tran Minh
- Gastroenterology Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
| | - Jean-Marc Gornet
- Gastroenterology Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
| | - Clotilde Baudry
- Gastroenterology Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
| | - Hélène Corte
- Digestive Surgery Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
| | - Léon Maggiori
- Digestive Surgery Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
| | - Antoine Toubert
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
| | - Jacqueline McBride
- OMNI Biomarker Development, Genentech Inc., South San Francisco, CA, United States
| | | | - Margaret Neighbors
- OMNI Biomarker Development, Genentech Inc., South San Francisco, CA, United States
| | - Lionel Le Bourhis
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
| | - Matthieu Allez
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
- Gastroenterology Department, AP-HP, Hôpital Saint-Louis/Lariboisière, Paris, France
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21
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Abstract
Parasitic helminth infections, while a major cause of neglected tropical disease burden, negatively correlate with the incidence of immune-mediated inflammatory diseases such as inflammatory bowel diseases (IBD). To evade expulsion, helminths have developed sophisticated mechanisms to regulate their host's immune responses. Controlled experimental human helminth infections have been assessed clinically for treating inflammatory conditions; however, such a radical therapeutic modality has challenges. An alternative approach is to harness the immunomodulatory properties within the worm's excretory-secretory (ES) complement, its secretome. Here, we report a biologics discovery and validation pipeline to generate and screen in vivo a recombinant cell-free secretome library of helminth-derived immunomodulatory proteins. We successfully expressed 78 recombinant ES proteins from gastrointestinal hookworms and screened the crude in vitro translation reactions for anti-IBD properties in a mouse model of acute colitis. After statistical filtering and ranking, 20 proteins conferred significant protection against various parameters of colitis. Lead candidates from distinct protein families, including annexins, transthyretins, nematode-specific retinol-binding proteins, and SCP/TAPS were identified. Representative proteins were produced in mammalian cells and further validated, including ex vivo suppression of inflammatory cytokine secretion by T cells from IBD patient colon biopsies. Proteins identified herein offer promise as novel, safe, and mechanistically differentiated biologics for treating the globally increasing burden of inflammatory diseases.
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22
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Lindholm M, Di Sabatino A, Manon-Jensen T, Mazza G, Madsen GI, Giuffrida P, Pinzani M, Krag A, Karsdal MA, Kjeldsen J, Mortensen JH. A Serological Biomarker of Laminin Gamma 1 Chain Degradation Reflects Altered Basement Membrane Remodeling in Crohn's Disease and DSS Colitis. Dig Dis Sci 2022; 67:3662-3671. [PMID: 34561759 DOI: 10.1007/s10620-021-07252-3] [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] [Received: 05/10/2021] [Accepted: 09/08/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND The laminin gamma 1 chain (LMγ1) is abundant along the crypt-villus axis in the intestinal basement membrane. AIMS We investigated whether a serological biomarker of laminin degradation was associated with disease activity in patients with Crohn's disease (CD) and in rats with dextran sulfate sodium (DSS)-induced colitis. METHODS Serum samples from CD patients (n = 43), healthy subjects (n = 19), and Sprague Dawley rats receiving 5-6% DSS water for five days and regular drinking water for 11 days were included in this study. The LG1M biomarker, a neo-epitope degradation fragment of the LMγ1 chain generated by matrix metalloproteinases-9 (MMP-9), was measured in serum to estimate the level of laminin degradation. RESULTS Serum LG1M was elevated in CD patients with active and inactive disease compared to healthy subjects (p < 0.0001). LG1M distinguished CD patients from healthy subjects, with an area under the curve (AUC) of 0.81 (p < 0.0001). Serum LG1M was decreased in DSS rats compared to controls 2 days after DSS withdrawal, and increased upon reversal of the disease. CONCLUSIONS Increased serum LG1M in active and inactive CD patients supports the evidence of altered LM expression in both inflamed and non-inflamed tissue. Moreover, lower LG1M levels in the early healing phase of DSS-induced colitis may reflect ongoing mucosal repair.
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Affiliation(s)
- Majken Lindholm
- Biomarkers and Research, Nordic Bioscience, Herlev hovedgade 205-207, 2730, Herlev, Denmark. .,Department of Medical Gastroenterology, University of Southern Denmark and Odense University Hospital, Odense, Denmark.
| | - Antonio Di Sabatino
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Tina Manon-Jensen
- Biomarkers and Research, Nordic Bioscience, Herlev hovedgade 205-207, 2730, Herlev, Denmark
| | - Giuseppe Mazza
- Institute for Liver and Digestive Health, University College of London, London, UK
| | - Gunvor I Madsen
- Department of Surgical Pathology, Odense University Hospital, Odense, Denmark
| | - Paolo Giuffrida
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Massimo Pinzani
- Institute for Liver and Digestive Health, University College of London, London, UK
| | - Aleksander Krag
- Department of Medical Gastroenterology, University of Southern Denmark and Odense University Hospital, Odense, Denmark
| | - Morten A Karsdal
- Biomarkers and Research, Nordic Bioscience, Herlev hovedgade 205-207, 2730, Herlev, Denmark
| | - Jens Kjeldsen
- Department of Medical Gastroenterology, University of Southern Denmark and Odense University Hospital, Odense, Denmark
| | - Joachim H Mortensen
- Biomarkers and Research, Nordic Bioscience, Herlev hovedgade 205-207, 2730, Herlev, Denmark
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23
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Lin H, Bai Z, Wu Q, Chu G, Zhang Y, Guo X, Qi X. Inflammatory Indexes for Assessing the Severity and Disease Progression of Ulcerative Colitis: A Single-Center Retrospective Study. Front Public Health 2022; 10:851295. [PMID: 35359771 PMCID: PMC8963422 DOI: 10.3389/fpubh.2022.851295] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 02/07/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Active and severe ulcerative colitis (UC) and non-response to 5-aminosalicylic acid (5-ASA) are related to poor outcomes and should be accurately identified. Several integrated inflammatory indexes are potentially useful to assess the disease severity in patients with acute or critical diseases but are underexplored in patients with UC. METHODS Patients with UC consecutively admitted to our hospital between January 2015 and December 2020 were retrospectively grouped according to the activity and severity of UC and response to 5-ASA. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), neutrophil-to-platelet ratio (NPR), platelet-to-albumin ratio (PAR), C-reactive protein-to-albumin ratio (CAR), and C-reactive protein-to-lymphocyte ratio (CLR) were calculated. The areas under receiver operating characteristic curves (AUC) were calculated. RESULTS Overall, 187 patients with UC were included, of whom 151 were active, 55 were severe, and 14 were unresponsive to 5-ASA. The active UC group had significantly higher NLR, PLR, SII, and PAR levels. SII had the greatest predictive accuracy for active UC, followed by PLR, PAR, and NLR (AUC = 0.647, 0.641, 0.634, and 0.626). The severe UC group had significantly higher NLR, PLR, SII, PAR, CAR, and CLR levels. CLR had the greatest predictive accuracy for severe UC, followed by CAR, PLR, SII, NLR, and PAR (AUC = 0.732, 0.714, 0.693, 0.669, 0.646, and 0.63). The non-response to the 5-ASA group had significantly higher CAR and CLR levels. CAR had a greater predictive accuracy for non-response to 5-ASA than CLR (AUC = 0.781 and 0.759). CONCLUSION SII, CLR, and CAR may be useful for assessing the severity and progression of UC, but remain not optimal.
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Affiliation(s)
- Hanyang Lin
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
- Postgraduate College, China Medical University, Shenyang, China
| | - Zhaohui Bai
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
- Postgraduate College, Shenyang Pharmaceutical University, Shenyang, China
| | - Qiong Wu
- Department of Thoracic Surgery, General Hospital of Northern Theater Command, Shenyang, China
| | - Guiyang Chu
- Information Section of Medical Security Center, General Hospital of Northern Theater Command, Shenyang, China
| | - Yongguo Zhang
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
| | - Xiaozhong Guo
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
| | - Xingshun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
- Postgraduate College, China Medical University, Shenyang, China
- Postgraduate College, Shenyang Pharmaceutical University, Shenyang, China
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24
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Räisänen L, Lommi S, Engberg E, Kolho K, Viljakainen H. Central obesity in school-aged children increases the likelihood of developing paediatric autoimmune diseases. Pediatr Obes 2022; 17:e12857. [PMID: 34608761 PMCID: PMC9285017 DOI: 10.1111/ijpo.12857] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 09/20/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND The incidences of both paediatric obesity and autoimmune diseases have been increasing, but their relationship with one another is unclear. OBJECTIVE To determine whether obesity or particular dietary patterns in school-aged children are potential risk factors for autoimmune diseases during adolescence. METHODS This matched case-control study included 525 children, followed up from a median age of 11.3 to 16.7 years. Of them, 105 children received primary autoimmune diagnoses (diabetes, thyroiditis, arthritis, or inflammatory bowel diseases) after baseline and generated the case group. Four children with matching age, sex, and residential area generated the control group of 420 children. At baseline, age- and sex-specific body mass index categories were acquired and waist-to-height ratio (WHTR) was calculated. Central obesity was present when WHTR ≥0.5. Dietary patterns were analysed using a food frequency questionnaire (FFQ). RESULTS School-aged children with central obesity were 2.11 (OR, 95% CI 1.11-3.98) times more likely to develop autoimmune diseases before age of 19 years than those without central obesity. Being overweight was not related to the onset of these diseases (OR 1.60, 95% CI 0.89-2.87, nor were dietary patterns. CONCLUSION Central obesity in school-aged children was related to the development of autoimmune diseases, while being overweight and dietary patterns were not.
