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Geng L, Li T, Liu Y, Liu X, Wang J, Zhang L, Yang J, Zhang B. Lycium barbarum polysaccharide corrects CCR9 + Th17/ Treg imbalance in patients with rheumatoid arthritis. Clin Rheumatol 2025:10.1007/s10067-025-07415-x. [PMID: 40146447 DOI: 10.1007/s10067-025-07415-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 03/18/2025] [Accepted: 03/20/2025] [Indexed: 03/28/2025]
Abstract
OBJECTIVES The imbalance of Th17 cells and Treg cells in synovium participates in rheumatoid arthritis (RA), and lycium barbarum polysaccharide (LBP) can attenuate arthritis in mice. The study aimed to explore the causes of Th17/Treg cell imbalance and investigate whether LBP could correct this imbalance in patients with RA. METHODS The study recruited 23 healthy controls and 58 RA patients. Flow cytometry was used to analyze the percentage of C-C chemokine receptor 9+ (CCR9) Th17 cells and CCR9+ Treg cells. IL-17A and IL-10 were evaluated by enzyme-linked immunosorbent assay. LBP was added to Treg cells or Th17 cells differentiation system to explore the role of LBP in differentiation of CCR9+ Th17/Treg cells. RESULTS In the peripheral blood (PB) and synovial fluid (SF) of RA patients, there was a rise in the proportion of CCR9+ Th17 cells and a decline in the proportion of CCR9+ Treg cells. Furthermore, a positive association was observed between the CCR9+ Th17/Treg ratio in PB and disease activity. In vitro, LBP could promote the differentiation of CCR9+ Treg cells and inhibit the differentiation of CCR9+ Th17 cells. CONCLUSIONS In summary, the CCR9+ Th17/ Treg ratio is increased in peripheral blood and synovial fluid in patients with RA, and LBP can correct the CCR9+ Th17/ Treg cells imbalance. Key Points • CCR9+ Th17/ Treg ratio is increased in PB and SF in patients with RA. • LBP can correct the CCR9+ Th17/ Treg cells imbalance in vitro.
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Affiliation(s)
- Lina Geng
- Department of Clinical Laboratory, The First Affiliated Hospital of Hebei North University, 13 Changqing Road, Zhangjiakou City, 075000, Hebei Province, China
| | - Ting Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Hebei North University, 13 Changqing Road, Zhangjiakou City, 075000, Hebei Province, China
| | - Yan Liu
- Department of Clinical Laboratory, The First Affiliated Hospital of Hebei North University, 13 Changqing Road, Zhangjiakou City, 075000, Hebei Province, China
| | - Xuntao Liu
- Department of Clinical Laboratory, The First Affiliated Hospital of Hebei North University, 13 Changqing Road, Zhangjiakou City, 075000, Hebei Province, China
| | - Jing Wang
- Department of Pharmacy, Zhangjiakou Second Hospital, 9 Changcheng West Street, Zhangjiakou City, 075000, Hebei Province, China
| | - Lei Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Hebei North University, 13 Changqing Road, Zhangjiakou City, 075000, Hebei Province, China
| | - Jinliang Yang
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Hebei North University, 13 Changqing Road, Zhangjiakou City, 075000, Hebei Province, China
| | - Bin Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Hebei North University, 13 Changqing Road, Zhangjiakou City, 075000, Hebei Province, China.
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Liu R, Zhang J, Chen S, Xiao Y, Hu J, Zhou Z, Xie L. Intestinal mucosal immunity and type 1 diabetes: Non-negligible communication between gut and pancreas. Diabetes Obes Metab 2025; 27:1045-1064. [PMID: 39618164 PMCID: PMC11802406 DOI: 10.1111/dom.16101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 11/16/2024] [Accepted: 11/18/2024] [Indexed: 02/08/2025]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by T cell-mediated pancreatic β cell loss, resulting in lifelong absolute insulin deficiency and hyperglycaemia. Environmental factors are recognized as a key contributor to the development of T1D, with the gut serving as a primary interface for environmental stimuli. Recent studies have revealed that the alterations in the intestinal microenvironment profoundly affect host immune responses, contributing to the aetiology and pathogenesis of T1D. However, the dominant intestinal immune cells and the underlying mechanisms remain incompletely elucidated. In this review, we provide an overview of the possible mechanisms of the intestinal mucosal system that underpin the pathogenesis of T1D, shedding light on the roles of both non-classical and classical immune cells in T1D. Our goal is to gain insights into how modulating these immune components may hold potential implications for T1D prevention and provide novel perspectives for immune-mediated therapy.
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Affiliation(s)
- Ruonan Liu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Jing Zhang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Si Chen
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life ScienceHunan Normal UniversityChangshaChina
| | - Yang Xiao
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Jingyi Hu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Lingxiang Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
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Kim K, Han M, Lee D. InTiCAR: Network-based identification of significant inter-tissue communicators for autoimmune diseases. Comput Struct Biotechnol J 2025; 27:333-345. [PMID: 39897058 PMCID: PMC11782887 DOI: 10.1016/j.csbj.2025.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 01/03/2025] [Accepted: 01/04/2025] [Indexed: 02/04/2025] Open
Abstract
Inter-tissue communicators (ITCs) are intricate and essential aspects of our body, as they are the keepers of homeostatic equilibrium. It is no surprise that the dysregulation of the exchange between tissues are at the core of various disorders. Among such conditions, autoimmune diseases (AIDs) refer to a collection of pathological conditions where the miscommunication drives the immune system to mistakenly attack one's own body. Due to their myriad and diverse pathophysiologies, AIDs cannot be easily diagnosed or treated, and continuous efforts are required to seek for potential diagnostic markers or therapeutic targets. The identification of ITCs with significant involvement in the disease states is therefore crucial. Here, we present InTiCAR, Inter-Tissue Communicators for Autoimmune diseases by Random walk with restart, which is a network exploration-based analysis method that suggests disease-specific ITCs based on prior knowledge of disease genes, without the need for the external expression data. We first show that distinct ITC profile s can be acquired for various diseases by InTiCAR. We further illustrate that, for autoimmune diseases (AIDs) specifically, the disease-specific ITCs outperform disease genes in diagnosing patients using the UK Biobank plasma proteome dataset. Also, through CMap LINCS dataset, we find that high perturbation on the AIDs genes can be observed by the disease-specific ITCs. Our results provide and highlight unique perspectives on biological network analysis by focusing on the entities of extracellular communications.
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Affiliation(s)
- Kwansoo Kim
- Department of Bio and Brain Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Manyoung Han
- Department of Bio and Brain Engineering, KAIST, Daejeon 34141, Republic of Korea
| | - Doheon Lee
- Department of Bio and Brain Engineering, KAIST, Daejeon 34141, Republic of Korea
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Campos J, Osorio-Barrios F, Villanelo F, Gutierrez-Maldonado SE, Vargas P, Pérez-Acle T, Pacheco R. Chemokinergic and Dopaminergic Signalling Collaborates through the Heteromer Formed by CCR9 and Dopamine Receptor D5 Increasing the Migratory Speed of Effector CD4 + T-Cells to Infiltrate the Colonic Mucosa. Int J Mol Sci 2024; 25:10022. [PMID: 39337509 PMCID: PMC11432204 DOI: 10.3390/ijms251810022] [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: 08/12/2024] [Revised: 09/10/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
Inflammatory bowel diseases (IBDs) involve chronic inflammation of the gastrointestinal tract, where effector CD4+ T-cells play a central role. Thereby, the recruitment of T-cells into the colonic mucosa represents a key process in IBD. We recently found that CCR9 and DRD5 might form a heteromeric complex on the T-cell surface. The increase in CCL25 production and the reduction in dopamine levels associated with colonic inflammation represent a dual signal stimulating the CCR9:DRD5 heteromer, which promotes the recruitment of CD4+ T-cells into the colonic lamina propria. Here, we aimed to analyse the molecular requirements involved in the heteromer assembly as well as to determine the underlying cellular mechanisms involved in the colonic tropism given by the stimulation of the CCR9:DRD5 complex. The results show that dual stimulation of the CCR9:DRD5 heteromer potentiates the phosphorylation of the myosin light chain 2 (MLC2) and the migration speed in confined microchannels. Accordingly, disrupting the CCR9:DRD5 assembly induced a sharp reduction in the pMLC2 in vitro, decreased the migratory speed in confined microchannels, and dampened the recruitment of CD4+ T-cells into the inflamed colonic mucosa. Furthermore, in silico analysis confirmed that the interface of interaction of CCR9:DRD5 is formed by the transmembrane segments 5 and 6 from each protomer. Our findings demonstrated that the CCR9:DRD5 heteromeric complex plays a fundamental role in the migration of CD4+ T-cells into the colonic mucosa upon inflammation. Thereby, the present study encourages the design of strategies for disassembling the formation of the CCR9:DRD5 as a therapeutic opportunity to treat IBD.
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Affiliation(s)
- Javier Campos
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Huechuraba 8580704, Santiago, Chile; (J.C.); (F.V.); (S.E.G.-M.); (T.P.-A.)
| | - Francisco Osorio-Barrios
- Gut Microbiology, Institute for Infectious Diseases, University of Bern, Friedbühlstrasse 25, 3001 Bern, Switzerland
| | - Felipe Villanelo
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Huechuraba 8580704, Santiago, Chile; (J.C.); (F.V.); (S.E.G.-M.); (T.P.-A.)
- Escuela de Ingeniería, Facultad de Ingeniería Arquitectura y Diseño, Universidad San Sebastián, Recoleta 8420524, Santiago, Chile
| | - Sebastian E. Gutierrez-Maldonado
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Huechuraba 8580704, Santiago, Chile; (J.C.); (F.V.); (S.E.G.-M.); (T.P.-A.)
- Escuela de Ingeniería, Facultad de Ingeniería Arquitectura y Diseño, Universidad San Sebastián, Recoleta 8420524, Santiago, Chile
| | - Pablo Vargas
- Institut Curie, PSL Research University, CNRS, UMR144, F-75005 Paris, France;
- Université Paris Cité, CNRS, INSERM, Inserm, INEM, F-75015 Paris, France
| | - Tomás Pérez-Acle
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Huechuraba 8580704, Santiago, Chile; (J.C.); (F.V.); (S.E.G.-M.); (T.P.-A.)
- Escuela de Ingeniería, Facultad de Ingeniería Arquitectura y Diseño, Universidad San Sebastián, Recoleta 8420524, Santiago, Chile
| | - Rodrigo Pacheco
- Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Huechuraba 8580704, Santiago, Chile; (J.C.); (F.V.); (S.E.G.-M.); (T.P.-A.)
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Providencia 7510157, Santiago, Chile
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Liu HX, Wang YY, Yang XF. Differential expression of plasma cytokines in sepsis patients and their clinical implications. World J Clin Cases 2024; 12:5681-5696. [PMID: 39247745 PMCID: PMC11263047 DOI: 10.12998/wjcc.v12.i25.5681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 05/25/2024] [Accepted: 07/01/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND Sepsis, which is characterized by acute systemic inflammation and is associated with high rates of morbidity and mortality, presents a significant challenge in health care. Some scholars have found that the sequential organ failure assessment (SOFA) and quick SOFA scores are not ideal for predicting severe sepsis and mortality. Microbial culture takes a long time (2-3 d) and provides no information for early diagnosis and treatment. Therefore, new diagnostic methods for sepsis need to be explored. AIM To assess cytokine levels in the plasma of sepsis patients and identify potential biomarkers for diagnosing sepsis. METHODS Ten sepsis patients admitted to the emergency department within 24 h of onset were enrolled as the observation group, whereas ten noninfected patients served as the control group. Of the 10 noninfected patients, 9 hypertension combined with cerebral infarction, 1 patients with vertiginous syndrome. Plasma Cytokines were measured using the Bio-Plex Pro™ Human Chemokine Panel 40-plex. Differentially expressed cytokines in plasma of sepsis and nonsepsis patients were analyzed using Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. RESULTS Interleukin (IL)-16, granulocyte-macrophage granulocyte-macrophage colony-stimulating factor (GM-CSF), CX3CL1, CXCL9, CXCL16, CCL25, and CCL23 plasma levels were significantly increased in sepsis patients. GO analysis revealed that these cytokines were mainly associated with cellular structures such as intermediates, nuclear plaques, adhesion plaques, lateral plasma membranes, and cell matrix junctions. These genes were involved in various molecular functions, such as cytokine activity, receptor ligand activity, and signal receptor activator activity, contributing to various biological functions, such as leukocyte chemotaxis, migration, and chemotaxis. KEGG analysis indicated involvement in cytokine cytokine receptor interactions, chemokine signaling pathways, virus-protein interactions with cytokines and cytokine receptors, and the tumor necrosis factor signaling pathway. CONCLUSION Elevated serum levels of IL-16, GM-CSF, CX3CL1, CXCL9, CXCL16, CCL25, and CCL23 in sepsis patients suggest their potential as diagnostic biomarkers for sepsis.