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Affiliation(s)
- Laura Räisänen
- Fin‐HIT Research GroupFolkhälsan Research CenterHelsinkiFinland,Faculty of Medicine and Health Technology (MET)Tampere UniversityTampereFinland,Department of PediatricsTampere University HospitalTampereFinland
| | - Sohvi Lommi
- Fin‐HIT Research GroupFolkhälsan Research CenterHelsinkiFinland,Department of Public HealthUniversity of HelsinkiHelsinkiFinland
| | - Elina Engberg
- Fin‐HIT Research GroupFolkhälsan Research CenterHelsinkiFinland,Department of Psychology and LogopedicsUniversity of HelsinkiHelsinkiFinland
| | - Kaija‐Leena Kolho
- Faculty of Medicine and Health Technology (MET)Tampere UniversityTampereFinland,Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
| | - Heli Viljakainen
- Fin‐HIT Research GroupFolkhälsan Research CenterHelsinkiFinland,Faculty of MedicineUniversity of HelsinkiHelsinkiFinland
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25
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Serafini MA, Paz AH, Nunes NS. Cholinergic immunomodulation in inflammatory bowel diseases. Brain Behav Immun Health 2022; 19:100401. [PMID: 34977822 PMCID: PMC8683952 DOI: 10.1016/j.bbih.2021.100401] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 11/29/2021] [Accepted: 12/04/2021] [Indexed: 12/28/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic intestinal disorders characterized by dysregulated immune responses to resident microbiota in genetically susceptible hosts. The activation of the cholinergic system has been proposed for the treatment of IBD patients according to its potential anti-inflammatory effect in vivo. The α-7-nicotinic-acetylcholine receptor (α7nAChR) is involved in the inhibition of inflammatory processes, modulating the production of cytokines, suppressing dendritic cells and macrophage activity, leading to the suppression of T cells. In this review, we address the most recent studies and clinical trials concerning cholinergic signaling and its therapeutic potential for inflammatory bowel diseases.
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Affiliation(s)
- Michele A. Serafini
- Biological Sciences, Physiology Graduate Program, Federal University of Rio Grande do Sul, 90050170, Porto Alegre, Brazil
- Cells, Tissue and Genes Laboratory, Experimental Research Center, Hospital de Clinicas de Porto Alegre, 90035903, Porto Alegre, Brazil
| | - Ana H. Paz
- Morphological Sciences Department, Basic Health Sciences Institute, Federal University of Rio Grande do Sul, 90050170, Porto Alegre, Brazil
- Cells, Tissue and Genes Laboratory, Experimental Research Center, Hospital de Clinicas de Porto Alegre, 90035903, Porto Alegre, Brazil
| | - Natalia S. Nunes
- Experimental Transplantation Immunotherapy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 20852, Bethesda, MD, USA
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26
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Műzes G, Bohusné Barta B, Sipos F. Colitis and Colorectal Carcinogenesis: The Focus on Isolated Lymphoid Follicles. Biomedicines 2022; 10:226. [PMID: 35203436 PMCID: PMC8869724 DOI: 10.3390/biomedicines10020226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/09/2022] [Accepted: 01/20/2022] [Indexed: 02/05/2023] Open
Abstract
Gut-associated lymphoid tissue is one of the most diverse and complex immune compartments in the human body. The subepithelial compartment of the gut consists of immune cells of innate and adaptive immunity, non-hematopoietic mesenchymal cells, and stem cells of different origins, and is organized into secondary (and even tertiary) lymphoid organs, such as Peyer's patches, cryptopatches, and isolated lymphoid follicles. The function of isolated lymphoid follicles is multifaceted; they play a role in the development and regeneration of the large intestine and the maintenance of (immune) homeostasis. Isolated lymphoid follicles are also extensively associated with the epithelium and its conventional and non-conventional immune cells; hence, they can also function as a starting point or maintainer of pathological processes such as inflammatory bowel diseases or colorectal carcinogenesis. These relationships can significantly affect both physiological and pathological processes of the intestines. We aim to provide an overview of the latest knowledge of isolated lymphoid follicles in colonic inflammation and colorectal carcinogenesis. Further studies of these lymphoid organs will likely lead to an extended understanding of how immune responses are initiated and controlled within the large intestine, along with the possibility of creating novel mucosal vaccinations and ways to treat inflammatory bowel disease or colorectal cancer.
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Affiliation(s)
| | | | - Ferenc Sipos
- Department of Internal Medicine and Hematology, Semmelweis University, 1088 Budapest, Hungary; (G.M.); (B.B.B.)
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27
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Abstract
Inflammatory bowel disease (IBD) is a chronic and nonspecific intestinal inflammatory condition with high relapse rate. Its pathogenesis has been linked to dysbacteriosis, genetic and environmental factors. In recent years, a new type of lymphocytes, termed innate lymphoid cells, has been described and classified into three subtypes of innate lymphoid cells-group 1, group 2 and group 3. An imbalance among these subsets' interaction with gut microbiome, and other immune cells affects intestinal mucosal homeostasis. Understanding the role of innate lymphoid cells may provide ideas for developing novel and targeted approaches for treatment of IBD.
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28
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Ihara Y, Torisu T, Miyawaki K, Umeno J, Kawasaki K, Hirano A, Fujioka S, Fuyuno Y, Matsuno Y, Sugio T, Sasaki K, Moriyama T, Akashi K, Kitazono T. Ustekinumab Improves Active Crohn's Disease by Suppressing the T Helper 17 Pathway. Digestion 2021; 102:946-955. [PMID: 34350861 DOI: 10.1159/000518103] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 06/10/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND Ustekinumab (UST), an antibody targeting the p40 subunit of interleukin (IL)-12 and IL-23, is effective in treating Crohn's disease (CD). To clarify the mechanism of UST, we investigated T-cell differentiation in CD patients treated with UST. METHODS Twenty-seven patients with active CD were enrolled in this study. Seventeen patients were treated with UST, and 10 patients were treated with anti-tumor necrosis factor (TNF)-alpha therapy. The changes in the proportions of T-cell subsets after these therapies were analyzed by flow cytometry. Comprehensive gene expression changes in the colonic mucosa were also evaluated. RESULTS The frequency of T helper (Th) 17 cells was significantly decreased in the peripheral blood of patients with active CD after UST therapy. Anti-TNF therapy had a minimal effect on Th17 cells but increased the proportion of regulatory T cells. Enrichment analysis showed the expression of genes involved in the Th17 differentiation pathway was downregulated in the colonic mucosa after UST but not anti-TNF therapy. There were no common differentially expressed genes between CD patients treated with UST and anti-TNF therapy, suggesting a clear difference in their mechanism of action. CONCLUSION In patients with active CD, UST therapy suppressed Th17 cell differentiation both in the peripheral blood and colonic tissues.
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Affiliation(s)
- Yutaro Ihara
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takehiro Torisu
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kohta Miyawaki
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Junji Umeno
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Keisuke Kawasaki
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Atsushi Hirano
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shin Fujioka
- Department of Endoscopic Diagnostics and Therapeutics, Kyushu University Hospital, Fukuoka, Japan
| | - Yuta Fuyuno
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuichi Matsuno
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeshi Sugio
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kensuke Sasaki
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomohiko Moriyama
- Department of International Medical, Kyushu University Hospital, Fukuoka, Japan
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takanari Kitazono
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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29
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Basso D, Padoan A, D'Incà R, Arrigoni G, Scapellato ML, Contran N, Franchin C, Lorenzon G, Mescoli C, Moz S, Bozzato D, Rugge M, Plebani M. Peptidomic and proteomic analysis of stool for diagnosing IBD and deciphering disease pathogenesis. Clin Chem Lab Med 2021; 58:968-979. [PMID: 32229654 DOI: 10.1515/cclm-2019-1125] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 03/02/2020] [Indexed: 12/12/2022]
Abstract
Background The sensitivities and specificities of C-reactive protein (CRP) and faecal calprotectin (fCal), as recommended for inflammatory bowel diseases (IBD) diagnosis and monitoring, are low. Our aim was to discover new stool protein/peptide biomarkers for diagnosing IBD. Methods For peptides, MALDI-TOF/MS (m/z 1000-4000) was performed using stools from an exploratory (34 controls; 72 Crohn's disease [CD], 56 ulcerative colitis [UC]) and a validation (28 controls, 27 CD, 15 UC) cohort. For proteins, LTQ-Orbitrap XL MS analysis (6 controls, 5 CD, 5 UC) was performed. Results MALDI-TOF/MS spectra of IBD patients had numerous features, unlike controls. Overall, 426 features (67 control-associated, 359 IBD-associated) were identified. Spectra were classified as control or IBD (absence or presence of IBD-associated features). In the exploratory cohort, the sensitivity and specificity of this classification algorithm were 81% and 97%, respectively. Blind analysis of the validation cohort confirmed 97% specificity, with a lower sensitivity (55%) paralleling active disease frequency. Following binary logistic regression analysis, IBD was independently correlated with MALDI-TOF/MS spectra (p < 0.0001), outperforming fCal measurements (p = 0.029). The IBD-correlated m/z 1810.8 feature was a fragment of APC2, homologous with APC, over-expressed by infiltrating cells lining the surface in UC or the muscularis-mucosae in CD (assessed by immunohistochemistry). IBD-associated over-expressed proteins included immunoglobulins and neutrophil proteins, while those under-expressed comprised proteins of the nucleic acid assembly or those (OLFM4, ENPP7) related to cancer risk. Conclusions Our study provides evidence for the clinical utility of a novel proteomic method for diagnosing IBD and insight on the pathogenic role of APC. Moreover, the newly described IBD-associated proteins might become tools for cancer risk assessment in IBD patients.
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Affiliation(s)
- Daniela Basso
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Andrea Padoan
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Renata D'Incà
- Department of Surgical, Oncological and Gastroenterological Sciences - DISCOG, University Hospital, Padova, Italy
| | - Giorgio Arrigoni
- Department of Biomedical Sciences - BIOMED, University of Padova, Padova, Italy.,Proteomic Center, University of Padova, Padua, Italy
| | - Maria Luisa Scapellato
- Department of Cardiologic, Thoracic and Vascular Sciences, Preventive Medicine and Risk Assessment Unit, University Hospital of Padova, Padova, Italy
| | - Nicole Contran
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Cinzia Franchin
- Department of Biomedical Sciences - BIOMED, University of Padova, Padova, Italy.,Proteomic Center, University of Padova, Padua, Italy
| | - Greta Lorenzon
- Department of Surgical, Oncological and Gastroenterological Sciences - DISCOG, University Hospital, Padova, Italy
| | - Claudia Mescoli
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Stefania Moz
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Dania Bozzato
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Massimo Rugge
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Mario Plebani
- Department of Medicine - DIMED, University of Padova, Padova, Italy
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Saez A, Gomez-Bris R, Herrero-Fernandez B, Mingorance C, Rius C, Gonzalez-Granado JM. Innate Lymphoid Cells in Intestinal Homeostasis and Inflammatory Bowel Disease. Int J Mol Sci 2021; 22:ijms22147618. [PMID: 34299236 PMCID: PMC8307624 DOI: 10.3390/ijms22147618] [Citation(s) in RCA: 119] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/13/2021] [Accepted: 07/14/2021] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a heterogeneous state of chronic intestinal inflammation of unknown cause encompassing Crohn’s disease (CD) and ulcerative colitis (UC). IBD has been linked to genetic and environmental factors, microbiota dysbiosis, exacerbated innate and adaptive immunity and epithelial intestinal barrier dysfunction. IBD is classically associated with gut accumulation of proinflammatory Th1 and Th17 cells accompanied by insufficient Treg numbers and Tr1 immune suppression. Inflammatory T cells guide innate cells to perpetuate a constant hypersensitivity to microbial antigens, tissue injury and chronic intestinal inflammation. Recent studies of intestinal mucosal homeostasis and IBD suggest involvement of innate lymphoid cells (ILCs). These lymphoid-origin cells are innate counterparts of T cells but lack the antigen receptors expressed on B and T cells. ILCs play important roles in the first line of antimicrobial defense and contribute to organ development, tissue protection and regeneration, and mucosal homeostasis by maintaining the balance between antipathogen immunity and commensal tolerance. Intestinal homeostasis requires strict regulation of the quantity and activity of local ILC subpopulations. Recent studies demonstrated that changes to ILCs during IBD contribute to disease development. A better understanding of ILC behavior in gastrointestinal homeostasis and inflammation will provide valuable insights into new approaches to IBD treatment. This review summarizes recent research into ILCs in intestinal homeostasis and the latest advances in the understanding of the role of ILCs in IBD, with particular emphasis on the interaction between microbiota and ILC populations and functions.
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Affiliation(s)
- Angela Saez
- LamImSys Lab, Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain; (A.S.); (R.G.-B.); (B.H.-F.); (C.M.)
- Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria (UFV), 28223 Madrid, Spain
| | - Raquel Gomez-Bris
- LamImSys Lab, Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain; (A.S.); (R.G.-B.); (B.H.-F.); (C.M.)
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
| | - Beatriz Herrero-Fernandez
- LamImSys Lab, Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain; (A.S.); (R.G.-B.); (B.H.-F.); (C.M.)
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
| | - Claudia Mingorance
- LamImSys Lab, Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain; (A.S.); (R.G.-B.); (B.H.-F.); (C.M.)
| | - Cristina Rius
- Faculty of Biomedical and Health Sciences, Universidad Europea de Madrid (UEM), Villaviciosa de Odón, 28670 Madrid, Spain;
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
- CIBER de Enfermedades Cardiovasculares, 28029 Madrid, Spain
| | - Jose M. Gonzalez-Granado
- LamImSys Lab, Instituto de Investigación Hospital 12 de Octubre (imas12), 28041 Madrid, Spain; (A.S.); (R.G.-B.); (B.H.-F.); (C.M.)
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain
- CIBER de Enfermedades Cardiovasculares, 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-913908766
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Hanson ED, Bates LC, Bartlett DB, Campbell JP. Does exercise attenuate age- and disease-associated dysfunction in unconventional T cells? Shining a light on overlooked cells in exercise immunology. Eur J Appl Physiol 2021; 121:1815-1834. [PMID: 33822261 DOI: 10.1007/s00421-021-04679-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 03/28/2021] [Indexed: 02/06/2023]
Abstract
Unconventional T Cells (UTCs) are a unique population of immune cells that links innate and adaptive immunity. Following activation, UTCs contribute to a host of immunological activities, rapidly responding to microbial and viral infections and playing key roles in tumor suppression. Aging and chronic disease both have been shown to adversely affect UTC numbers and function, with increased inflammation, change in body composition, and physical inactivity potentially contributing to the decline. One possibility to augment circulating UTCs is through increased physical activity. Acute exercise is a potent stimulus leading to the mobilization of immune cells while the benefits of exercise training may include anti-inflammatory effects, reductions in fat mass, and improved fitness. We provide an overview of age-related changes in UTCs, along with chronic diseases that are associated with altered UTC number and function. We summarize how UTCs respond to acute exercise and exercise training and discuss potential mechanisms that may lead to improved frequency and function.
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Affiliation(s)
- Erik D Hanson
- Department of Exercise and Sport Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27517, USA. .,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. .,Human Movement Science Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Lauren C Bates
- Department of Exercise and Sport Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27517, USA.,Human Movement Science Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - David B Bartlett
- Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC, USA
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Manon‐Jensen T, Sun S, Lindholm M, Domislović V, Giuffrida P, Brinar M, Mazza G, Pinzani M, Krznarić Z, Di Sabatino A, Karsdal MA, Mortensen JH. Elevated ectodomain of type 23 collagen is a novel biomarker of the intestinal epithelium to monitor disease activity in ulcerative colitis and Crohn's disease. United European Gastroenterol J 2021; 9:268-278. [PMID: 33351719 PMCID: PMC8259268 DOI: 10.1177/2050640620977371] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 10/29/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Impaired intestinal epithelial barrier is highly affected in inflammatory bowel disease. Transmembrane collagens connecting the epithelial cells to the extracellular matrix have an important role in epithelial cell homeostasis. Thus, we sought to determine whether the transmembrane type 23 collagen could serve as a surrogate marker for disease activity in patients with Crohn's disease and ulcerative colitis. METHODS We developed an enzyme-linked immunosorbent assay to detect the ectodomain of type 23 collagen (PRO-C23) in serum, followed by evaluation of its levels in both acute and chronic dextran sulphate sodium colitis models in rats and human inflammatory bowel disease cohorts. Serum from 44 Crohn's disease and 29 ulcerative colitis patients with active and inactive disease was included. RESULTS In the acute and chronic dextran sulphate sodium-induced rat colitis model, the PRO-C23 serum levels were significantly increased after colitis and returned to normal levels after disease remission. Serum levels of PRO-C23 were elevated in Crohn's disease (p < 0.05) and ulcerative colitis (p < 0.001) patients with active disease compared to healthy donors. PRO-C23 differentiated healthy donors from ulcerative colitis (area under the curve [AUC]: 0.81, p = 0.0009) and Crohn's disease (AUC: 0.70, p = 0.0124). PRO-C23 differentiated ulcerative colitis patients with active disease from those in remission (AUC: 0.75, p = 0.0219) and Crohn's disease patients with active disease from those in remission (AUC: 0.68, p = 0.05). CONCLUSION PRO-C23 was elevated in rats with active colitis, and inflammatory bowel disease patients with active disease. Therefore, PRO-C23 may be used as a surrogate marker for monitoring disease activity in ulcerative colitis and Crohn's disease.