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Affiliation(s)
- Hui-Xiu Liu
- Interventional Diagnosis and Treatment Center, The Affiliated Second Hospital, Hengyang Medical School, University of South China, Hengyang 421001, Hunan Province, China
| | - Yu-Ying Wang
- Department of Emergency, The Shanghai Putuo District People's Hospital, Shanghai 200060, China
- Department of Gastroenterology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang 421002, Hunan Province, China
| | - Xue-Feng Yang
- Department of Gastroenterology, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang 421002, Hunan Province, China
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Cheong KL, Xie XT, Zhou T, Malairaj S, Veeraperumal S, Zhong S, Tan K. Exploring the therapeutic potential of porphyran extracted from Porphyra haitanensis in the attenuation of DSS-induced intestinal inflammation. Int J Biol Macromol 2024; 271:132578. [PMID: 38788872 DOI: 10.1016/j.ijbiomac.2024.132578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 05/01/2024] [Accepted: 05/20/2024] [Indexed: 05/26/2024]
Abstract
Ulcerative colitis is a chronic, spontaneous inflammatory bowel disease that primarily affects the colon. This study aimed to explore how Porphyra haitanensis porphyran (PHP) modulates the immune response and the associated mechanisms that alleviate dextran sulphate sodium-induced colitis in mice. Histological assessments via H&E staining and AB-PAS staining revealed that PHP intervention partially restored the number of goblet cells and improved intestinal mucosal function. Immunohistochemical and Western blot analyses of claudin-1, occludin, and MUC-2 demonstrated that PHP could repair the intestinal barrier and reduce colon damage by upregulating the expression of these proteins. PHP intervention was associated with a decrease in pro-inflammatory cytokine expression and an increase in anti-inflammatory cytokine expression. Moreover, the expression of proteins involved in intestinal immune homing, such as CCR-9, CCL-25, MAdCAM-1, and α4β7, was significantly suppressed in response to PHP treatment. Conversely, PHP upregulates the expression of CD40 and TGF-β1, both of these can promote healing and reduce inflammation in the gut lining. This study demonstrates that PHP can ameliorate ulcerative colitis by enhancing the intestinal barrier and modulating immune responses. These findings offer valuable insights into the potential utility of P. haitanensis as a promising natural product for managing ulcerative colitis.
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Affiliation(s)
- Kit-Leong Cheong
- College of Food Science and Technology, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Province Engineering Laboratory for Marine Biological Products, Guangdong Provincial Engineering Technology Research Center of Seafood, Guangdong Provincial Engineering Technology Research Center of Prefabricated Seafood Processing and Quality Control, Zhanjiang 524088, China; Department of Biology, College of Science, Shantou University, Shantou 515063, Guangdong, PR China.
| | - Xu-Ting Xie
- Department of Biology, College of Science, Shantou University, Shantou 515063, Guangdong, PR China
| | - Tao Zhou
- College of Food Science and Technology, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Province Engineering Laboratory for Marine Biological Products, Guangdong Provincial Engineering Technology Research Center of Seafood, Guangdong Provincial Engineering Technology Research Center of Prefabricated Seafood Processing and Quality Control, Zhanjiang 524088, China
| | - Sathuvan Malairaj
- Department of Biology, College of Science, Shantou University, Shantou 515063, Guangdong, PR China
| | - Suresh Veeraperumal
- Department of Biology, College of Science, Shantou University, Shantou 515063, Guangdong, PR China
| | - Saiyi Zhong
- College of Food Science and Technology, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Province Engineering Laboratory for Marine Biological Products, Guangdong Provincial Engineering Technology Research Center of Seafood, Guangdong Provincial Engineering Technology Research Center of Prefabricated Seafood Processing and Quality Control, Zhanjiang 524088, China.
| | - Karsoon Tan
- Guangxi Key Laboratory of Beibu Gulf Biodiversity Conservation, Beibu Gulf University, Qinzhou, Guangxi, China.
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Lina G, Cuixin Q, Xia Z, Jing Y, Zhirong L, Zirou O, Jiayiren L, Yulian Z, Qiuyue H, Qianqing L, Yan L, Pu Q, Bin Z, Jianhong Z. CCR9+CD4+ T cells are associated with disease activity in patients with rheumatoid arthritis. Medicine (Baltimore) 2024; 103:e37803. [PMID: 38640336 PMCID: PMC11030009 DOI: 10.1097/md.0000000000037803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 03/04/2024] [Accepted: 03/14/2024] [Indexed: 04/21/2024] Open
Abstract
An increase in CD4+ T cells in the synovium is closely linked to the pathogenesis of rheumatoid arthritis (RA). We aimed to identify the possible causes of the elevated CD4+ T cell levels and to explore the factors influencing disease activity in RA. Fifty-five RA patients, including 28 with active RA (ARA), 27 with inactive RA, and 22 healthy controls, were recruited for this study. The proportion of CCR9+CD4+ T cells and the expression of chemokine receptor 9 (CCR9) on CD4+ T cells were analyzed by flow cytometry. Enzyme-linked immunosorbent assay and chemiluminescent immunoassay were used to evaluate interleukin (IL)-17A and IL-6 levels, respectively. The proportion of CCR9+CD4+ T cells and the expression of CCR9 on CD4+ T cells increased significantly in peripheral blood (PB) and synovial fluid (SF) in ARA compared to those in inactive RA. Furthermore, SF contained more CCR9+CD4+ T cells, IL-6, and IL-17A than PB in RA patients. Moreover, CD4+ T cells in the PB of patients with RA, especially ARA, expressed more CCR9 and secreted more IL-6 and IL-17A after activation. Here, we also demonstrated that both the percentage of CCR9+ cells in CD4+ T cells and the expression of CCR9 on circulating CD4+ T cells were positively correlated with erythrocyte sedimentation rate, hypersensitive C-reactive protein, rheumatoid factor, and anti-cyclic citrullinated peptide antibody. CCR9+CD4+ T cells are elevated in PB and SF, and are associated with disease activity in patients with RA.
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Affiliation(s)
- Geng Lina
- Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Clinical Laboratory, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China
| | - Qiang Cuixin
- Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Zhang Xia
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China
| | - Yang Jing
- Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Li Zhirong
- Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Ouyang Zirou
- Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Li Jiayiren
- Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Zhang Yulian
- Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Huo Qiuyue
- Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Li Qianqing
- Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Liu Yan
- Department of Clinical Laboratory, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China
| | - Qin Pu
- Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Zhang Bin
- Department of Clinical Laboratory, The First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, China
| | - Zhao Jianhong
- Provincial Center for Clinical Laboratories, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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Glyn T, Williams S, Whitehead M, Eglinton T, West N, Purcell RV. Digital spatial profiling identifies molecular changes involved in development of colitis-associated colorectal cancer. Front Oncol 2024; 14:1247106. [PMID: 38505585 PMCID: PMC10949367 DOI: 10.3389/fonc.2024.1247106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 02/01/2024] [Indexed: 03/21/2024] Open
Abstract
Objective Chronic colonic inflammation seen in inflammatory bowel disease (IBD) is a risk factor for colorectal cancer (CRC). Colitis-associated cancers (CAC) are molecularly different from sporadic CRC. This study aimed to evaluate spatially defined molecular changes associated with neoplastic progression to identify mechanisms of action and potential biomarkers for prognostication. Design IBD patients who had undergone colectomy for treatment of their IBD or dysplasia were identified from an institutional database. Formalin-fixed paraffin embedded samples from areas of normal, inflamed, dysplastic and adenocarcinoma tissue were identified for digital spatial profiling using the Nanostring GeoMx™ Cancer Transcriptome Atlas. RNA expression and quantification of 1812 genes was measured and analysed in a spatial context to compare differences in gene expression. Results Sixteen patients were included, nine patients had CAC, two had dysplasia only and five had colitis only. Significant, step-wise differences in gene expression were seen between tissue types, mainly involving progressive over-expression of collagen genes associated with stromal remodelling. Similarly, MYC over-expression was associated with neoplastic progression. Comparison of normal and inflamed tissue from patients who progressed to those who did not also showed significant differences in immune-related genes, including under-expression of thte chemokines CCL18, CCL25 and IL-R7, as well as CD3, CD6 and lysozyme. The known oncogene CD24 was significantly overexpressed. Conclusion Both tissue types and patient groups are molecularly distinguishable on the basis of their gene expression patterns. Further prospective work is necessary to confirm these differences and establish their clinical significance and potential utility as biomarkers.
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Affiliation(s)
- Tamara Glyn
- Department of Surgery and Critical Care, University of Otago, Christchurch, New Zealand
| | - Sarah Williams
- Griffith Health, Griffith University, Gold Coast, QLD, Australia
| | - Martin Whitehead
- Department of Anatomical Pathology, Te Whatu Ora Waitaha, Christchurch, New Zealand
| | - Tim Eglinton
- Department of Surgery and Critical Care, University of Otago, Christchurch, New Zealand
| | - Nicholas West
- Griffith Health, Griffith University, Gold Coast, QLD, Australia
| | - Rachel V. Purcell
- Department of Surgery and Critical Care, University of Otago, Christchurch, New Zealand
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Gustafsson A, Johansson E, Henckel E, Olin A, Rodriguez L, Brodin P, Lange S, Bohlin K. Antisecretory factor in breastmilk is associated with reduced incidence of sepsis in preterm infants. Pediatr Res 2024; 95:762-769. [PMID: 38001236 PMCID: PMC10899102 DOI: 10.1038/s41390-023-02909-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 10/28/2023] [Accepted: 11/03/2023] [Indexed: 11/26/2023]
Abstract
BACKGROUND Antisecretory Factor (AF) is a protein present in breastmilk that regulates inflammatory processes. We aimed to investigate the level of AF in mothers' own milk (MOM) in relation to sepsis and other neonatal morbidities in preterm infants. METHODS Samples of breastmilk and infant plasma were collected at 1, 4, and 12 weeks after birth from 38 mothers and their 49 infants born before 30 weeks gestation. AF-compleasome in MOM was determined by a sandwich enzyme-linked immunosorbent assay (ELISA) and inflammatory markers in infant plasma by a panel of 92 inflammatory proteins. Neonatal treatments and outcomes were recorded. RESULTS The level of AF in MOM week 1 was lower for infants with later sepsis compared to no sepsis (p = 0.005). Corrected for nutritional intake of MOM, higher levels of AF decreased the risk for sepsis, OR 0.24. AF in MOM week 1 was negatively correlated to inflammatory proteins in infant plasma week 4, markedly IL-8, which was also associated with infant sepsis. Overall, higher AF levels in MOM was associated with fewer major morbidities of prematurity. CONCLUSION Mother's milk containing high levels of antisecretory factor is associated with reduced risk for sepsis and inflammation in preterm infants. IMPACT High level of antisecretory factor (AF) in mothers' own milk is associated with less risk for later sepsis in preterm infants. Receiving mothers' milk with low AF levels during the first week after birth is correlated with more inflammatory proteins in infant's plasma 2-4 weeks later. Human breastmilk has anti-inflammatory properties, and antisecretory factor in mothers' own milk is a component of potential importance for infants born preterm. The findings suggest that food supplementation with AF to mothers of preterm infants to increase AF-levels in breastmilk may be a means to decrease the risk of inflammatory morbidities of prematurity.
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Affiliation(s)
- Anna Gustafsson
- Department of Neonatology, Karolinska University Hospital, SE-17176, Stockholm, Sweden.
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
| | - Ewa Johansson
- Institute of Biomedicine, Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden
- Sahlgrenska University Hospital, Department of Clinical Microbiology, Västra Götaland Region, Gothenburg, Sweden
| | - Ewa Henckel
- Department of Neonatology, Karolinska University Hospital, SE-17176, Stockholm, Sweden
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
| | - Axel Olin
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, and Unit of Infectious Diseases, Karolinska University Hospital, SE-17176, Stockholm, Sweden
| | - Lucie Rodriguez
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, and Unit of Infectious Diseases, Karolinska University Hospital, SE-17176, Stockholm, Sweden
| | - Petter Brodin
- Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, and Unit of Infectious Diseases, Karolinska University Hospital, SE-17176, Stockholm, Sweden
| | - Stefan Lange
- Institute of Biomedicine, Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden
- Sahlgrenska University Hospital, Department of Clinical Microbiology, Västra Götaland Region, Gothenburg, Sweden
| | - Kajsa Bohlin
- Department of Neonatology, Karolinska University Hospital, SE-17176, Stockholm, Sweden
- Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
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10
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Canziani KE, Ruiz MC, Candia MR, Ilid M, Feregotti E, Curciarello R, Álvarez MC, Guzmán L, Bernedo V, García M, Bohle B, Docena GH, Muglia CI. Food-sensitized pediatric patients show colonic cow's milk protein-specific Th2 cells. J Leukoc Biol 2023; 114:434-442. [PMID: 37478370 DOI: 10.1093/jleuko/qiad083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 06/21/2023] [Accepted: 07/07/2023] [Indexed: 07/23/2023] Open
Abstract
Food allergies have become a health concern worldwide. Around 6% to 10% of children are allergic to cow's milk proteins. We have previously characterized colorectal polyps in patients sensitized to food allergens. These polyps are classified as inflammatory and present a type 2 environment, with elevated interleukin (IL)-13 and IL-4, and are a site of immunoglobulin E synthesis. In this study, we characterized and isolated cow's milk protein-specific T cell lines and T cell clones from the lamina propria of polyps from patients sensitized to these proteins. Isolated T cells responded to cow's milk proteins similarly to peripheral blood T cells, showing antigen-specific cell proliferation and Th2 cytokines release in vitro. T cell clones obtained were all CD4+ T cells and expressed the membrane TCRαβ receptor and secreted higher IL-4, IL-5, and IL-13 amounts than unstimulated cells, whereas interferon γ secretion remained unchanged. Remarkably, the gut homing chemokine receptor CCR9 was augmented in cow's milk-specific peripheral and lamina propria T cells, and CCL25 was found to be expressed in the inflammatory polyp tissue and not in the adjacent mucosa. In conclusion, we isolated and characterized cow's milk-specific lamina propria CD4+ Th2 cells from colonic inflammatory polyps. CCR9 expression on these cells, along with increase secretion of CCL25 in the polyp, favors recruitment and cow's milk-specific allergic response within the inflammatory polyp tissue. Our findings may be critical to understand the underlying mechanism that promotes immunoglobulin E synthesis in the colon of cow's milk proteins allergic patients, contributing to the development of novel T cell-targeted immunotherapies.