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Affiliation(s)
- T. Manon‐Jensen
- Institute for Liver and Digestive HealthUniversity College of LondonLondonUK
| | - S. Sun
- Institute for Liver and Digestive HealthUniversity College of LondonLondonUK
| | - M. Lindholm
- Institute for Liver and Digestive HealthUniversity College of LondonLondonUK
| | - V. Domislović
- Biomarkers and ResearchNordic BioscienceHerlevDenmark
| | - P. Giuffrida
- Department of Gastroenterology and HepatologyClinical Hospital CentreZagrebCroatia
| | - M. Brinar
- Biomarkers and ResearchNordic BioscienceHerlevDenmark
| | - G. Mazza
- First Department of Internal MedicineUniversity of PaviaPaviaItaly
| | - M. Pinzani
- First Department of Internal MedicineUniversity of PaviaPaviaItaly
| | - Z. Krznarić
- Biomarkers and ResearchNordic BioscienceHerlevDenmark
| | - A. Di Sabatino
- Department of Gastroenterology and HepatologyClinical Hospital CentreZagrebCroatia
- First Department of Internal MedicineUniversity of PaviaPaviaItaly
| | - M. A. Karsdal
- Institute for Liver and Digestive HealthUniversity College of LondonLondonUK
| | - J. H. Mortensen
- Institute for Liver and Digestive HealthUniversity College of LondonLondonUK
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Zhang MH, Wang H, Wang HG, Wen X, Yang XZ. Effective immune-inflammation index for ulcerative colitis and activity assessments. World J Clin Cases 2021; 9:334-343. [PMID: 33521101 PMCID: PMC7812895 DOI: 10.12998/wjcc.v9.i2.334] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 09/28/2020] [Accepted: 11/21/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The inverse association between systemic immune-inflammation index (SII) and overall survival in tumors has been studied.
AIM To evaluate the hematological indexes for assessing the activity of ulcerative colitis (UC).
METHODS In this case-control study, 172 UC patients and healthy participants were included. Comparisons were made among groups of white blood cells, hemoglobin, platelets, neutrophils, lymphocytes, monocytes, SII, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR). The relationship with hematological inflammation was verified by Spearman correlation analyses. The efficiency of SII, NLR, and PLR for distinguishing between UC and severe disease status was assessed by the receiver operator curve and logistic regression analyses.
RESULTS The values of SII, NLR, and PLR were higher in UC patients than in controls (P < 0.001) and were positively correlated with the Mayo endoscopic score, extent, Degree of Ulcerative Colitis Burden of Luminal Inflammation (DUBLIN) score, and Ulcerative Colitis Endoscopic Index of Severity (UCEIS). The cut-off NLR value of 562.22 predicted UC with a sensitivity of 79.65% and a specificity of 76.16%. Logistic regression analysis revealed that patients with SII and NLR levels above the median had a significantly higher risk of UC (P < 0.05). Risk factors independently associated with DUBLIN ≥ 3 included SII ≥ 1776.80 [odds ratio (OR) = 11.53, P = 0.027] and NLR value of 2.67-4.23 (OR = 2.96, P = 0.047) on multivariate analysis. Compared with the first quartile, SII ≥ 1776.80 was an independent predictor of UCEIS ≥ 5 (OR = 18.46, P = 0.012).
CONCLUSION SII has a certain value in confirming UC and identifying its activity.
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Affiliation(s)
- Meng-Hui Zhang
- Department of Gastroenterology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai’an 223300, Jiangsu Province, China
| | - Han Wang
- Department of Gastroenterology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai’an 223300, Jiangsu Province, China
| | - Hong-Gang Wang
- Department of Gastroenterology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai’an 223300, Jiangsu Province, China
| | - Xin Wen
- Department of Gastroenterology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai’an 223300, Jiangsu Province, China
| | - Xiao-Zhong Yang
- Department of Gastroenterology, The Affiliated Huaian No. 1 People’s Hospital of Nanjing Medical University, Huai’an 223300, Jiangsu Province, China
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Räisänen L, Viljakainen H, Sarkkola C, Kolho KL. Perinatal risk factors for pediatric onset type 1 diabetes, autoimmune thyroiditis, juvenile idiopathic arthritis, and inflammatory bowel diseases. Eur J Pediatr 2021; 180:2115-2123. [PMID: 33624160 PMCID: PMC8195774 DOI: 10.1007/s00431-021-03987-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 01/11/2021] [Accepted: 02/05/2021] [Indexed: 02/07/2023]
Abstract
Type 1 diabetes mellitus (DM), autoimmune thyroiditis (AIT), juvenile idiopathic arthritis (JIA), and inflammatory bowel diseases (IBD) are common pediatric autoimmune diseases with unknown risk factors. Using nationwide registers, we searched for their perinatal risk factors. Our study followed up 11,407 children (born 2000-2005) for a median of 16.6 years (from birth to 2018). Of them, 2.15% received primary diagnosis and 0.08% also secondary: 0.89% had DM, 0.60% had AIT, 0.48% had JIA, and 0.25% had IBD. The incidences per 100,000 children/year were 106.1 for DM, 46.0 for AIT, 55.0 for JIA, and 23.7 for IBD. There were more preterm births (< 37 weeks) among children with studied autoimmune diseases compared with the rest of the cohort (8.6% vs. 5.3%, p = 0.035). Among those born preterm, children with studied autoimmune diseases received more postnatal antibiotics compared with other preterm children in the cohort (47.6% vs. 27.7%, p = 0.046). Children with IBD were born to older mothers compared with those without studied diagnoses (33.0 vs 30.2, p = 0.004).Conclusion: Preterm birth was a shared risk factor for autoimmune diseases in our study, especially when combined with postnatal antibiotic treatments. High maternal age was associated with IBD. What is Known: • Type 1 diabetes (DM), autoimmune thyroiditis (AIT), juvenile idiopathic arthritis (JIA), and inflammatory bowel diseases (IBD) are common pediatric autoimmune diseases • It is unclear whether these diseases have shared risk factors, since there are no previous simultaneous epidemiological nor follow-up studies on them in one cohort What is New: • Preterm births were more common in children with DM, AIT, JIA, or IBD compared with other children in the cohort, and preterm children who developed these diseases recieved more postnatal antibiotics compared with other preterm children • High maternal age was associated with IBD.
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Affiliation(s)
- Laura Räisänen
- Faculty of Medicine and Health Technology (MET), Tampere University, Tampere, Finland. .,Folkhälsan Research Center, Helsinki, Finland.
| | - Heli Viljakainen
- grid.428673.c0000 0004 0409 6302Folkhälsan Research Center, Helsinki, Finland ,grid.7737.40000 0004 0410 2071Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Catharina Sarkkola
- grid.428673.c0000 0004 0409 6302Folkhälsan Research Center, Helsinki, Finland
| | - Kaija-Leena Kolho
- grid.502801.e0000 0001 2314 6254Faculty of Medicine and Health Technology (MET), Tampere University, Tampere, Finland ,grid.7737.40000 0004 0410 2071Faculty of Medicine and Children´s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
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Priya R, Brutkiewicz RR. Brain astrocytes and microglia express functional MR1 molecules that present microbial antigens to mucosal-associated invariant T (MAIT) cells. J Neuroimmunol 2020; 349:577428. [PMID: 33096293 DOI: 10.1016/j.jneuroim.2020.577428] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 10/13/2020] [Accepted: 10/13/2020] [Indexed: 12/24/2022]
Abstract
It is unknown whether brain astrocytes and microglia have the capacity to present microbial antigens via the innate immune MR1/MAIT cell axis. We have detected MAIT cells in the normal mouse brain and found that both astrocytes and microglia are MR1+. When we stimulated brain astrocytes and microglia with E. coli, and then co-cultured them with MAIT cells, MR1 surface expression was upregulated and MAIT cells were activated in an antigen-dependent manner. Considering the association of MAIT cells with inflammatory conditions, including those in the CNS, the MR1/MAIT cell axis could be a novel therapeutic target in neuroinflammatory disorders.