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Affiliation(s)
- Karina E Canziani
- Instituto de Estudios Inmunológicos y Fisiopatológicos, CONICET - Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, asociado Comisión de Investigaciones Científicas de la Provincia de Buenos Aires, Boulevard 120 N°1489, 1900, La Plata, Argentina
| | - María Carolina Ruiz
- Instituto de Estudios Inmunológicos y Fisiopatológicos, CONICET - Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, asociado Comisión de Investigaciones Científicas de la Provincia de Buenos Aires, Boulevard 120 N°1489, 1900, La Plata, Argentina
| | - Martín R Candia
- Instituto de Estudios Inmunológicos y Fisiopatológicos, CONICET - Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, asociado Comisión de Investigaciones Científicas de la Provincia de Buenos Aires, Boulevard 120 N°1489, 1900, La Plata, Argentina
| | - Manuela Ilid
- Instituto de Estudios Inmunológicos y Fisiopatológicos, CONICET - Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, asociado Comisión de Investigaciones Científicas de la Provincia de Buenos Aires, Boulevard 120 N°1489, 1900, La Plata, Argentina
| | - Emanuel Feregotti
- Instituto de Estudios Inmunológicos y Fisiopatológicos, CONICET - Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, asociado Comisión de Investigaciones Científicas de la Provincia de Buenos Aires, Boulevard 120 N°1489, 1900, La Plata, Argentina
| | - Renata Curciarello
- Instituto de Estudios Inmunológicos y Fisiopatológicos, CONICET - Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, asociado Comisión de Investigaciones Científicas de la Provincia de Buenos Aires, Boulevard 120 N°1489, 1900, La Plata, Argentina
| | - María Cecilia Álvarez
- Instituto de Estudios Inmunológicos y Fisiopatológicos, CONICET - Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, asociado Comisión de Investigaciones Científicas de la Provincia de Buenos Aires, Boulevard 120 N°1489, 1900, La Plata, Argentina
| | - Luciana Guzmán
- Servicio de Gastroenterología, Hospital de Niños Sor María Ludovica, La Plata, Calle 14 N°1631, 1900, La Plata, Argentina
| | - Viviana Bernedo
- Servicio de Gastroenterología, Hospital de Niños Sor María Ludovica, La Plata, Calle 14 N°1631, 1900, La Plata, Argentina
| | - Marcela García
- Sala de Alergia, Hospital de Niños Sor María Ludovica, Calle 14 N°1631, 1900, La Plata, Argentina
| | - Barbara Bohle
- Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Kinderspitalgasse 15, 1090 Vienna, Austria
| | - Guillermo Horacio Docena
- Instituto de Estudios Inmunológicos y Fisiopatológicos, CONICET - Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, asociado Comisión de Investigaciones Científicas de la Provincia de Buenos Aires, Boulevard 120 N°1489, 1900, La Plata, Argentina
| | - Cecilia Isabel Muglia
- Instituto de Estudios Inmunológicos y Fisiopatológicos, CONICET - Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, asociado Comisión de Investigaciones Científicas de la Provincia de Buenos Aires, Boulevard 120 N°1489, 1900, La Plata, Argentina
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11
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He R, Zhao S, Cui M, Chen Y, Ma J, Li J, Wang X. Cutaneous manifestations of inflammatory bowel disease: basic characteristics, therapy, and potential pathophysiological associations. Front Immunol 2023; 14:1234535. [PMID: 37954590 PMCID: PMC10637386 DOI: 10.3389/fimmu.2023.1234535] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 10/16/2023] [Indexed: 11/14/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease typically involving the gastrointestinal tract but not limited to it. IBD can be subdivided into Crohn's disease (CD) and ulcerative colitis (UC). Extraintestinal manifestations (EIMs) are observed in up to 47% of patients with IBD, with the most frequent reports of cutaneous manifestations. Among these, pyoderma gangrenosum (PG) and erythema nodosum (EN) are the two most common skin manifestations in IBD, and both are immune-related inflammatory skin diseases. The presence of cutaneous EIMs may either be concordant with intestinal disease activity or have an independent course. Despite some progress in research on EIMs, for instance, ectopic expression of gut-specific mucosal address cell adhesion molecule-1 (MAdCAM-1) and chemokine CCL25 on the vascular endothelium of the portal tract have been demonstrated in IBD-related primary sclerosing cholangitis (PSC), little is understood about the potential pathophysiological associations between IBD and cutaneous EIMs. Whether cutaneous EIMs are inflammatory events with a commonly shared genetic background or environmental risk factors with IBD but independent of IBD or are the result of an extraintestinal extension of intestinal inflammation, remains unclear. The review aims to provide an overview of the two most representative cutaneous manifestations of IBD, describe IBD's epidemiology, clinical characteristics, and histology, and discuss the immunopathophysiology and existing treatment strategies with biologic agents, with a focus on the potential pathophysiological associations between IBD and cutaneous EIMs.
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Affiliation(s)
- Ronghua He
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Subei Zhao
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mingyu Cui
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Yanhao Chen
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Jinrong Ma
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Jintao Li
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Xiaodong Wang
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, Jilin, China
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12
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Ibidapo-Obe O, Bruns T. Tissue-resident and innate-like T cells in patients with advanced chronic liver disease. JHEP Rep 2023; 5:100812. [PMID: 37691689 PMCID: PMC10485156 DOI: 10.1016/j.jhepr.2023.100812] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 05/07/2023] [Accepted: 05/09/2023] [Indexed: 09/12/2023] Open
Abstract
Chronic liver disease results from the orchestrated interplay of components of innate and adaptive immunity in response to liver tissue damage. Recruitment, positioning, and activation of immune cells can contribute to hepatic cell death, inflammation, and fibrogenesis. With disease progression and increasing portal pressure, repeated translocation of bacterial components from the intestinal lumen through the epithelial and vascular barriers leads to persistent mucosal, hepatic, and systemic inflammation which contributes to tissue damage, immune dysfunction, and microbial infection. It is increasingly recognised that innate-like and adaptive T-cell subsets located in the liver, mucosal surfaces, and body cavities play a critical role in the progression of advanced liver disease and inflammatory complications of cirrhosis. Mucosal-associated invariant T cells, natural killer T cells, γδ T cells, and tissue-resident memory T cells in the gut, liver, and ascitic fluid share certain characteristic features, which include that they recognise microbial products, tissue alarmins, cytokines, and stress ligands in tissues, and perform effector functions in chronic liver disease. This review highlights recent advances in the comprehension of human tissue-resident and unconventional T-cell populations and discusses the mechanisms by which they contribute to inflammation, fibrosis, immunosuppression, and antimicrobial surveillance in patients with cirrhosis. Understanding the complex interactions of immune cells in different compartments and their contribution to disease progression will provide further insights for effective diagnostic interventions and novel immunomodulatory strategies in patients with advanced chronic liver disease.
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Affiliation(s)
- Oluwatomi Ibidapo-Obe
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Tony Bruns
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
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13
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Gordon H, Rodger B, Lindsay JO, Stagg AJ. Recruitment and Residence of Intestinal T Cells - Lessons for Therapy in Inflammatory Bowel Disease. J Crohns Colitis 2023; 17:1326-1341. [PMID: 36806613 DOI: 10.1093/ecco-jcc/jjad027] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Indexed: 02/23/2023]
Abstract
Targeting leukocyte trafficking in the management of inflammatory bowel disease [IBD] has been a significant therapeutic advance over the past 15 years. However, as with other advanced therapies, phase III clinical trials report response to trafficking inhibitors in only a proportion of patients, with fewer achieving clinical remission or mucosal healing. Additionally, there have been significant side effects, most notably progressive multifocal leukoencephalopathy in association with the α4 inhibitor natalizumab. This article reviews the mechanisms underpinning T cell recruitment and residence, to provide a background from which the strength and limitations of agents that disrupt leukocyte trafficking can be further explored. The therapeutic impact of trafficking inhibitors is underpinned by the complexity and plasticity of the intestinal immune response. Pathways essential for gut homing in health may be bypassed in the inflamed gut, thus providing alternative routes of entry when conventional homing molecules are targeted. Furthermore, there is conservation of trafficking architecture between proinflammatory and regulatory T cells. The persistence of resident memory cells within the gut gives rise to local established pro-inflammatory populations, uninfluenced by inhibition of trafficking. Finally, trafficking inhibitors may give rise to effects beyond the intended response, such as the impact of vedolizumab on innate immunity, as well as on target side effects. With significant research efforts into predictive biomarkers already underway, it is ultimately hoped that a better understanding of trafficking and residence will help us predict which patients are most likely to respond to inhibition of leukocyte trafficking, and how best to combine therapies.
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Affiliation(s)
- Hannah Gordon
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
- Department of Gastroenterology, Barts Health NHS Trust, London, UK
| | - Beverley Rodger
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
| | - James O Lindsay
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
- Department of Gastroenterology, Barts Health NHS Trust, London, UK
| | - Andrew J Stagg
- Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, London, UK
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14
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Jensen SB, Sheikh MA, Akkouh IA, Szabo A, O’Connell KS, Lekva T, Engh JA, Agartz I, Elvsåshagen T, Ormerod MBEG, Weibell MA, Johnsen E, Kroken RA, Melle I, Drange OK, Nærland T, Vaaler AE, Westlye LT, Aukrust P, Djurovic S, Eiel Steen N, Andreassen OA, Ueland T. Elevated Systemic Levels of Markers Reflecting Intestinal Barrier Dysfunction and Inflammasome Activation Are Correlated in Severe Mental Illness. Schizophr Bull 2023; 49:635-645. [PMID: 36462169 PMCID: PMC10154716 DOI: 10.1093/schbul/sbac191] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
BACKGROUND AND HYPOTHESIS Gut microbiota alterations have been reported in severe mental illness (SMI) but fewer studies have probed for signs of gut barrier disruption and inflammation. We hypothesized that gut leakage of microbial products due to intestinal inflammation could contribute to systemic inflammasome activation in SMI. STUDY DESIGN We measured plasma levels of the chemokine CCL25 and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) as markers of T cell homing, adhesion and inflammation in the gut, lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP) as markers of bacterial translocation and gut barrier dysfunction, in a large SMI cohort (n = 567) including schizophrenia (SCZ, n = 389) and affective disorder (AFF, n = 178), relative to healthy controls (HC, n = 418). We assessed associations with plasma IL-18 and IL-18BPa and leukocyte mRNA expression of NLRP3 and NLRC4 as markers of inflammasome activation. STUDY RESULTS Our main findings were: (1) higher levels of sMAdCAM-1 (P = .002), I-FABP (P = 7.6E-11), CCL25 (P = 9.6E-05) and LBP (P = 2.6E-04) in SMI compared to HC in age, sex, BMI, CRP and freezer storage time adjusted analysis; (2) the highest levels of sMAdCAM-1 and CCL25 (both P = 2.6E-04) were observed in SCZ and I-FABP (P = 2.5E-10) and LBP (3) in AFF; and (3), I-FABP correlated with IL-18BPa levels and LBP correlated with NLRC4. CONCLUSIONS Our findings support that intestinal barrier inflammation and dysfunction in SMI could contribute to systemic inflammation through inflammasome activation.