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Affiliation(s)
- Raj Priya
- Department of Microbiology and Immunology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
| | - Randy R Brutkiewicz
- Department of Microbiology and Immunology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
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Tang Q, Zhang W, Zhang C, Guan Y, Ding J, Yuan C, Tan C, Gao X, Tan S. Oxymatrine loaded nitric oxide-releasing liposomes for the treatment of ulcerative colitis. Int J Pharm 2020; 586:119617. [DOI: 10.1016/j.ijpharm.2020.119617] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 06/18/2020] [Accepted: 07/01/2020] [Indexed: 02/07/2023]
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Giuffrida P, Arpa G, Grillo F, Klersy C, Sampietro G, Ardizzone S, Fociani P, Fiocca R, Latella G, Sessa F, D'Errico A, Malvi D, Mescoli C, Rugge M, Nesi G, Ferrero S, Furlan D, Poggioli G, Rizzello F, Macciomei MC, Santini D, Volta U, De Giorgio R, Caio G, Calabrò A, Ciacci C, D'Armiento M, Rizzo A, Solina G, Martino M, Tonelli F, Villanacci V, Cannizzaro R, Canzonieri V, Florena AM, Biancone L, Monteleone G, Caronna R, Ciardi A, Elli L, Caprioli F, Vecchi M, D'Incà R, Zingone F, D'Odorico A, Lenti MV, Oreggia B, Reggiani Bonetti L, Astegiano M, Biletta E, Cantoro L, Giannone AG, Orlandi A, Papi C, Perfetti V, Quaquarini E, Sandri G, Silano M, Usai P, Barresi V, Ciccocioppo R, Luinetti O, Pedrazzoli P, Pietrabissa A, Viglio A, Paulli M, Corazza GR, Solcia E, Vanoli A, Di Sabatino A. PD-L1 in small bowel adenocarcinoma is associated with etiology and tumor-infiltrating lymphocytes, in addition to microsatellite instability. Mod Pathol 2020; 33:1398-1409. [PMID: 32066859 DOI: 10.1038/s41379-020-0497-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 01/25/2020] [Accepted: 01/27/2020] [Indexed: 12/13/2022]
Abstract
Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn's disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly (p = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly (p = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1+ immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1+ cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1+ microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.
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Affiliation(s)
- Paolo Giuffrida
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Giovanni Arpa
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Federica Grillo
- Pathology Unit, Department of Surgical and Diagnostic Sciences, University of Genoa and San Martino/IST University Hospital, Genoa, Italy
| | - Catherine Klersy
- Biometry and Statistics Service, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | | | - Sandro Ardizzone
- Gastroenterology Unit, Luigi Sacco University Hospital, Milan, Italy
| | - Paolo Fociani
- Pathology Unit, Luigi Sacco University Hospital, Milan, Italy
| | - Roberto Fiocca
- Pathology Unit, Department of Surgical and Diagnostic Sciences, University of Genoa and San Martino/IST University Hospital, Genoa, Italy
| | - Giovanni Latella
- Gastroenterology Unit, Department of Life and Enviromental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Fausto Sessa
- Pathology Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Antonietta D'Errico
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Oncology and Transplant Pathology, University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy
| | - Deborah Malvi
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Oncology and Transplant Pathology, University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy
| | - Claudia Mescoli
- Pathology Unit, Department of Medicine, University of Padua, Padua, Italy
| | - Massimo Rugge
- Pathology Unit, Department of Medicine, University of Padua, Padua, Italy
| | - Gabriella Nesi
- Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | - Stefano Ferrero
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
| | - Daniela Furlan
- Pathology Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Gilberto Poggioli
- Surgery of the Alimentary Tract, Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Fernando Rizzello
- Intestinal Chronic Bowel Disease Unit, Department of Medical and Surgical Sciences, Sant'Orsola-Malpighi Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | | | - Donatella Santini
- Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Institute of Oncology and Transplant Pathology, University of Bologna, St. Orsola-Malpighi Hospital, Bologna, Italy
| | - Umberto Volta
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Giacomo Caio
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Antonio Calabrò
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Carolina Ciacci
- Department of Medicine and Surgery, University of Salerno, Salerno, Italy
| | - Maria D'Armiento
- Public Health Department, Federico II University of Naples, Naples, Italy
| | - Aroldo Rizzo
- Units of Pathology, Cervello Hospital, Palermo, Italy
| | - Gaspare Solina
- Units of General Surgery, Cervello Hospital, Palermo, Italy
| | - Michele Martino
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Francesco Tonelli
- Surgery and Translational Medicine, University of Florence, Florence, Italy
| | | | - Renato Cannizzaro
- Department of Gastroenterology, Centro di Riferimento Oncologico (CRO) di Aviano IRCCS, Aviano, Italy
| | - Vincenzo Canzonieri
- Pathology Unit, Centro di Riferimento Oncologico (CRO) di Aviano IRCCS, Aviano, Italy
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Ada M Florena
- Pathologic Anatomy Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Livia Biancone
- Department of Systems Medicine, University of Tor Vergata, Rome, Italy
| | | | - Roberto Caronna
- Department of Surgical Sciences, La Sapienza University, Rome, Italy
| | - Antonio Ciardi
- Department of Radiological, Oncological, Pathological Sciences, Umberto I Hospital, La Sapienza University, Rome, Italy
| | - Luca Elli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Flavio Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Maurizio Vecchi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Renata D'Incà
- Gastroenterology Section, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Fabiana Zingone
- Gastroenterology Section, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Anna D'Odorico
- Gastroenterology Section, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Marco Vincenzo Lenti
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Barbara Oreggia
- General Surgery Unit, Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy
| | - Luca Reggiani Bonetti
- Section of Pathology, Department of Diagnostic Medicine and Public Health, University of Modena and Reggio Emilia, Modena, Italy
| | - Marco Astegiano
- General and Specialistic Surgery, Città della Salute e della Scienza-Molinette Hospital, Turin, Italy
| | | | | | - Antonino G Giannone
- Pathologic Anatomy Unit, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Augusto Orlandi
- Department of Biopathology and Image Diagnostics, University of Tor Vergata, Rome, Italy
| | - Claudio Papi
- IBD Unit, San Filippo Neri Hospital, Rome, Italy
| | - Vittorio Perfetti
- Internal Medicine Unit, S.S. Annunziata Hospital, ASST-Pavia, Varzi, Italy
| | - Erica Quaquarini
- Medical Oncology Unit, IRCCS ICS Maugeri and Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | | | - Marco Silano
- Unit of Human Nutrition and Health, Istituto Superiore di Sanità, Rome, Italy
| | - Paolo Usai
- Department of Internal Medicine, University of Cagliari, Cagliari, Italy
| | - Valeria Barresi
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Rachele Ciccocioppo
- Gastroenterology Unit, Department of Medicine, AOUI Policlinico G.B. Rossi, University of Verona, Verona, Italy
| | - Ombretta Luinetti
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Paolo Pedrazzoli
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
- Oncology Unit, IRCCS San Matteo Hospital, Pavia, Italy
| | - Andrea Pietrabissa
- Department of Surgery, General Surgery II, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Alessandra Viglio
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Marco Paulli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Gino R Corazza
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Enrico Solcia
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Antonio Di Sabatino
- Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy.
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Ye M, Joosse ME, Liu L, Sun Y, Dong Y, Cai C, Song Z, Zhang J, Brant SR, Lazarev M, Li X. Deletion of IL-6 Exacerbates Colitis and Induces Systemic Inflammation in IL-10-Deficient Mice. J Crohns Colitis 2020; 14:831-840. [PMID: 31679013 PMCID: PMC7346894 DOI: 10.1093/ecco-jcc/jjz176] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Interleukin 6 [IL-6] or its receptor is currently a candidate for targeted biological therapy of inflammatory bowel disease [IBD]. Thus, a comprehensive understanding of the consequences of blocking IL-6 is imperative. We investigated this by evaluating the effects of IL-6 deletion on the spontaneous colitis of IL-10-deficient mice [IL-10-/-]. METHODS IL-6/IL-10 double-deficient mice [IL-6-/-/IL-10-/-] were generated and analysed for intestinal inflammation, general phenotypes and molecular/biochemical changes in the colonic mucosa compared with wild-type and IL-10-/- mice. RESULTS Unexpectedly, the IL-6-/-/IL-10-/- mice showed more pronounced gut inflammation and earlier disease onset than IL-10-/- mice, both locally [colon and small bowel] and systemically [splenomegaly, ulcerative dermatitis, leukocytosis, neutrophilia and monocytosis]. IL-6-/-/IL-10-/- mice exhibited elevations of multiple cytokines [IL-1β, IL-4, IL-12, TNFα] and chemokines [MCP-1 and MIG], but not IFN-γ [Th1], IL-17A and IL-17G [Th17], or IL-22 [Th22]. FOXP3 and TGF-β, two key factors for regulatory T [Treg] cell differentiation, were significantly down-regulated in the colonic mucosa, but not in the thymus or mesenteric lymph nodes, of IL-6-/-/IL-10-/- mice. CTLA-4 was diminished while iNOS was up-regulated in the colonic mucosa of IL-6-/-/IL-10-/- mice. CONCLUSION In IL-10-/- mice, complete IL-6 blockade significantly aggravates gut inflammation, at least in part by suppressing Treg/CTLA-4 and promoting the IL-1β/Th2 pathway. In addition, the double mutant exhibits signs of severe systemic inflammation. Our data define a new function of IL-6 and suggest that caution should be exercised when targeting IL-6 in IBD patients, particularly those with defects in IL-10 signalling.