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Affiliation(s)
- Søren B Jensen
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
| | - Mashhood A Sheikh
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
| | - Ibrahim A Akkouh
- Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research, NORMENT, Oslo University Hospital, Oslo, Norway
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
| | - Attila Szabo
- Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research, NORMENT, Oslo University Hospital, Oslo, Norway
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
- K.G. Jebsen Center for Neurodevelopmental disorders, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Kevin S O’Connell
- Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research, NORMENT, Oslo University Hospital, Oslo, Norway
| | - Tove Lekva
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
| | - John A Engh
- Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research, NORMENT, Oslo University Hospital, Oslo, Norway
- Division of Mental health and Addiction, Vestfold Hospital Trust, Tønsberg, Norway
| | - Ingrid Agartz
- K.G. Jebsen Center for Neurodevelopmental disorders, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden
- Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
- Norwegian Centre for Mental Disorders Research, NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Torbjørn Elvsåshagen
- Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research, NORMENT, Oslo University Hospital, Oslo, Norway
| | - Monica B E G Ormerod
- Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research, NORMENT, Oslo University Hospital, Oslo, Norway
- Norwegian Centre for Mental Disorders Research, NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Melissa A Weibell
- Division of Psychiatry, Network for Clinical Psychosis Research, Stavanger University Hospital, Stavanger, Norway
- Network for Medical Sciences, Faculty of Health, University of Stavanger, Stavanger, Norway
| | - Erik Johnsen
- Division of Psychiatry, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- NORMENT Center of Excellence, University of Bergen and Haukeland University Hospital, Bergen, Norway
| | - Rune A Kroken
- Division of Psychiatry, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
- NORMENT Center of Excellence, University of Bergen and Haukeland University Hospital, Bergen, Norway
| | - Ingrid Melle
- Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research, NORMENT, Oslo University Hospital, Oslo, Norway
- Norwegian Centre for Mental Disorders Research, NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Ole K Drange
- Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Østmarka, Division of Mental Health, St. Olavs University Hospital, Trondheim, Norway
- Department of Psychiatry, Sørlandet Hospital, Kristiansand, Norway
| | - Terje Nærland
- K.G. Jebsen Center for Neurodevelopmental disorders, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Rare Disorders, Division of Child and Adolescent medicine, Oslo University Hospital, Oslo, Norway
| | - Arne E Vaaler
- Department of Mental Health, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Østmarka, Division of Mental Health, St. Olavs University Hospital, Trondheim, Norway
| | - Lars T Westlye
- Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research, NORMENT, Oslo University Hospital, Oslo, Norway
- K.G. Jebsen Center for Neurodevelopmental disorders, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Psychology, University of Oslo, Oslo, Norway
| | - Pål Aukrust
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
- Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Srdjan Djurovic
- Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research, NORMENT, Oslo University Hospital, Oslo, Norway
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
- K.G. Jebsen Center for Neurodevelopmental disorders, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Department of Psychology, University of Oslo, Oslo, Norway
| | - Nils Eiel Steen
- Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research, NORMENT, Oslo University Hospital, Oslo, Norway
- Norwegian Centre for Mental Disorders Research, NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Ole A Andreassen
- Division of Mental Health and Addiction, Norwegian Centre for Mental Disorders Research, NORMENT, Oslo University Hospital, Oslo, Norway
- K.G. Jebsen Center for Neurodevelopmental disorders, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Norwegian Centre for Mental Disorders Research, NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Thor Ueland
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- K.G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway
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15
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Doumas SA, Tsironis C, Bolaji AA, Garantziotis P, Frangou E. Glomerulonephritis and inflammatory bowel disease: A tale of gut-kidney axis dysfunction. Autoimmun Rev 2023; 22:103327. [PMID: 36990134 DOI: 10.1016/j.autrev.2023.103327] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 03/22/2023] [Indexed: 03/30/2023]
Abstract
The incidence and prevalence of Inflammatory Bowel Disease (IBD) has increased over the past decades, imposing a growing socioeconomic burden on healthcare systems globally. Most of the morbidity and mortality related to IBD is typically attributed to gut inflammation and its complications; yet the disease is characterized by various extraintestinal manifestations that can be severe. Glomerulonephritis (GN) is of particular interest since a significant proportion of patients evolve into end-stage kidney disease, requiring kidney replacement therapy and associated with high morbidity and mortality. Herein, we review the GN landscape in IBD and define the clinical and pathogenic associations reported to date in the literature. Underlying pathogenic mechanisms suggest either the initiation of antigen-specific immune responses in the inflamed gut that cross react with non-intestinal sites, such as the glomerulus, or that extraintestinal manifestations are gut-independent events that occur due to an interaction between common genetic and environmental risk factors. We present data associating GN with IBD either as a bona fide extraintestinal manifestation or reporting it as an extraneous co-existing entity, involving various histological subtypes, such as focal segmental glomerulosclerosis, proliferative GN, minimal change disease, crescentic GN, but most emphatically IgA nephropathy. Supporting the pathogenic interplay between gut inflammation and intrinsic glomerular processes, enteric targeting the intestinal mucosa with budesonide reduced IgA nephropathy-mediated proteinuria. Elucidating the mechanisms at play would provide insight not only into IBD pathogenesis but also into the gut's role in the development of extraintestinal diseases, such as glomerular diseases.
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16
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Hov JR, Karlsen TH. The microbiota and the gut-liver axis in primary sclerosing cholangitis. Nat Rev Gastroenterol Hepatol 2023; 20:135-154. [PMID: 36352157 DOI: 10.1038/s41575-022-00690-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/13/2022] [Indexed: 11/11/2022]
Abstract
Primary sclerosing cholangitis (PSC) offers unique opportunities to explore the gut-liver axis owing to the close association between liver disease and colonic inflammation. It is well established that the gut microbiota in people with PSC differs from that of healthy individuals, but details of the microbial factors that demarcate PSC from inflammatory bowel disease (IBD) without PSC are poorly understood. In this Review, we aim to provide an overview of the latest literature on the gut microbiome in PSC and PSC with IBD, critically examining hypotheses on how microorganisms could contribute to the pathogenesis of PSC. A particular emphasis will be put on pathogenic features of the gut microbiota that might explain the occurrence of bile duct inflammation and liver disease in the context of IBD, and we postulate the potential existence of a specific yet unknown factor related to the gut-liver axis as causative in PSC. Available data are scrutinized in the perspective of therapeutic approaches related to the gut-liver axis.
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Affiliation(s)
- Johannes R Hov
- Norwegian PSC Research Center and Section of gastroenterology and Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Tom H Karlsen
- Norwegian PSC Research Center and Section of gastroenterology and Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway. .,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
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17
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Zundler S, Schulze LL, Neurath MF. Controlling in and out - the future of interfering with immune cell trafficking in inflammatory bowel disease. Expert Rev Clin Immunol 2023; 19:155-167. [PMID: 36427088 DOI: 10.1080/1744666x.2023.2152794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
INTRODUCTION Immune cell trafficking is a key requirement in the pathogenesis of inflammatory bowel diseases. Consistently, therapeutic strategies to target immune cell trafficking have been established and continue to be developed for the treatment of ulcerative colitis and Crohn's disease. AREAS COVERED In this review, we briefly summarize the most important checkpoints of intestinal immune cell trafficking and their importance during IBD. Moreover, we provide an overview of associated therapeutic targets and previous as well as current efforts on treatment strategies related to these targets. EXPERT OPINION Finally, we comment on potential future developments that might shape the field of immune cell trafficking in the context of IBD.
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Affiliation(s)
- Sebastian Zundler
- Department of Medicine 1 and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Lisa Lou Schulze
- Department of Medicine 1 and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1 and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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18
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Li ZJ, Gou HZ, Zhang YL, Song XJ, Zhang L. Role of intestinal flora in primary sclerosing cholangitis and its potential therapeutic value. World J Gastroenterol 2022; 28:6213-6229. [PMID: 36504550 PMCID: PMC9730442 DOI: 10.3748/wjg.v28.i44.6213] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 10/31/2022] [Accepted: 11/10/2022] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is an autoimmune disease characterized by chronic cholestasis, a persistent inflammation of the bile ducts that leads to sclerotic occlusion and cholestasis. Gut microbes, consisting of microorganisms colonized in the human gut, play an important role in nutrient intake, metabolic homeostasis, immune regulation, and immune regulation; however, their presence might aid PSC development. Studies have found that gut-liver axis interactions also play an important role in the pathogenesis of PSC. Patients with PSC have considerably reduced intestinal flora diversity and increased abundance of potentially pathogenic bacteria. Dysbiosis of the intestinal flora leads to increased intestinal permeability, homing of intestinal lymphocytes, entry of bacteria and their associated metabolites, such as bile acids, into the liver, stimulation of hepatic immune activation, and promotion of PSC. Currently, PSC effective treatment is lacking. However, a number of studies have recently investigated the targeted modulation of gut microbes for the treatment of various liver diseases (alcoholic liver disease, metabolic fatty liver, cirrhosis, and autoimmune liver disease). In addition, antibiotics, fecal microbiota transplantation, and probiotics have been reported as successful PSC therapies as well as for the treatment of gut dysbiosis, suggesting their effectiveness for PSC treatment. Therefore, this review briefly summarizes the role of intestinal flora in PSC with the aim of providing new insights into PSC treatment.
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Affiliation(s)
- Zhen-Jiao Li
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
- Laboratory of Biological Therapy and Regenerative Medicine Transformation Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Hong-Zhong Gou
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
- Laboratory of Biological Therapy and Regenerative Medicine Transformation Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Yu-Lin Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
- Laboratory of Biological Therapy and Regenerative Medicine Transformation Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Xiao-Jing Song
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
- Laboratory of Biological Therapy and Regenerative Medicine Transformation Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Lei Zhang
- The First Clinical Medical College, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
- Laboratory of Biological Therapy and Regenerative Medicine Transformation Gansu Province, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
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19
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Biomolecular Mechanisms of Autoimmune Diseases and Their Relationship with the Resident Microbiota: Friend or Foe? PATHOPHYSIOLOGY 2022; 29:507-536. [PMID: 36136068 PMCID: PMC9505211 DOI: 10.3390/pathophysiology29030041] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/23/2022] [Accepted: 08/26/2022] [Indexed: 12/02/2022] Open
Abstract
The use of innovative approaches to elucidate the pathophysiological mechanisms of autoimmune diseases, as well as to further study of the factors which can have either a positive or negative effect on the course of the disease, is essential. In this line, the development of new molecular techniques and the creation of the Human Genome Program have allowed access to many more solutions to the difficulties that exist in the identification and characterization of the microbiome, as well as changes due to various factors. Such innovative technologies can rekindle older hypotheses, such as molecular mimicry, allowing us to move from hypothesis to theory and from correlation to causality, particularly regarding autoimmune diseases and dysbiosis of the microbiota. For example, Prevotella copri appears to have a strong association with rheumatoid arthritis; it is expected that this will be confirmed by several scientists, which, in turn, will make it possible to identify other mechanisms that may contribute to the pathophysiology of the disease. This article seeks to identify new clues regarding similar correlations between autoimmune activity and the human microbiota, particularly in relation to qualitative and quantitative microbial variations therein.
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20
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Zhang S, Lu S, Li Z. Extrahepatic factors in hepatic immune regulation. Front Immunol 2022; 13:941721. [PMID: 36052075 PMCID: PMC9427192 DOI: 10.3389/fimmu.2022.941721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/28/2022] [Indexed: 11/13/2022] Open
Abstract
The liver is a site of complex immune activity. The hepatic immune system tolerates harmless immunogenic loads in homeostasis status, shelters liver function, while maintaining vigilance against possible infectious agents or tissue damage and providing immune surveillance at the same time. Activation of the hepatic immunity is initiated by a diverse repertoire of hepatic resident immune cells as well as non-hematopoietic cells, which can sense "danger signals" and trigger robust immune response. Factors that mediate the regulation of hepatic immunity are elicited not only in liver, but also in other organs, given the dual blood supply of the liver via both portal vein blood and arterial blood. Emerging evidence indicates that inter-organ crosstalk between the liver and other organs such as spleen, gut, lung, adipose tissue, and brain is involved in the pathogenesis of liver diseases. In this review, we present the features of hepatic immune regulation, with particular attention to the correlation with factors from extrahepatic organ. We describe the mechanisms by which other organs establish an immune association with the liver and then modulate the hepatic immune response. We discuss their roles and distinct mechanisms in liver homeostasis and pathological conditions from the cellular and molecular perspective, highlighting their potential for liver disease intervention. Moreover, we review the available animal models and methods for revealing the regulatory mechanisms of these extrahepatic factors. With the increasing understanding of the mechanisms by which extrahepatic factors regulate liver immunity, we believe that this will provide promising targets for liver disease therapy.
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Affiliation(s)
- Shaoying Zhang
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi International Cooperation Base for Inflammation and Immunity, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
| | - Shemin Lu
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi International Cooperation Base for Inflammation and Immunity, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi’an, China
| | - Zongfang Li
- National-Local Joint Engineering Research Center of Biodiagnosis & Biotherapy, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi Provincial Clinical Medical Research Center for Liver and Spleen Diseases, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
- Shaanxi International Cooperation Base for Inflammation and Immunity, The Second Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China
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21
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Maciocia PM, Wawrzyniecka PA, Maciocia NC, Burley A, Karpanasamy T, Devereaux S, Hoekx M, O'Connor D, Leon T, Rapoz-D'Silva T, Pocock R, Rahman S, Gritti G, Yánez DC, Ross S, Crompton T, Williams O, Lee L, Pule MA, Mansour MR. Anti-CCR9 chimeric antigen receptor T cells for T-cell acute lymphoblastic leukemia. Blood 2022; 140:25-37. [PMID: 35507686 DOI: 10.1182/blood.2021013648] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 04/19/2022] [Indexed: 11/20/2022] Open
Abstract
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of immature T lymphocytes, associated with higher rates of induction failure compared with those in B cell acute lymphoblastic leukemia. The potent immunotherapeutic approaches applied in B cell acute lymphoblastic leukemia, which have revolutionized the treatment paradigm, have proven more challenging in T-ALL, largely due to a lack of target antigens expressed on malignant but not healthy T cells. Unlike B cell depletion, T-cell aplasia is highly toxic. Here, we show that the chemokine receptor CCR9 is expressed in >70% of cases of T-ALL, including >85% of relapsed/refractory disease, and only on a small fraction (<5%) of normal T cells. Using cell line models and patient-derived xenografts, we found that chimeric antigen receptor (CAR) T-cells targeting CCR9 are resistant to fratricide and have potent antileukemic activity both in vitro and in vivo, even at low target antigen density. We propose that anti-CCR9 CAR-T cells could be a highly effective treatment strategy for T-ALL, avoiding T cell aplasia and the need for genome engineering that complicate other approaches.
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Affiliation(s)
- Paul M Maciocia
- Department of Haematology, Cancer Institute, University College London, London, United Kingdom
| | - Patrycja A Wawrzyniecka
- Department of Haematology, Cancer Institute, University College London, London, United Kingdom
| | - Nicola C Maciocia
- Department of Haematology, Cancer Institute, University College London, London, United Kingdom
| | - Amy Burley
- Department of Haematology, Cancer Institute, University College London, London, United Kingdom
| | - Thaneswari Karpanasamy
- Department of Haematology, Cancer Institute, University College London, London, United Kingdom
| | - Sam Devereaux
- Department of Haematology, Cancer Institute, University College London, London, United Kingdom
| | - Malika Hoekx
- Department of Haematology, Cancer Institute, University College London, London, United Kingdom
| | - David O'Connor
- Department of Haematology, Cancer Institute, University College London, London, United Kingdom
| | - Theresa Leon
- Department of Haematology, Cancer Institute, University College London, London, United Kingdom
| | - Tanya Rapoz-D'Silva
- Department of Haematology, Cancer Institute, University College London, London, United Kingdom
| | - Rachael Pocock
- Department of Haematology, Cancer Institute, University College London, London, United Kingdom
| | - Sunniyat Rahman
- Department of Haematology, Cancer Institute, University College London, London, United Kingdom
| | - Giuseppe Gritti
- Department of Haematology, Ospedale Papa Giovanni XXIII, Bergamo, Italy; and
| | - Diana C Yánez
- Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Susan Ross
- Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Tessa Crompton
- Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Owen Williams
- Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Lydia Lee
- Department of Haematology, Cancer Institute, University College London, London, United Kingdom
| | - Martin A Pule
- Department of Haematology, Cancer Institute, University College London, London, United Kingdom
| | - Marc R Mansour
- Department of Haematology, Cancer Institute, University College London, London, United Kingdom
- Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
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22
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Xia D, Wang S, Liu A, Li L, Zhou P, Xu S. CCL25 Inhibition Alleviates Sepsis-Induced Acute Lung Injury and Inflammation. Infect Drug Resist 2022; 15:3309-3321. [PMID: 35782530 PMCID: PMC9241997 DOI: 10.2147/idr.s352544] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 05/20/2022] [Indexed: 12/03/2022] Open
Abstract
Purpose Acute lung injury (ALI) is a common clinical syndrome with high mortality. The chemokine ligand 25 (CCL25) is involved in inflammation, leukocyte trafficking and immunoregulation. However, the role and mechanism of CCL25 in ALI are not fully understood yet. The aim of this study was to explore the relationship between acute lung injury and CCL25. Patients and Methods In this study, we first examined chemokine expression in sepsis patients and found that serum CCL25 expression levels were relatively high in sepsis patients compared to healthy individuals. Based on this, we designed in vitro and in vivo experiments to verify the validity of the theory. In vitro, we used lipopolysaccharide-stimulated human pulmonary microvascular endothelial cells (HPMECs). In vivo, we established male C57BL/6 mice cecal ligation puncture (CLP) model of sepsis. Results In vitro, we used lipopolysaccharide-stimulated human pulmonary microvascular endothelial cells (HPMECs) and found significantly higher expression of CCL25 by enzyme-linked immunosorbent assay. Inhibition of CCL25 resulted in a significant decrease in the expression of inflammatory cytokines in HPMECs. In addition, we found that CCL25 promoted increased endothelial permeability by reducing the expression of tight junction proteins and was associated with activation of the P38 MAPK pathway by measuring the transepithelial electrical resistance and fluorescence intensity of fluorescein isothiocyanate. Results from luciferase assays and chromatin immunoprecipitation assays showed that inhibition of NF-κB activity in HPMECs decreased CCL25 expression, but addition of recombinant CCL25 increased cell permeability and inflammatory cytokine expression. In vivo, we established male C57BL/6 mice cecal ligation puncture (CLP) model of sepsis. We found that inhibition of CCL25 significantly reduced inflammatory cytokine expression in a CLP-induced sepsis model, thereby alleviating lung tissue damage in mice. Conclusion Our study suggests that CCL25 contributed to the development of ALI by modulating the functions of microvascular endothelial cells.
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Affiliation(s)
- Demeng Xia
- Luodian Clinical Drug Research Center, Shanghai Baoshan Luodian Hospital, Shanghai University, Shanghai, People’s Republic of China
| | - Sheng Wang
- Department of Emergency, Changhai Hospital, The Naval Medical University, Shanghai, People’s Republic of China
| | - Anwei Liu
- Luodian Clinical Drug Research Center, Shanghai Baoshan Luodian Hospital, Shanghai University, Shanghai, People’s Republic of China
- Department of Critical Care Medicine, Hospital of Southern Theatre Command of PLA, Guangzhou, People’s Republic of China
| | - Lei Li
- Department of Emergency, Changhai Hospital, The Naval Medical University, Shanghai, People’s Republic of China
| | - Panyu Zhou
- Department of Emergency, Changhai Hospital, The Naval Medical University, Shanghai, People’s Republic of China
| | - Shuogui Xu
- Department of Emergency, Changhai Hospital, The Naval Medical University, Shanghai, People’s Republic of China
- Correspondence: Shuogui Xu; Panyu Zhou, Department of Emergency, Changhai Hospital, Naval Medical University, Xiangyin Road, Shanghai, 200433, People’s Republic of China, Tel +8613176535161; +8619821317892, Email ;
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23
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Higher levels of Bifidobacteria and tumor necrosis factor in children with drug-resistant epilepsy are associated with anti-seizure response to the ketogenic diet. EBioMedicine 2022; 80:104061. [PMID: 35598439 PMCID: PMC9126955 DOI: 10.1016/j.ebiom.2022.104061] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 04/22/2022] [Accepted: 04/29/2022] [Indexed: 12/02/2022] Open
Abstract
Background Recently, studies have suggested a role for the gut microbiota in epilepsy. Gut microbial changes during ketogenic diet (KD) treatment of drug-resistant epilepsy have been described. Inflammation is associated with certain types of epilepsy and specific inflammation markers decrease during KD. The gut microbiota plays an important role in the regulation of the immune system and inflammation. Methods 28 children with drug-resistant epilepsy treated with the ketogenic diet were followed in this observational study. Fecal and serum samples were collected at baseline and three months after dietary intervention. Findings We identified both gut microbial and inflammatory changes during treatment. KD had a general anti-inflammatory effect. Novel bioinformatics and machine learning approaches identified signatures of specific Bifidobacteria and TNF (tumor necrosis factor) associated with responders before starting KD. During KD, taxonomic and inflammatory profiles between responders and non-responders were more similar than at baseline. Interpretation Our results suggest that children with drug-resistant epilepsy are more likely to benefit from KD treatment when specific Bifidobacteria and TNF are elevated. We here present a novel signature of interaction of the gut microbiota and the immune system associated with anti-epileptic response to KD treatment. This signature could be used as a prognostic biomarker to identify potential responders to KD before starting treatment. Our findings may also contribute to the development of new anti-seizure therapies by targeting specific components of the gut microbiota. Funding This study was supported by the Swedish Brain Foundation, Margarethahemmet Society, Stiftelsen Sunnerdahls Handikappfond, Linnea & Josef Carlssons Foundation, and The McCormick Genomic & Proteomic Center.
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24
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Fang Z, Zhang Y, Zhu Z, Wang C, Hu Y, Peng X, Zhang D, Zhao J, Shi B, Shen Z, Wu M, Xu C, Chen J, Zhou X, Xie Y, Yu H, Zhang X, Li J, Hu Y, Kozlowski M, Bertoletti A, Yuan Z. Monocytic MDSCs homing to thymus contribute to age-related CD8+ T cell tolerance of HBV. J Exp Med 2022; 219:213051. [PMID: 35254403 PMCID: PMC8906470 DOI: 10.1084/jem.20211838] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 12/02/2021] [Accepted: 01/31/2022] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus exposure in children usually develops into chronic hepatitis B (CHB). Although hepatitis B surface antigen (HBsAg)–specific CD8+ T cells contribute to resolve HBV infection, they are preferentially undetected in CHB patients. Moreover, the mechanism for this rarely detected HBsAg-specific CD8+ T cells remains unexplored. We herein found that the frequency of HBsAg-specific CD8+ T cells was inversely correlated with expansion of monocytic myeloid-derived suppressor cells (mMDSCs) in young rather than in adult CHB patients, and CCR9 was upregulated by HBsAg on mMDSCs via activation of ERK1/2 and IL-6. Sequentially, the interaction between CCL25 and CCR9 mediated thymic homing of mMDSCs, which caused the cross-presentation, transferring of peripheral HBsAg into the thymic medulla, and then promoted death of HBsAg-specific CD8+ thymocytes. In mice, adoptive transfer of mMDSCs selectively obliterated HBsAg-specific CD8+ T cells and facilitated persistence of HBV in a CCR9-dependent manner. Taken together, our results uncovered a novel mechanism for establishing specific CD8+ tolerance to HBsAg in chronic HBV infection.
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Affiliation(s)
- Zhong Fang
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.,Liver Cancer Institute of Zhongshan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, China
| | - Yi Zhang
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Zhaoqin Zhu
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Cong Wang
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.,Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Yao Hu
- Department of Infectious Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Xiuhua Peng
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Dandan Zhang
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Jun Zhao
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Bisheng Shi
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.,Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Zhongliang Shen
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Min Wu
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Chunhua Xu
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Jieliang Chen
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Xiaohui Zhou
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Youhua Xie
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Hui Yu
- Department of Infectious Diseases, Children's Hospital of Fudan University, Shanghai, China
| | - Xiaonan Zhang
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Jianhua Li
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Yunwen Hu
- Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | - Maya Kozlowski
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.,Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China
| | | | - Zhenghong Yuan
- Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.,Shanghai Public Health Clinical Center, Shanghai Medical College of Fudan University, Shanghai, China.,Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Shanghai, China
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25
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Tieranu C, Olteanu A, Preda C, Bacalbasa N, Milanesi E, Dobre M, Tieranu I, Manuc T, Klimko A, Becheanu G, Ionescu E. Mucosal gene expression profile of stricturing Crohn's disease: A preliminary study. Exp Ther Med 2021; 23:149. [DOI: 10.3892/etm.2021.11072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 10/21/2021] [Indexed: 11/06/2022] Open
Affiliation(s)
- Cristian Tieranu
- Department of Gastroenterology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Andrei Olteanu
- Department of Gastroenterology, ‘Elias’ Emergency University Hospital, 011461 Bucharest, Romania
| | - Carmen Preda
- Department of Gastroenterology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Nicolae Bacalbasa
- Department of Gastroenterology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Elena Milanesi
- Department of Radiobiology, ‘Victor Babeş’ National Institute of Pathology, 050096 Bucharest, Romania
| | - Maria Dobre
- Department of Pathology, ‘Victor Babeş’ National Institute of Pathology, 050096 Bucharest, Romania
| | - Ioana Tieranu
- Department of Gastroenterology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Teodora Manuc
- Department of Gastroenterology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Artsiom Klimko
- Department of Gastroenterology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Gabriel Becheanu
- Department of Gastroenterology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Elena Ionescu
- Department of Gastroenterology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
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26
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Abbas N, Quraishi MN, Trivedi P. Emerging drugs for the treatment of primary sclerosing cholangitis. Curr Opin Pharmacol 2021; 62:23-35. [PMID: 34894541 DOI: 10.1016/j.coph.2021.11.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 11/02/2021] [Accepted: 11/07/2021] [Indexed: 12/11/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a rare immune-mediated cholestatic disease for which no medical therapy has been shown to slow disease progression. Consequently, liver transplantation is the only lifesaving intervention for patients, and despite being a rare disease, PSC is the lead indication for transplantation across several European countries. The vast majority of patients (>70%) also develop inflammatory bowel disease (IBD) at some point in their lifetime, which imparts added lifetime risks of hepatobiliary malignancy and colorectal cancer. The rare disease nature, variable and often slow rates of disease progression (years rather than months), and lack of robust surrogate biomarkers for early stage yet high risk disease, represent critical challenges in trial design that have long precluded the development of effective medical treatment. However, the horizon for new treatments is encouraging, given innovative clinical trial programmes led by industry, alongside several investigator-initiated studies. Herein, we outline the current platform of interventional trials in PSC, before discussing emerging areas of therapeutic interest.
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Affiliation(s)
- Nadir Abbas
- Liver Unit, University Hospitals Birmingham Queen Elizabeth, Birmingham, UK; NIHR Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, UK
| | - Mohammad Nabil Quraishi
- Department of Gastroenterology, University Hospital Birmingham NHS Trust, UK; University of Birmingham Microbiome Treatment Centre, University of Birmingham, UK
| | - Palak Trivedi
- Liver Unit, University Hospitals Birmingham Queen Elizabeth, Birmingham, UK; NIHR Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, UK; Institute of Immunology and Immunotherapy, University of Birmingham, UK.
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27
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Aggarwal C, Saini K, Reddy ES, Singla M, Nayak K, Chawla YM, Maheshwari D, Singh P, Sharma P, Bhatnagar P, Kumar S, Gottimukkala K, Panda H, Gunisetty S, Davis CW, Kissick HT, Kabra SK, Lodha R, Medigeshi GR, Ahmed R, Murali-Krishna K, Chandele A. Immunophenotyping and Transcriptional Profiling of Human Plasmablasts in Dengue. J Virol 2021; 95:e0061021. [PMID: 34523972 PMCID: PMC8577383 DOI: 10.1128/jvi.00610-21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 09/11/2021] [Indexed: 12/07/2022] Open
Abstract
Plasmablasts represent a specialized class of antibody-secreting effector B cells that transiently appear in blood circulation following infection or vaccination. The expansion of these cells generally tends to be massive in patients with systemic infections such as dengue or Ebola that cause hemorrhagic fever. To gain a detailed understanding of human plasmablast responses beyond antibody expression, here, we performed immunophenotyping and RNA sequencing (RNA-seq) analysis of the plasmablasts from dengue febrile children in India. We found that plasmablasts expressed several adhesion molecules and chemokines or chemokine receptors that are involved in endothelial interactions or homing to inflamed tissues, including skin, mucosa, and intestine, and upregulated the expression of several cytokine genes that are involved in leukocyte extravasation and angiogenesis. These plasmablasts also upregulated the expression of receptors for several B-cell prosurvival cytokines that are known to be induced robustly in systemic viral infections such as dengue, some of which generally tend to be relatively higher in patients manifesting hemorrhage and/or shock than in patients with mild febrile infection. These findings improve our understanding of human plasmablast responses during the acute febrile phase of systemic dengue infection. IMPORTANCE Dengue is globally spreading, with over 100 million clinical cases annually, with symptoms ranging from mild self-limiting febrile illness to more severe and sometimes life-threatening dengue hemorrhagic fever or shock, especially among children. The pathophysiology of dengue is complex and remains poorly understood despite many advances indicating a key role for antibody-dependent enhancement of infection. While serum antibodies have been extensively studied, the characteristics of the early cellular factories responsible for antibody production, i.e., plasmablasts, are only beginning to emerge. This study provides a comprehensive understanding of the transcriptional profiles of human plasmablasts from dengue patients.