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Affiliation(s)
- Mei Ye
- Division of Gastroenterology, Department of Medicine, Johns Hopkins Medicine, Baltimore, MD, USA,Department of Gastroenterology, Zhongnan Hospital, Wuhan University, Hubei Province, China
| | - Maria E Joosse
- Division of Gastroenterology, Department of Medicine, Johns Hopkins Medicine, Baltimore, MD, USA
| | - Ling Liu
- Division of Gastroenterology, Department of Medicine, Johns Hopkins Medicine, Baltimore, MD, USA,Department of Gastroenterology, West China Hospital, Sichuan University, Sichuan Province, China
| | - Yu Sun
- Division of Gastroenterology, Department of Medicine, Johns Hopkins Medicine, Baltimore, MD, USA
| | - Ying Dong
- Division of Gastroenterology, Department of Medicine, Johns Hopkins Medicine, Baltimore, MD, USA
| | - Changchun Cai
- Division of Gastroenterology, Department of Medicine, Johns Hopkins Medicine, Baltimore, MD, USA
| | - Zhenmei Song
- Division of Gastroenterology, Department of Medicine, Johns Hopkins Medicine, Baltimore, MD, USA
| | - Jennifer Zhang
- Division of Gastroenterology, Department of Medicine, Johns Hopkins Medicine, Baltimore, MD, USA
| | - Steven R Brant
- Division of Gastroenterology, Department of Medicine, Johns Hopkins Medicine, Baltimore, MD, USA
| | - Mark Lazarev
- Division of Gastroenterology, Department of Medicine, Johns Hopkins Medicine, Baltimore, MD, USA
| | - Xuhang Li
- Division of Gastroenterology, Department of Medicine, Johns Hopkins Medicine, Baltimore, MD, USA,Corresponding author: Xuhang Li, PhD, Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross 918, Baltimore, MD 21205, USA.
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Giuffrida P, Di Sabatino A. Targeting T cells in inflammatory bowel disease. Pharmacol Res 2020; 159:105040. [PMID: 32585338 DOI: 10.1016/j.phrs.2020.105040] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 06/16/2020] [Accepted: 06/17/2020] [Indexed: 12/13/2022]
Abstract
T cells play a pivotal role in the immune response underlying inflammatory bowel disease (IBD) pathogenesis. On this basis, over the past 25 years several drugs have assessed to target T cells in IBD patients. Amongst anti-CD3 antibodies, visilizumab and foralumab did not show clinical efficacy in ulcerative colitis (UC) and Crohn's disease (CD) patients, respectively, whereas otelixizumab has been tested in vitro only. The anti-CD4 BF-5 and cM-T412, and the anti-CD25 basiliximab and daclizumab were not effective in CD and UC patients, respectively. The anti-NKG2D antibody NNC0142-0002 showed clinical benefit in CD patients, in particular in biologic naïve ones, in a randomized, double-blind, parallel-group, placebo-controlled trial. The anti-CD40L M90 and the GSK1349571A blocking calcium release-activated calcium (CRAC) channels, which are involved in the T cell activation and proliferation, were tested only in ex vivo/in vitro experiments. Apart from ustekinumab, all the other drugs targeting T cell-derived cytokines failed. The reinduction of lamina propria T cell apoptosis is a mechanism to modulate T cell survival exploited by cyclosporin A, azathioprine and anti-tumor necrosis factor-α agents, such as infliximab, adalimumab and golimumab. In this article, we review the drugs targeting T cells via surface receptors, via T cell-derived cytokines, via CRAC channels or by inducing apoptosis.
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Affiliation(s)
- Paolo Giuffrida
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Antonio Di Sabatino
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy.
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40
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Ronchetti S, Gentili M, Ricci E, Migliorati G, Riccardi C. Glucocorticoid-Induced Leucine Zipper as a Druggable Target in Inflammatory Bowel Diseases. Inflamm Bowel Dis 2020; 26:1017-1025. [PMID: 31961437 DOI: 10.1093/ibd/izz331] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Indexed: 12/11/2022]
Abstract
Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex pathogenesis, affecting people of all ages. They are characterized by alternating phases of clinical relapse and remission, depending on the fine balance between immune cells and the gut microbiota. The cross talk between cells of the immune system and the gut microbiota can result in either tolerance or inflammation, according to multifactorial triggers, ranging from environmental factors to genetic susceptibility. Glucocorticoid (GC) administration remains the first-line treatment for IBDs, although long-term use is limited by development of serious adverse effects. Recently, new alternative pharmacological therapies have been developed, although these are not always effective in IBD patients. There is a constant demand for effective new drug targets to guarantee total remission and improve the quality of life for IBD patients. The glucocorticoid-induced leucine zipper (GILZ) has been implicated as a promising candidate for this purpose, in view of its powerful anti-inflammatory effects that mimic those of GCs while avoiding their unwanted adverse reactions. Here we present and discuss the latest findings about the involvement of GILZ in IBDs.
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Affiliation(s)
- Simona Ronchetti
- Department of Medicine, Pharmacology Division, University of Perugia, Italy
| | - Marco Gentili
- Department of Medicine, Pharmacology Division, University of Perugia, Italy
| | - Erika Ricci
- Department of Medicine, Pharmacology Division, University of Perugia, Italy
| | | | - Carlo Riccardi
- Department of Medicine, Pharmacology Division, University of Perugia, Italy
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41
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Ju JK, Cho YN, Park KJ, Kwak HD, Jin HM, Park SY, Kim HS, Kee SJ, Park YW. Activation, Deficiency, and Reduced IFN-γ Production of Mucosal-Associated Invariant T Cells in Patients with Inflammatory Bowel Disease. J Innate Immun 2020; 12:422-434. [PMID: 32535589 DOI: 10.1159/000507931] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 03/30/2020] [Indexed: 12/19/2022] Open
Abstract
Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can activate either in response to T-cell receptor (TCR) engagement or through activating cytokines and play an important role in autoimmune disorders. The study examined the level and function of MAIT cells in patients with inflammatory bowel disease (IBD). Circulating MAIT cell levels were significantly reduced in IBD patients. This MAIT cell deficiency was correlated with IBD disease activity grades, hemoglobin, and CRP. IFN-γ production of circulating MAIT cells in response to both MHC class 1b-like related protein (MR1)-dependent and -independent stimulations was decreased in IBD patients, which was partially associated with reduced activation of nuclear factor of activated T cells 1 (NFAT1) transcription factor, a main regulator of IFN-γ production. Expression levels of CD69, programmed death-1 (PD-1), and annexin V in MAIT cells were elevated in IBD patients. CCL20, CXCL10, CXCL16, and CCL25 were expressed higher in inflamed intestinal tissues than in noninflamed tissues. This study demonstrates that circulating MAIT cells are activated and numerically and functionally deficient in IBD patients. Furthermore, activated MAIT cells have the potential to migrate to inflamed tissues. These findings suggest an important role of MAIT cells in mucosal immunity in IBD.
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Affiliation(s)
- Jae Kyun Ju
- Department of Surgery, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Young-Nan Cho
- Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Ki-Jeong Park
- Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Han Deok Kwak
- Department of Surgery, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Hye-Mi Jin
- Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Seon-Young Park
- Department of Gastroenterology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Hyun Soo Kim
- Department of Gastroenterology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Seung-Jung Kee
- Department of Laboratory Medicine, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
| | - Yong-Wook Park
- Department of Rheumatology, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea,
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Holm Nielsen S, Mortensen JH, Willumsen N, Rasmussen DGK, Mogensen DJ, Di Sabatino A, Mazza G, Jørgensen LN, Giuffrida P, Pinzani M, Klinge L, Kjeldsen J, Leeming DJ, Karsdal MA, Genovese F. A Fragment of Collagen Type VI alpha-3 chain is Elevated in Serum from Patients with Gastrointestinal Disorders. Sci Rep 2020; 10:5910. [PMID: 32245981 PMCID: PMC7125205 DOI: 10.1038/s41598-020-62474-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 03/12/2020] [Indexed: 11/16/2022] Open
Abstract
Extracellular matrix (ECM) remodeling is a hallmark of the pathology of gastrointestinal disorders. Collagen type VI (COL6) is produced by fibroblasts, and the COL6 α3-chain has shown to be elevated in patients with ulcerative colitis (UC), Crohn’s disease (CD) and colorectal cancer (CRC). Measuring COL6α3 in serum may therefore have potential as a biomarker for gastrointestinal disorders. The aims of this study were to develop and validate a competitive ELISA targeting a specific neo-epitope of COL6α3 and evaluate its associations with the gastrointestinal disorders UC, CD and CRC, in comparison to healthy controls. A monoclonal antibody was raised against a matrix metalloproteinase-2 and -9 specific cleavage site of COL6α3 (C6Mα3) and employed in a competitive enzyme-linked immunosorbent assay (ELISA). The assay was developed and technically validated. Levels of C6Mα3 were measured in serum from patients with UC (n = 58), CD (n = 44) and CRC (n = 39) and compared to healthy controls (n = 32). The levels of C6Mα3 were elevated in patients with UC, CD and CRC patients compared to healthy controls (all p < 0.0001). The area under the receiver operating characteristics (AUROC) curve for separation of patients with UC from healthy controls was 0.972 (95% CI: 0.925–1.020, p < 0.0001), with CD from healthy controls was 0.947 (95% CI: 0.885–1.009, p < 0.0001) and with CRC from healthy controls was 0.890 (95% CI: 0.809–0.972, p < 0.0001). We developed a technically robust assay targeting a fragment of COL6, which was elevated in serum from patients with UC, CD and CRC.