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Affiliation(s)
- Charu Aggarwal
- ICGEB-Emory Vaccine Center, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Keshav Saini
- ICGEB-Emory Vaccine Center, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Elluri Seetharami Reddy
- ICGEB-Emory Vaccine Center, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
- Kusuma School of Biological Sciences, Indian Institute of Technology, New Delhi, India
| | - Mohit Singla
- Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - Kaustuv Nayak
- ICGEB-Emory Vaccine Center, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Yadya M. Chawla
- ICGEB-Emory Vaccine Center, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Deepti Maheshwari
- ICGEB-Emory Vaccine Center, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Prabhat Singh
- ICGEB-Emory Vaccine Center, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Pragati Sharma
- ICGEB-Emory Vaccine Center, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
- Department of Biotechnology, School of Chemical and Life Sciences, New Delhi, India
| | - Priya Bhatnagar
- ICGEB-Emory Vaccine Center, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
- TERI School of Advanced Studies, New Delhi, India
| | - Sanjeev Kumar
- ICGEB-Emory Vaccine Center, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Kamalvishnu Gottimukkala
- ICGEB-Emory Vaccine Center, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Harekrushna Panda
- ICGEB-Emory Vaccine Center, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Sivaram Gunisetty
- Department of Pediatrics, Division of Infectious Disease, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Carl W. Davis
- Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Haydn Thomas Kissick
- Department of Microbiology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Sushil Kumar Kabra
- Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | - Rakesh Lodha
- Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
| | | | - Rafi Ahmed
- Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA
- Department of Microbiology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Kaja Murali-Krishna
- ICGEB-Emory Vaccine Center, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
- Department of Pediatrics, Division of Infectious Disease, Emory University School of Medicine, Atlanta, Georgia, USA
- Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Anmol Chandele
- ICGEB-Emory Vaccine Center, International Centre for Genetic Engineering and Biotechnology, New Delhi, India
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Chen ZR, Jin SF, Ma WB, Jiang RL. Intestinal microecology: A crucial strategy for targeted therapy of liver diseases. Hepatobiliary Pancreat Dis Int 2021; 20:499-500. [PMID: 34340922 DOI: 10.1016/j.hbpd.2021.07.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 07/13/2021] [Indexed: 02/05/2023]
Affiliation(s)
- Zeng-Rui Chen
- Intensive Care Unit, People's Hospital of Yuhuan, Taizhou 317600, China
| | - Shui-Fang Jin
- Intensive Care Unit, First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou 310006, China
| | - Wei-Bin Ma
- Department of Pharmacy, First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou 310006, China
| | - Rong-Lin Jiang
- Intensive Care Unit, First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou 310006, China.
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29
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de Krijger M, Wildenberg ME, Mookhoek A, Verheul S, de Jonge WJ, Ponsioen CY. Expression of MAdCAM-1 and Gut-homing T Cells in Inflamed Pouch Mucosa. J Crohns Colitis 2021; 15:1491-1499. [PMID: 33675360 DOI: 10.1093/ecco-jcc/jjab041] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS Pouchitis is a common complication following formation of an ileal pouch-anal anastomosis [IPAA] after proctocolectomy for ulcerative colitis [UC]. Gut-specific lymphocyte trafficking mechanisms have been identified as players in the pathogenesis of UC. In the present study, we aimed to characterise the presence of lymphocyte subsets expressing gut-homing molecules in pouches and peripheral blood of UC patients with and without pouchitis. METHODS Biopsy samples and peripheral blood were collected from 29 patients with an IPAA [seven with active inflammation, 22 without inflammation]. Expression of adhesion molecule MAdCAM-1 was assessed using immunohistochemistry, and flow cytometry was used to characterise expression of integrin α4β7, C-chemokine receptor 9 [CCR9], and CD103 on T cell subsets. RESULTS MAdCAM-1 expression was significantly increased in case of active inflammation in the pouch. T cells expressing integrin α4β7 were abundant in the pouch mucosa, but the frequency of integrin α4β7-expressing T cells was decreased on CD4+ lymphocytes during inflammation. Co-expression of gut-homing markers CCR9 and α4β7 was more pronounced in biopsies compared with peripheral blood, but was not enhanced upon active inflammation. CONCLUSIONS Gut-homing T cells are abundant in pouch mucosa, but the classic hypothesis that the chronic inflammatory state is maintained by an accumulation of α4β7-expressing effector T cells is not supported by our data.
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Affiliation(s)
- Manon de Krijger
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.,Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Manon E Wildenberg
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.,Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Aart Mookhoek
- Department of Pathology, Amsterdam UMC, VU University Medical Center, Amsterdam, The Netherlands
| | - Sascha Verheul
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands
| | - Wouter J de Jonge
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands.,Department of Surgery, University of Bonn, Bonn, Germany
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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30
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Bourgonje AR, Hu S, Spekhorst LM, Zhernakova DV, Vich Vila A, Li Y, Voskuil MD, van Berkel LA, Bley Folly B, Charrout M, Mahfouz A, Reinders MJT, van Heck JIP, Joosten LAB, Visschedijk MC, van Dullemen HM, Faber KN, Samsom JN, Festen EAM, Dijkstra G, Weersma RK. The Effect of Phenotype and Genotype on the Plasma Proteome in Patients with Inflammatory Bowel Disease. J Crohns Colitis 2021; 16:414-429. [PMID: 34491321 PMCID: PMC8919819 DOI: 10.1093/ecco-jcc/jjab157] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND AND AIMS Protein profiling in patients with inflammatory bowel diseases [IBD] for diagnostic and therapeutic purposes is underexplored. This study analysed the association between phenotype, genotype, and the plasma proteome in IBD. METHODS A total of 92 inflammation-related proteins were quantified in plasma of 1028 patients with IBD (567 Crohn's disease [CD]; 461 ulcerative colitis [UC]) and 148 healthy individuals to assess protein-phenotype associations. Corresponding whole-exome sequencing and global screening array data of 919 patients with IBD were included to analyse the effect of genetics on protein levels (protein quantitative trait loci [pQTL] analysis). Intestinal mucosal RNA sequencing and faecal metagenomic data were used for complementary analyses. RESULTS Thirty-two proteins were differentially abundant between IBD and healthy individuals, of which 22 proteins were independent of active inflammation; 69 proteins were associated with 15 demographic and clinical factors. Fibroblast growth factor-19 levels were decreased in CD patients with ileal disease or a history of ileocecal resection. Thirteen novel cis-pQTLs were identified and 10 replicated from previous studies. One trans-pQTL of the fucosyltransferase 2 [FUT2] gene [rs602662] and two independent cis-pQTLs of C-C motif chemokine 25 [CCL25] affected plasma CCL25 levels. Intestinal gene expression data revealed an overlapping cis-expression [e]QTL-variant [rs3745387] of the CCL25 gene. The FUT2 rs602662 trans-pQTL was associated with reduced abundances of faecal butyrate-producing bacteria. CONCLUSIONS This study shows that genotype and multiple disease phenotypes strongly associate with the plasma inflammatory proteome in IBD, and identifies disease-associated pathways that may help to improve disease management in the future.
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Affiliation(s)
| | | | | | - Daria V Zhernakova
- Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands,Laboratory of Genomic Diversity, Center for Computer Technologies, ITMO University, St Petersburg, Russia
| | - Arnau Vich Vila
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands,Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
| | - Yanni Li
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands,Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
| | - Michiel D Voskuil
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands,Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
| | - Lisette A van Berkel
- Department of Pediatrics, Division of Gastroenterology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Brenda Bley Folly
- Department of Pediatrics, Division of Gastroenterology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Mohammed Charrout
- Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands,Leiden Computational Biology Center, Leiden University Medical Center, Leiden, The Netherlands
| | - Ahmed Mahfouz
- Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands,Leiden Computational Biology Center, Leiden University Medical Center, Leiden, The Netherlands,Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Marcel J T Reinders
- Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands,Leiden Computational Biology Center, Leiden University Medical Center, Leiden, The Netherlands
| | - Julia I P van Heck
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Leo A B Joosten
- Department of Internal Medicine and Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marijn C Visschedijk
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Hendrik M van Dullemen
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Janneke N Samsom
- Department of Pediatrics, Division of Gastroenterology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Eleonora A M Festen
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands,Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, The Netherlands
| | - Rinse K Weersma
- Corresponding author: Prof. Rinse K. Weersma, MD, PhD, Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. Tel.: +31 50 361 26 20; fax: +31 50 361 93 06;
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31
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Bozward AG, Ronca V, Osei-Bordom D, Oo YH. Gut-Liver Immune Traffic: Deciphering Immune-Pathogenesis to Underpin Translational Therapy. Front Immunol 2021; 12:711217. [PMID: 34512631 PMCID: PMC8425300 DOI: 10.3389/fimmu.2021.711217] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 08/09/2021] [Indexed: 12/12/2022] Open
Abstract
The tight relationship between the gut and liver on embryological, anatomical and physiological levels inspired the concept of a gut-liver axis as a central element in the pathogenesis of gut-liver axis diseases. This axis refers to the reciprocal regulation between these two organs causing an integrated system of immune homeostasis or tolerance breakdown guided by the microbiota, the diet, genetic background, and environmental factors. Continuous exposure of gut microbiome, various hormones, drugs and toxins, or metabolites from the diet through the portal vein adapt the liver to maintain its tolerogenic state. This is orchestrated by the combined effort of immune cells network: behaving as a sinusoidal and biliary firewall, along with a regulatory network of immune cells including, regulatory T cells and tolerogenic dendritic cells (DC). In addition, downregulation of costimulatory molecules on hepatic sinusoids, hepatocytes and biliary epithelial cells as well as regulating the bile acids chain also play a part in hepatic immune homeostasis. Recent evidence also demonstrated the link between changes in the gut microbiome and liver resident immune cells in the progression of cirrhosis and the tight correlation among primary sclerosing cholangitis (PSC) and also checkpoint induced liver and gut injury. In this review, we will summarize the most recent evidence of the bidirectional relationship among the gut and the liver and how it contributes to liver disease, focusing mainly on PSC and checkpoint induced hepatitis and colitis. We will also focus on completed therapeutic options and on potential targets for future treatment linking with immunology and describe the future direction of this research, taking advantage of modern technologies.
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Affiliation(s)
- Amber G. Bozward
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network - Rare Liver Centre, Birmingham, United Kingdom
- Birmingham Advanced Cellular Therapy Facility, University of Birmingham, Birmingham, United Kingdom
| | - Vincenzo Ronca
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network - Rare Liver Centre, Birmingham, United Kingdom
| | - Daniel Osei-Bordom
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Queen Elizabeth Hospital, University Hospital of Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
| | - Ye Htun Oo
- Centre for Liver and Gastrointestinal Research and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network - Rare Liver Centre, Birmingham, United Kingdom
- Birmingham Advanced Cellular Therapy Facility, University of Birmingham, Birmingham, United Kingdom
- Queen Elizabeth Hospital, University Hospital of Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
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32
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Narula N, Aruljothy A, Wong ECL, Homenauth R, Alshahrani AA, Marshall JK, Reinisch W. The impact of ustekinumab on extraintestinal manifestations of Crohn's disease: A post hoc analysis of the UNITI studies. United European Gastroenterol J 2021; 9:581-589. [PMID: 34077627 PMCID: PMC8259251 DOI: 10.1002/ueg2.12094] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 02/26/2021] [Indexed: 12/11/2022] Open
Abstract
This post hoc analysis of the UNITI studies found ustekinumab (UST) did not significantly improve overall extraintestinal manifestations (EIMs) of Crohn's disease compared to placebo-treated patients at weeks 6 and 52. BACKGROUND AND AIMS The UNITI trials demonstrated that UST was effective in inducing and maintaining clinical remission in Crohn's disease (CD). However, limited data exists regarding its effectiveness for treatment of EIMs. This post hoc analysis evaluated the efficacy of UST in treatment of EIMs. METHODS Data from UNITI-1/2 and IM-UNITI (NCT01369329, NCT01369342, NCT01369355) were obtained from the Yale Open Data Access Project (2019-4104). Nine hundred and fourty-one patients eligible for UST induction and 263 patients eligible for maintenance UST were included. The primary outcome of interest was EIM resolution at Week 6 in UST and placebo-treated patients using the chi-square test. EIM resolution at Week 52 was also assessed. McNemar's test was used to compare the proportion of patients who reported active EIMs at weeks 6 and 52 versus baseline. RESULTS From 941 UST-treated patients in UNITI-1/2, 504 had 527 EIMs at baseline. Overall, there was no significant difference in EIM resolution observed in UST-treated patients (186/504, 36.9%) compared to placebo (90/230, 39.1%; p = 0.564) at Week 6. Patients treated with continuous UST (91/119, 76.4%) had no significant difference in overall EIMs resolved at Week 52 compared to placebo (72/90, 80.0%; p = 0.542). Although many EIMs demonstrated reduction in prevalence compared to baseline at initiation of UST, only erythema nodosum was more likely to improve at Week 52 on treatment versus placebo. CONCLUSION Overall, UST did not lead to significant resolution of EIMs for CD compared to placebo at weeks 6 and 52.
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Affiliation(s)
- Neeraj Narula
- Department of Medicine (Division of Gastroenterology) and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Achuthan Aruljothy
- Department of Medicine (Division of Gastroenterology) and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Emily C L Wong
- Department of Medicine (Division of Gastroenterology) and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Ravi Homenauth
- Department of Medicine (Division of Gastroenterology) and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Abdul-Aziz Alshahrani
- Department of Medicine (Division of Gastroenterology) and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada.,Department of Gastroenterology, Najran University, Najran, Saudi Arabia
| | - John K Marshall
- Department of Medicine (Division of Gastroenterology) and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Walter Reinisch
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
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Wiendl M, Becker E, Müller TM, Voskens CJ, Neurath MF, Zundler S. Targeting Immune Cell Trafficking - Insights From Research Models and Implications for Future IBD Therapy. Front Immunol 2021; 12:656452. [PMID: 34017333 PMCID: PMC8129496 DOI: 10.3389/fimmu.2021.656452] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 04/16/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC) are multifactorial diseases with still unknown aetiology and an increasing prevalence and incidence worldwide. Despite plentiful therapeutic options for IBDs, the lack or loss of response in certain patients demands the development of further treatments to tackle this unmet medical need. In recent years, the success of the anti-α4β7 antibody vedolizumab highlighted the potential of targeting the homing of immune cells, which is now an important pillar of IBD therapy. Due to its complexity, leukocyte trafficking and the involved molecules offer a largely untapped resource for a plethora of potential therapeutic interventions. In this review, we aim to summarise current and future directions of specifically interfering with immune cell trafficking. We will comment on concepts of homing, retention and recirculation and particularly focus on the role of tissue-derived chemokines. Moreover, we will give an overview of the mode of action of drugs currently in use or still in the pipeline, highlighting their mechanisms and potential to reduce disease burden.
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Affiliation(s)
- Maximilian Wiendl
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Emily Becker
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Tanja M. Müller
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Caroline J. Voskens
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Markus F. Neurath
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Sebastian Zundler
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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Dopaminergic signalling limits suppressive activity and gut homing of regulatory T cells upon intestinal inflammation. Mucosal Immunol 2021; 14:652-666. [PMID: 33184477 DOI: 10.1038/s41385-020-00354-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 10/09/2020] [Accepted: 10/21/2020] [Indexed: 02/04/2023]
Abstract
Evidence from inflammatory bowel diseases (IBD) patients and animal models has indicated that gut inflammation is driven by effector CD4+ T-cell, including Th1 and Th17. Conversely, Treg seem to be dysfunctional in IBD. Importantly, dopamine, which is abundant in the gut mucosa under homoeostasis, undergoes a sharp reduction upon intestinal inflammation. Here we analysed the role of the high-affinity dopamine receptor D3 (DRD3) in gut inflammation. Our results show that Drd3 deficiency confers a stronger immunosuppressive potency to Treg, attenuating inflammatory colitis manifestation in mice. Mechanistic analyses indicated that DRD3-signalling attenuates IL-10 production and limits the acquisition of gut-tropism. Accordingly, the ex vivo transduction of wild-type Treg with a siRNA for Drd3 induced a potent therapeutic effect abolishing gut inflammation. Thus, our findings show DRD3-signalling as a major regulator of Treg upon gut inflammation.
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35
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Tong X, Zheng Y, Li Y, Xiong Y, Chen D. Soluble ligands as drug targets for treatment of inflammatory bowel disease. Pharmacol Ther 2021; 226:107859. [PMID: 33895184 DOI: 10.1016/j.pharmthera.2021.107859] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/19/2021] [Accepted: 04/19/2021] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is characterized by persistent inflammation in a hereditarily susceptible host. In addition to gastrointestinal symptoms, patients with IBD frequently suffer from extra-intestinal complications such as fibrosis, stenosis or cancer. Mounting evidence supports the targeting of cytokines for effective treatment of IBD. Cytokines can be included in a newly proposed classification "soluble ligands" that has become the third major target of human protein therapeutic drugs after enzymes and receptors. Soluble ligands have potential significance for research and development of anti-IBD drugs. Compared with traditional drug targets for IBD treatment, such as receptors, at least three factors contribute to the increasing importance of soluble ligands as drug targets. Firstly, cytokines are the main soluble ligands and targeting of them has demonstrated efficacy in patients with IBD. Secondly, soluble ligands are more accessible than receptors, which are embedded in the cell membrane and have complex tertiary membrane structures. Lastly, certain potential target proteins that are present in membrane-bound forms can become soluble following cleavage, providing further opportunities for intervention in the treatment of IBD. In this review, 49 drugs targeting 25 distinct ligands have been evaluated, including consideration of the characteristics of the ligands and drugs in respect of IBD treatment. In addition to approved drugs targeting soluble ligands, we have also assessed drugs that are in preclinical research and drugs inhibiting ligand-receptor binding. Some new types of targetable soluble ligands/proteins, such as epoxide hydrolase and p-selectin glycoprotein ligand-1, are also introduced. Targeting soluble ligands not only opens a new field of anti-IBD drug development, but the circulating soluble ligands also provide diagnostic insights for early prediction of treatment response. In conclusion, soluble ligands serve as the third-largest protein target class in medicine, with much potential for the drugs targeting them.
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Affiliation(s)
- Xuhui Tong
- Compartive Medicine Department of Researching and Teaching, Dalian Medical University, Dalian City 116044, Liaoning Province, China
| | - Yuanyuan Zheng
- Compartive Medicine Department of Researching and Teaching, Dalian Medical University, Dalian City 116044, Liaoning Province, China
| | - Yu Li
- Compartive Medicine Department of Researching and Teaching, Dalian Medical University, Dalian City 116044, Liaoning Province, China
| | - Yongjian Xiong
- Central Laboratory, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Dapeng Chen
- Compartive Medicine Department of Researching and Teaching, Dalian Medical University, Dalian City 116044, Liaoning Province, China.
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Umar S, Palasiewicz K, Van Raemdonck K, Volin MV, Romay B, Ahmad I, Tetali C, Sweiss N, Amin MA, Zomorrodi RK, Shahrara S. CCL25 and CCR9 is a unique pathway that potentiates pannus formation by remodeling RA macrophages into mature osteoclasts. Eur J Immunol 2021; 51:903-914. [PMID: 33347617 PMCID: PMC10041658 DOI: 10.1002/eji.202048681] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 10/26/2020] [Accepted: 12/18/2020] [Indexed: 12/18/2022]
Abstract
This study elucidates the mechanism of CCL25 and CCR9 in rheumatoid arthritis (RA). RA synovial fluid (SF) expresses elevated levels of CCL25 compared to OA SF and plasma from RA and normal. CCL25 was released into RA SF by fibroblasts (FLS) and macrophages (MΦs) stimulated with IL-1β and IL-6. CCR9 is also presented on IL-1β and IL-6 activated RA FLS and differentiated MΦs. Conversely, in RA PBMCs neither CCL25 nor CCR9 are impacted by 3-month longitudinal TNF inhibitor therapy. CCL25 amplifies RA FLS and monocyte infiltration via p38 and ERK phosphorylation. CCL25-stimulated RA FLS secrete potentiated levels of IL-8 which is disrupted by p38 and ERK inhibitors. CCL25 polarizes RA monocytes into nontraditional M1 MΦs that produce IL-8 and CCL2. Activation of p38 and ERK cascades are also responsible for the CCL25-induced M1 MΦ development. Unexpectedly, CCL25 was unable to polarize RA PBMCs into effector Th1/Th17 cells. Consistently, lymphokine like RANKL was uninvolved in CCL25-induced osteoclastogenesis; however, this manifestation was regulated by osteoclastic factors such as RANK, cathepsin K (CTSK), and TNF-α. In short, we reveal that CCL25/CCR9 manipulates RA FLS and MΦ migration and inflammatory phenotype in addition to osteoclast formation via p38 and ERK activation.
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Affiliation(s)
- Sadiq Umar
- Jesse Brown VA Medical Center, Chicago, IL
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL
| | - Karol Palasiewicz
- Jesse Brown VA Medical Center, Chicago, IL
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL
| | - Katrien Van Raemdonck
- Jesse Brown VA Medical Center, Chicago, IL
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL
| | - Michael V. Volin
- Department of Microbiology and Immunology, Midwestern University, Downers Grove, IL
| | - Bianca Romay
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL
| | - Imran Ahmad
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL
| | - Chandana Tetali
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL
| | - Nadera Sweiss
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL
| | - M Asif Amin
- Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, MI 481096
| | - Ryan K Zomorrodi
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL
| | - Shiva Shahrara
- Jesse Brown VA Medical Center, Chicago, IL
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL
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Ruiz F, Wyss A, Rossel JB, Sulz MC, Brand S, Moncsek A, Mertens JC, Roth R, Clottu AS, Burri E, Juillerat P, Biedermann L, Greuter T, Rogler G, Pot C, Misselwitz B. A single nucleotide polymorphism in the gene for GPR183 increases its surface expression on blood lymphocytes of patients with inflammatory bowel disease. Br J Pharmacol 2021; 178:3157-3175. [PMID: 33511653 DOI: 10.1111/bph.15395] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 01/11/2021] [Accepted: 01/12/2021] [Indexed: 02/06/2023] Open
Affiliation(s)
- Florian Ruiz
- Laboratories of Neuroimmunology, Neuroscience Research Center and Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Annika Wyss
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Jean-Benoît Rossel
- Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland
| | - Michael Christian Sulz
- Department of Gastroenterology and Hepatology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Stephan Brand
- Department of Gastroenterology and Hepatology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Anja Moncsek
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Joachim C Mertens
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - René Roth
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Aurélie S Clottu
- Laboratories of Neuroimmunology, Neuroscience Research Center and Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Emanuel Burri
- Department of Gastroenterology and Hepatology, University Medical Clinic, Kantonsspital Baselland, Liestal, Switzerland
| | - Pascal Juillerat
- Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Luc Biedermann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Thomas Greuter
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Caroline Pot
- Laboratories of Neuroimmunology, Neuroscience Research Center and Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Benjamin Misselwitz
- Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
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38
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Plichta DR, Somani J, Pichaud M, Wallace ZS, Fernandes AD, Perugino CA, Lähdesmäki H, Stone JH, Vlamakis H, Chung DC, Khanna D, Pillai S, Xavier RJ. Congruent microbiome signatures in fibrosis-prone autoimmune diseases: IgG4-related disease and systemic sclerosis. Genome Med 2021; 13:35. [PMID: 33648559 PMCID: PMC7919092 DOI: 10.1186/s13073-021-00853-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 02/11/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Immunoglobulin G4-related disease (IgG4-RD) and systemic sclerosis (SSc) are rare autoimmune diseases characterized by the presence of CD4+ cytotoxic T cells in the blood as well as inflammation and fibrosis in various organs, but they have no established etiologies. Similar to other autoimmune diseases, the gut microbiome might encode disease-triggering or disease-sustaining factors. METHODS The gut microbiomes from IgG4-RD and SSc patients as well as healthy individuals with no recent antibiotic treatment were studied by metagenomic sequencing of stool DNA. De novo assembly-based taxonomic and functional characterization, followed by association and accessory gene set enrichment analysis, were applied to describe microbiome changes associated with both diseases. RESULTS Microbiomes of IgG4-RD and SSc patients distinctly separated from those of healthy controls: numerous opportunistic pathogenic Clostridium and typically oral Streptococcus species were significantly overabundant, while Alistipes, Bacteroides, and butyrate-producing species were depleted in the two diseases compared to healthy controls. Accessory gene content analysis in these species revealed an enrichment of Th17-activating Eggerthella lenta strains in IgG4-RD and SSc and a preferential colonization of a homocysteine-producing strain of Clostridium bolteae in SSc. Overabundance of the classical mevalonate pathway, hydroxyproline dehydratase, and fibronectin-binding protein in disease microbiomes reflects potential functional differences in host immune recognition and extracellular matrix utilization associated with fibrosis. Strikingly, the majority of species that were differentially abundant in IgG4-RD and SSc compared to controls showed the same directionality in both diseases. Compared with multiple sclerosis and rheumatoid arthritis, the gut microbiomes of IgG4-RD and SSc showed similar signatures; in contrast, the most differentially abundant taxa were not the facultative anaerobes consistently identified in inflammatory bowel diseases, suggesting the microbial signatures of IgG4-RD and SSc do not result from mucosal inflammation and decreased anaerobism. CONCLUSIONS These results provide an initial characterization of gut microbiome ecology in fibrosis-prone IgG4-RD and SSc and reveal microbial functions that offer insights into the pathophysiology of these rare diseases.
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Affiliation(s)
| | - Juhi Somani
- Department of Computer Science, Aalto University, 02150, Espoo, Finland
| | | | - Zachary S Wallace
- Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, MA, USA
- Clinical Epidemiology Program and Rheumatology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ana D Fernandes
- Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, MA, USA
| | - Cory A Perugino
- Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, MA, USA
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Harri Lähdesmäki
- Department of Computer Science, Aalto University, 02150, Espoo, Finland
| | - John H Stone
- Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, MA, USA
| | - Hera Vlamakis
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Daniel C Chung
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Center for Cancer Risk Assessment, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Dinesh Khanna
- University of Michigan Scleroderma Program, Ann Arbor, MI, USA
| | - Shiv Pillai
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
| | - Ramnik J Xavier
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Center for Microbiome Informatics and Therapeutics, MIT, Cambridge, MA, USA.