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Affiliation(s)
- Signe Holm Nielsen
- Nordic Bioscience, Biomarkers and Research, Herlev, Denmark. .,Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark.
| | | | | | | | - Ditte J Mogensen
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Antonio Di Sabatino
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Giuseppe Mazza
- University College of London, Institute for Liver and Digestive Health, London, UK
| | | | - Paolo Giuffrida
- First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Massimo Pinzani
- University College of London, Institute for Liver and Digestive Health, London, UK
| | - Lone Klinge
- Department of Gastroenterology, University of Odense, Odense, Denmark
| | - Jens Kjeldsen
- Department of Gastroenterology, University of Odense, Odense, Denmark
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Ameliorative Effect of Heat-Killed Lactobacillus plantarum L.137 and/or Aloe vera against Colitis in Mice. Processes (Basel) 2020. [DOI: 10.3390/pr8020225] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Inflammatory bowel disease (IBD) is one of the predominant intestinal diseases associated with chronic inflammation and ulceration of the colon. This study explored the ameliorative effect of Aloe vera extract (Aloe) and/or heat-killed Lactobacillus plantarum L.137 (HK L.137) on dextran sodium sulfate (DSS)-induced colitis in mice. Aloe and/or HK L.137 were supplied for 9 days and the mice were challenged with DSS for 7 days. The DSS group demonstrated bloody diarrhea, colitis of high histologic grade, increased nuclear factor-kappa B (NF-κB) p65, inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO), interleukin (IL)-6, and tumor necrosis factor (TNF)-α, and decreased IL-10 expression. These alterations were dwindled in DSS-induced mice treated with Aloe and HK L.137 separately. Aloe and HK L.137 together have augmented the therapeutic effect of each other. In conclusion, our findings demonstrated that Aloe and/or HK L.137 ameliorated DSS-induced colitis by promoting the secretion of anti-inflammatory cytokines and suppressing pro-inflammatory mediators. This study indicated that A. vera may function synergistically with HK L.137 to confer an effective strategy to prevent colitis.
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44
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Wu H, Rao Q, Ma GC, Yu XH, Zhang CE, Ma ZJ. Effect of Triptolide on Dextran Sodium Sulfate-Induced Ulcerative Colitis and Gut Microbiota in Mice. Front Pharmacol 2020; 10:1652. [PMID: 32063856 PMCID: PMC7000629 DOI: 10.3389/fphar.2019.01652] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 12/17/2019] [Indexed: 12/20/2022] Open
Abstract
Triptolide is beneficial for the treatment of ulcerative colitis (UC), which is closely related to the gut microbiota. However, whether the therapeutic effects of triptolide involve the regulation of the gut microbiota is still unclear. In the present study, animal models of UC mice induced by dextran sodium sulfate (DSS) were established, the changes of gut microbiota in mice were detected by high-throughput sequencing. The effects of triptolide on DSS-induced UC mouse and its gut microbiota were studied. As a result, we found that triptolide exerted anti-inflammatory and therapeutic effects on UC mice. Sequencing results for the gut microbiota showed that the composition of the gut microbiota from DSS group was disordered as compared with that from the control group, consistent with a decrease in the abundance of flora. Triptolide treatment accelerated the recovery of the population of the gut microbiota and significantly improved the microbial diversity. At the phylum level, the population of Bacteroidetes decreased and that of Firmicutes increased. At the genus level, Bacteroides and Lachnospiraceae counts decreased. Thus, triptolide could regulate the composition of the gut microbiota, accelerate the recovery of microbiota, and exert good therapeutic effects in UC mice. Our results also revealed that fecal transplantation from triptolide-treated mice could relieve UC. This study provides a reference for the rational use of triptolide for the treatment of UC.
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Affiliation(s)
- Hao Wu
- The Department of General Surgeryis a part of Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Quan Rao
- The Department of General Surgeryis a part of Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Guang-Chao Ma
- The Department of General Surgeryis a part of Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiao-Hong Yu
- The Department of General Surgeryis a part of Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Cong-En Zhang
- The Department of General Surgeryis a part of Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhi-Jie Ma
- The Department of General Surgeryis a part of Beijing Friendship Hospital, Capital Medical University, Beijing, China
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Park CH, Lee AR, Ahn SB, Eun CS, Han DS. Role of innate lymphoid cells in chronic colitis during anti-IL-17A therapy. Sci Rep 2020; 10:297. [PMID: 31941937 PMCID: PMC6962146 DOI: 10.1038/s41598-019-57233-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 12/26/2019] [Indexed: 12/23/2022] Open
Abstract
IL-17A is an important cytokine in intestinal inflammation. However, anti-IL-17A therapy does not improve clinical outcomes in patients with Crohn's disease. We aimed to evaluate the role of RORγt+ innate lymphoid cells (ILCs) in murine colitis models in the absence of IL-17A. An acute colitis model was induced with either dextran sulfate sodium (DSS) or trinitrobenzenesulfonic acid (TNBS) and a chronic colitis model was induced by CD4+CD45RBhi T cell transfer from either wild-type C57BL/6 or Il17a-/- mice. An anti-IL-17A antibody, secukinumab, was also used to inhibit IL-17A function in the colitis model. Flow cytometry was performed to analyze the population of RORγt+ ILCs in the colonic lamina propria of mice with chronic colitis. Acute intestinal inflammation due to DSS and TNBS was attenuated in IL-17A knockout mice, whereas chronic colitis was not relieved by T cell transfer from Il17a-/- mice (% of original body weight: wild-type mice vs. Il17a-/- mice, 81.9% vs. 82.2%; P = 0.922). However, the mean proportion of Lin-RORγt+ lymphocytes was higher after T cell transfer from Il17a-/- mice than that after T cell transfer from wild-type mice (28.8% vs. 18.5%). The proportion of Lin-RORγt+ was also increased in Rag2-/- mice that received T cell transfer from wild-type mice when anti-IL-17A antibody was administered (31.7%). Additionally, Il6 and Il22 tended to be highly expressed after T cell transfer from Il17a-/- mice. In conclusion, RORγt+ ILCs may have an important role in the pathogenesis of chronic colitis in the absence of IL-17A. Blocking the function of IL-17A may upregulate Il6 and recruit RORγt+ ILCs in chronic colitis, thereby upregulating IL-22 and worsening the clinical outcomes of patients with Crohn's disease.
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Affiliation(s)
- Chan Hyuk Park
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - A-Reum Lee
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Sang Bong Ahn
- Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University, Seoul, Korea
| | - Chang Soo Eun
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Dong Soo Han
- Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea.
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Hu J, Kang H, Liu C, Hu P, Yang M, Zhou F. Regulatory T Cells Could Improve Intestinal Barrier Dysfunction in Heatstroke. Inflammation 2020; 42:1228-1238. [PMID: 30820807 DOI: 10.1007/s10753-019-00983-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Intestinal barrier dysfunction plays a pivotal role in multiorgan dysfunction during heatstroke (HS). Neutrophils are involved in intestinal inflammation and thus dampen the mucosal integrity. Regulatory T cells (Tregs) have been shown to orchestrate neutrophils and thus sustain mucosal integrity in miscellaneous inflammation-related diseases. However, whether Tregs are involved in HS-induced intestinal barrier dysfunction remains unknown. Thus, we investigated whether Tregs could alleviate intestinal barrier dysfunction in mice. We found that HS could induce intestinal injury and mucosal barrier dysfunction 0, 24, and 72 h after heat stress. Flow cytometry revealed an increase of neutrophil infiltration and a decrease of Treg frequencies in the small intestinal epithelium 72 h after heat stress. Treg depletion starting 2 days before HS exacerbated intestinal damage and mucosal barrier dysfunction. Adoptive transfer of Tregs at 0 h improved intestinal injury and mucosal barrier dysfunction at 72 h. The manipulation of Tregs affected the neutrophil frequencies in the small intestinal epithelium 72 h after heat stress. Our study demonstrated that Tregs could improve HS-induced intestinal barrier dysfunction, probably via modulation of neutrophils in the intestine of mice during HS.
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Affiliation(s)
- Jie Hu
- Critical Care Medicine, Chinese PLA General Hospital, 28th Fuxing Road, Haidian District, Beijing, 100853, China
| | - Hongjun Kang
- Critical Care Medicine, Chinese PLA General Hospital, 28th Fuxing Road, Haidian District, Beijing, 100853, China
| | - Chao Liu
- Critical Care Medicine, Chinese PLA General Hospital, 28th Fuxing Road, Haidian District, Beijing, 100853, China
| | - Pan Hu
- Critical Care Medicine, Chinese PLA General Hospital, 28th Fuxing Road, Haidian District, Beijing, 100853, China
| | - Mengmeng Yang
- Critical Care Medicine, Chinese PLA General Hospital, 28th Fuxing Road, Haidian District, Beijing, 100853, China
| | - Feihu Zhou
- Critical Care Medicine, Chinese PLA General Hospital, 28th Fuxing Road, Haidian District, Beijing, 100853, China.
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Digby-Bell JL, Atreya R, Monteleone G, Powell N. Interrogating host immunity to predict treatment response in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2020; 17:9-20. [PMID: 31767987 DOI: 10.1038/s41575-019-0228-5] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/14/2019] [Indexed: 02/07/2023]
Abstract
IBD treatment is undergoing a transformation with an expanding repertoire of drugs targeting different aspects of the immune response. Three novel classes of drugs have emerged in the past decade that target leukocyte trafficking to the gut (vedolizumab), neutralize key cytokines with antibodies (ustekinumab) and inhibit cytokine signalling pathways (tofacitinib). In advanced development are other drugs for IBD, including therapies targeting other cytokines such as IL-23 and IL-6. However, all agents tested so far are hampered by primary and secondary loss of response, so it is desirable to develop personalized strategies to identify which patients should be treated with which drugs. Stratification of patients with IBD by clinical parameters alone lacks sensitivity, and alternative modalities are now needed to deliver precision medicine in IBD. High-resolution profiling of immune response networks in individual patients is a promising approach and different technical platforms, including in vivo real-time molecular endoscopy, tissue transcriptomics and germline genetics, are promising tools to help predict responses to specific therapies. However, important challenges remain regarding the clinical utility of these technologies, including their scalability and accessibility. This Review focuses on unravelling some of the complexity of mucosal immune responses in IBD pathogenesis and how current and emerging analytical platforms might be harnessed to effectively stratify and individualise IBD therapy.
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Affiliation(s)
| | - Raja Atreya
- Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | | | - Nick Powell
- School of Immunology and Microbial Sciences, King's College London, London, UK. .,Department of Medicine, Imperial College London, London, UK.
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48
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Allez M, Auzolle C, Ngollo M, Bottois H, Chardiny V, Corraliza AM, Salas A, Perez K, Stefanescu C, Nancey S, Buisson A, Pariente B, Fumery M, Sokol H, Tréton X, Barnich N, Seksik P, Le Bourhis L. T cell clonal expansions in ileal Crohn's disease are associated with smoking behaviour and postoperative recurrence. Gut 2019; 68:1961-1970. [PMID: 30792246 DOI: 10.1136/gutjnl-2018-317878] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 01/21/2019] [Accepted: 01/22/2019] [Indexed: 12/14/2022]
Abstract
UNLABELLED T cell clonal expansions are present in the inflamed mucosa of patients with Crohn's disease (CD) and may be implicated in postoperative recurrence after ileocolonic resection. METHODS T cell receptor (TCR) analysis was performed in 57 patients included in a prospective multicentre cohort. Endoscopic recurrence was defined by a Rutgeerts score >i0. DNA and mRNA were extracted from biopsies collected from the surgical specimen and endoscopy, and analysed by high throughput sequencing and microarray, respectively. RESULTS TCR repertoire in the mucosa of patients with CD displayed diverse clonal expansions. Active smokers at time of surgery had a significantly increased proportion of clonal expansions as compared with non-smokers (25.9%vs17.9%, p=0.02). The percentage of high frequency clones in the surgical specimen was significantly higher in patients with recurrence and correlated with postoperative endoscopic recurrence (area under the curve (AUC) 0.69, 95% CI 0.54 to 0.83). All patients with clonality above 26.8% (18/57) had an endoscopic recurrence. These patients with a high clonality were more frequently smokers than patients with a low clonality (61% vs 23%, p=0.005). The persistence of a similar TCR repertoire at postoperative endoscopy was associated with smoking and disease recurrence. Patients with high clonality showed increased expression of genes associated with CD8 T cells and reduced expression of inflammation-related genes. Expanded clones were found predominantly in the CD8 T cell compartment. CONCLUSION Clonal T cell expansions are implicated in postoperative endoscopic recurrence. CD patients with increased proportion of clonal T cell expansions in the ileal mucosa represent a subgroup associated with smoking and where pathogenesis appears as T cell driven. TRIAL REGISTRATION NUMBER NCT03458195.
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Affiliation(s)
- Matthieu Allez
- Department of Gastroenterology, Hopital Saint Louis, Paris, France.,INSERM U1160, Hôpital Saint-Louis, Paris, France
| | - Claire Auzolle
- Department of Gastroenterology, Hopital Saint Louis, Paris, France
| | | | - Hugo Bottois
- INSERM U1160, Hôpital Saint-Louis, Paris, France
| | | | | | - Azucena Salas
- Hospital Clinic Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Kevin Perez
- INSERM U1160, Hôpital Saint-Louis, Paris, France
| | - Carmen Stefanescu
- Service de Gastroentérologie, MICI et Assistance Nutritive, Hôpital Beaujon, Clichy, France
| | - Stéphane Nancey
- Department of Gastroenterology, Lyon Sud Hospital, Hospices Civils de Lyon, Pierre Benite, Lyon, France
| | - Anthony Buisson
- Gastroenterology Department, University Hospital Estaing, Clermont-Ferrand, France
| | - Benjamin Pariente
- Department of Gastroenterology, Hopital Claude huriez, Lille, France
| | - Mathurin Fumery
- Hepato-Gastroenterology Department, CHU Amiens, Amiens, France
| | - Harry Sokol
- Department of Gastroenterology, Hopital Saint-Antoine, Paris, Île-de-France, France
| | - Xavier Tréton
- Service de Gastroentérologie, MICI et Assistance Nutritive, Hopital Beaujon, Clichy, France
| | - Nicolas Barnich
- M2iSH, UMR Inserm U1071, USC INRA 2018, Université d'Auvergne, Clermont Ferrand, France
| | - Philippe Seksik
- Department of Gastroenterology, Hopital Saint-Antoine, Paris, Île-de-France, France
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Giuffrida P, Caprioli F, Facciotti F, Di Sabatino A. The role of interleukin-13 in chronic inflammatory intestinal disorders. Autoimmun Rev 2019; 18:549-555. [DOI: 10.1016/j.autrev.2019.03.012] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Accepted: 01/04/2019] [Indexed: 12/17/2022]
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Giuffrida P, Cococcia S, Delliponti M, Lenti MV, Di Sabatino A. Controlling Gut Inflammation by Restoring Anti-Inflammatory Pathways in Inflammatory Bowel Disease. Cells 2019; 8:E397. [PMID: 31052214 PMCID: PMC6562982 DOI: 10.3390/cells8050397] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 04/24/2019] [Accepted: 04/25/2019] [Indexed: 12/15/2022] Open
Abstract
Inflammatory bowel disease (IBD) is caused by a dysregulated immune response against normal components of the intestinal microflora combined with defective functioning of anti-inflammatory pathways. Currently, all therapies approved for IBD manipulate the immune system by inhibiting pro-inflammatory mechanisms, such as tumor necrosis factor-α, gut-homing α4β7 integrin, interleukin-12/interleukin-23, and Janus kinases. However, some IBD patients are non-responders to these drugs, which are also associated with serious side effects. Thus, it has been hypothesized that therapies aimed at restoring anti-inflammatory signals, by exploiting the tolerogenic potential of cytokines (interleukin-10, transforming growth factor-β, granulocyte macrophage colony-stimulating factor), immune cells (regulatory T cells, tolerogenic dendritic cells), or mesenchymal stem cells, might offer promising results in terms of clinical efficacy with fewer side effects. In this review, we provide new insights into putative novel treatments aimed at restoring anti-inflammatory signaling pathways in IBD.
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Affiliation(s)
- Paolo Giuffrida
- First Department of Internal Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Sara Cococcia
- First Department of Internal Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Mariangela Delliponti
- First Department of Internal Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Marco Vincenzo Lenti
- First Department of Internal Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
| | - Antonio Di Sabatino
- First Department of Internal Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
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