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39
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Hanzel J, Ma C, Casteele NV, Khanna R, Jairath V, Feagan BG. Vedolizumab and Extraintestinal Manifestations in Inflammatory Bowel Disease. Drugs 2021; 81:333-347. [PMID: 33400241 DOI: 10.1007/s40265-020-01460-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
In Crohn's disease and ulcerative colitis, inflammation is not limited to the digestive tract. Extraintestinal manifestations (EIMs), which affect up to 50% of patients, can substantially impair quality of life. EIMs may parallel luminal disease activity or have an independent course. They most commonly involve the musculoskeletal system (e.g., peripheral or axial arthritis) and skin (e.g., erythema nodosum and pyoderma gangrenosum). Less commonly, the hepatobiliary tract (e.g., primary sclerosing cholangitis [PSC]) and the eye (e.g., episcleritis, scleritis, and uveitis) are involved. Although the pathophysiology of EIMs is poorly understood, they are likely either manifestations of a primary systemic immune disease with variable expression amongst organs, or secondary phenomena to bowel inflammation. Additional pathophysiologic mechanisms may include aberrant lymphocyte homing mediated by ectopic expression of gut-specific chemokines and adhesion molecules, cross-reactivity between microbial and self-antigens, autoantibodies against epitopes shared by the intestine and extraintestinal tissues, elevated serum concentrations of cytokines, and alterations in innate immunity. Many EIMs independent of intestinal disease activity can be successfully treated with tumor necrosis factor (TNF) antagonists. The efficacy of vedolizumab-a monoclonal antibody targeting the α4β7 integrin-for the treatment of EIMs is uncertain, but data are emerging from post hoc analyses of randomized controlled trials, prospective and retrospective cohort studies, and case series. Vedolizumab may be effective in treating EIMs related to luminal disease activity (e.g., type 1 peripheral arthritis and erythema nodosum) but has not shown biochemical improvement in PSC. Its postulated role in the development of de novo EIMs is heavily confounded by the high proportion of patients previously exposed to TNF antagonists; new EIMs could result from TNF antagonist treatment cessation rather than being caused by vedolizumab. A common limitation of clinical studies is the lack of multidisciplinary involvement in the diagnosis and monitoring of EIMs, which may lead to misdiagnosis and overreporting. Future studies should rigorously measure EIMs in parallel with objective measures of luminal disease activity to provide more robust data on the relative efficacy of new drugs, especially as increasing numbers of gut-selective compounds enter clinical development.
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Affiliation(s)
- Jurij Hanzel
- Department of Gastroenterology, University Medical Center Ljubljana, Ljubljana, Slovenia.,Alimentiv, #200, 100 Dundas Street, London, N6A 5B6, ON, Canada.,, Hullenbergweg 278-308, 1101 BV, Amsterdam, The Netherlands
| | - Christopher Ma
- Alimentiv, #200, 100 Dundas Street, London, N6A 5B6, ON, Canada.,Division of Gastroenterology and Hepatology, Cumming School of Medicine, University of Calgary, 6D61 Teaching Research Wellness Building, 3280 Hospital Drive NW, Calgary, Alberta, T2N 4Z6, Canada
| | - Niels Vande Casteele
- Alimentiv, #200, 100 Dundas Street, London, N6A 5B6, ON, Canada.,Department of Medicine, University of California San Diego, 9500 Gilman Drive #0956, La Jolla, CA, 92093, USA
| | - Reena Khanna
- Division of Gastroenterology, University of Western Ontario, 1151 Richmond Street, London, N6A 2K7, ON, Canada
| | - Vipul Jairath
- Alimentiv, #200, 100 Dundas Street, London, N6A 5B6, ON, Canada.,Division of Gastroenterology, University of Western Ontario, 1151 Richmond Street, London, N6A 2K7, ON, Canada.,Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada
| | - Brian G Feagan
- Alimentiv, #200, 100 Dundas Street, London, N6A 5B6, ON, Canada. .,Division of Gastroenterology, University of Western Ontario, 1151 Richmond Street, London, N6A 2K7, ON, Canada. .,Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada. .,Department of Medicine, University of Western Ontario, London, ON, Canada.
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40
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Hoffsten A, Markasz L, Lilja HE, Olsson KW, Sindelar R. Early Postnatal Comprehensive Biomarkers Cannot Identify Extremely Preterm Infants at Risk of Developing Necrotizing Enterocolitis. Front Pediatr 2021; 9:755437. [PMID: 34746064 PMCID: PMC8570110 DOI: 10.3389/fped.2021.755437] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 09/16/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Necrotizing enterocolitis (NEC) is a fatal disease where current diagnostic tools are insufficient for preventing NEC. Early predictive biomarkers could be beneficial in identifying infants at high risk of developing NEC. Objective: To explore early biomarkers for predicting NEC in extremely preterm infants (EPIs). Methods: Blood samples were collected on day 2 (median 1.7; range 1.5-2.0) from 40 EPI (median 25 gestational weeks; range 22-27): 11 developed NEC and 29 did not (controls). In each infant, 189 inflammatory, oncological, and vascular proteomic biomarkers were quantified through Proximity Extension Assay. Biomarker expression and clinical data were compared between the NEC group and Controls. Based on biomarker differences, controls were sorted automatically into three subgroups (1, 2, and 3) by a two-dimensional hierarchical clustering analysis. Results: None of the biomarkers differed in expression between all controls and the NEC group. Two biomarkers were higher in Control 1, and 16 biomarkers were lower in Control group 2 compared with the NEC group. No biomarker distinguished Control 3 from the NEC group. Perinatal data were similar in the whole population. Conclusions: Early postnatal comprehensive biomarkers do not identify EPIs at risk of developing NEC in our study. Future studies of predictors of NEC should include sequential analysis of comprehensive proteomic markers in large cohorts.
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Affiliation(s)
- Alice Hoffsten
- Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden
| | - Laszlo Markasz
- Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.,Neonatal Intensive Care Unit, University Children's Hospital, Uppsala, Sweden
| | - Helene Engstrand Lilja
- Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.,Section of Pediatric Surgery, University Children's Hospital, Uppsala, Sweden
| | - Karl Wilhelm Olsson
- Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.,Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Richard Sindelar
- Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.,Neonatal Intensive Care Unit, University Children's Hospital, Uppsala, Sweden
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41
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Wang R, Tang R, Li B, Ma X, Schnabl B, Tilg H. Gut microbiome, liver immunology, and liver diseases. Cell Mol Immunol 2021; 18:4-17. [PMID: 33318628 PMCID: PMC7852541 DOI: 10.1038/s41423-020-00592-6] [Citation(s) in RCA: 228] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 11/08/2020] [Indexed: 02/08/2023] Open
Abstract
The gut microbiota is a complex and plastic consortium of microorganisms that are intricately connected with human physiology. The liver is a central immunological organ that is particularly enriched in innate immune cells and constantly exposed to circulating nutrients and endotoxins derived from the gut microbiota. The delicate interaction between the gut and liver prevents accidental immune activation against otherwise harmless antigens. Work on the interplay between the gut microbiota and liver has assisted in understanding the pathophysiology of various liver diseases. Of immense importance is the step from high-throughput sequencing (correlation) to mechanistic studies (causality) and therapeutic intervention. Here, we review the gut microbiota, liver immunology, and the interaction between the gut and liver. In addition, the impairment in the gut-liver axis found in various liver diseases is reviewed here, with an emphasis on alcohol-associated liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), and autoimmune liver disease (AILD). On the basis of growing evidence from these preclinical studies, we propose that the gut-liver axis paves the way for targeted therapeutic modalities for liver diseases.
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Affiliation(s)
- Rui Wang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, 200001, Shanghai, China
| | - Ruqi Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, 200001, Shanghai, China
| | - Bo Li
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, 200001, Shanghai, China
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, 200001, Shanghai, China.
| | - Bernd Schnabl
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA.
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria.
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42
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Giannoudaki E, Gargan S, Hussey S, Long A, Walsh PT. Opportunities to Target T Cell Trafficking in Pediatric Inflammatory Bowel Disease. Front Pediatr 2021; 9:640497. [PMID: 33816403 PMCID: PMC8012547 DOI: 10.3389/fped.2021.640497] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 02/08/2021] [Indexed: 12/12/2022] Open
Abstract
T cell subsets are considered central orchestrators of inflammation and homeostasis in the intestine and are established targets for the treatment of inflammatory bowel disease. While approaches aimed at the neutralization of T cell effector cytokines have provided significant benefits for pediatric and adult patients, more recent strategies aimed at inhibiting the infiltration of pathogenic T cell subsets have also emerged. In this review, we describe current knowledge surrounding the function of T cell subsets in pediatric inflammatory bowel disease and outline approaches aimed at targeting T cell trafficking to the intestine which may represent a new treatment option for pediatric inflammatory bowel disease.
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Affiliation(s)
- Eirini Giannoudaki
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Siobhan Gargan
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Seamus Hussey
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Department of Paediatrics, Royal College of Surgeons of Ireland, Dublin, Ireland
| | - Aideen Long
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Patrick T Walsh
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
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43
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Atanes P, Lee V, Huang GC, Persaud SJ. The role of the CCL25-CCR9 axis in beta-cell function: potential for therapeutic intervention in type 2 diabetes. Metabolism 2020; 113:154394. [PMID: 33058852 DOI: 10.1016/j.metabol.2020.154394] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 09/15/2020] [Accepted: 10/05/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND PURPOSE Chemokines are known to play essential roles mediating immunity and inflammation in many physiological and pathophysiological processes, with reports linking their action to the development of obesity, insulin resistance and type 2 diabetes (T2D). Given our findings of highly upregulated mRNA expression of the chemokine receptor CCR9 in islets from obese human donors, we have determined the effects of CCR9 activation by CCL25 on islet function and viability. BASIC PROCEDURES RT-qPCR was used to measure expression of 384 GPCR mRNAs in human islets from organ donors with normal and elevated BMI. mRNA encoding CCR9, a receptor that was highly upregulated in islets from obese donors, was also quantified in islets from lean and high-fat diet (HFD) mice. The effects of CCR9 activation by exogenous CCL25 in human and mouse islets and its inhibition by the CCR9 antagonist vercirnon on insulin secretion, apoptosis and cAMP accumulation were examined using standard techniques. MAIN FINDINGS The qPCR analysis showed altered expression of several GPCRs in islets isolated from lean and obese donors. CCR9 displayed over 90-fold upregulation in islets from obese individuals, and it was also significantly upregulated in islets from obese mice. In isolated human and mouse islets exogenous CCL25 inhibited glucose-induced insulin secretion in a concentration-dependent manner, enhanced cytokine-induced apoptosis and significantly reduced forskolin-induced elevation in cAMP levels. These detrimental effects of CCL25 in islets were blocked by vercirnon, which had no effect on its own. PRINCIPAL CONCLUSIONS We have shown that CCL25 acts via the Gαi-coupled receptor CCR9 to impair beta-cell function by inhibiting insulin secretion and promoting cytokine-induced apoptosis. Upregulation of CCR9 in islets in obesity, possibly secondary to accumulation of passenger immune cells, may predispose to metabolic dysfunction and our data suggest that CCL25 downregulation or CCR9 inhibition could be explored to treat T2D.
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Affiliation(s)
- Patricio Atanes
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, London, SE1 1UL, United Kingdom.
| | - Vivian Lee
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, London, SE1 1UL, United Kingdom.
| | - Guo Cai Huang
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, London, SE1 1UL, United Kingdom.
| | - Shanta J Persaud
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, London, SE1 1UL, United Kingdom.
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44
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Harrison LM, Lacher DW, Mammel MK, Leonard SR. Comparative Transcriptomics of Shiga Toxin-Producing and Commensal Escherichia coli and Cytokine Responses in Colonic Epithelial Cell Culture Infections. Front Cell Infect Microbiol 2020; 10:575630. [PMID: 33194815 PMCID: PMC7649339 DOI: 10.3389/fcimb.2020.575630] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 10/07/2020] [Indexed: 12/12/2022] Open
Abstract
Ingestion of Shiga toxin-producing Escherichia coli (STEC) can result in a range of illness severity from asymptomatic to hemorrhagic colitis and death; thus risk assessment of STEC strains for human pathogenicity is important in the area of food safety. Illness severity depends in part on the combination of virulence genes carried in the genome, which can vary between strains even of identical serotype. To better understand how core genes are regulated differently among strains and to identify possible novel STEC virulence gene candidates that could be added to the risk assessment repertoire, we used comparative transcriptomics to investigate global gene expression differences between two STEC strains associated with severe illness and a commensal E. coli strain during in vitro intestinal epithelial cell (IEC) infections. Additionally, we compared a wide array of concomitant cytokine levels produced by the IECs. The cytokine expression levels were examined for a pattern representing STEC pathogenicity; however, while one STEC strain appeared to elicit a proinflammatory response, infection by the other strain produced a pattern comparable to the commensal E. coli. This result may be explained by the significant differences in gene content and expression observed between the STEC strains. RNA-Seq analysis revealed considerable disparity in expression of genes in the arginine and tryptophan biosynthesis/import pathways between the STEC strains and the commensal E. coli strain, highlighting the important role some amino acids play in STEC colonization and survival. Contrasting differential expression patterns were observed for genes involved in respiration among the three strains suggesting that metabolic diversity is a strategy utilized to compete with resident microflora for successful colonization. Similar temporal expression results for known and putative virulence genes were observed in the STEC strains, revealing strategies used for survival prior to and after initial adherence to IECs. Additionally, three genes encoding hypothetical proteins located in mobile genetic elements were, after interrogation of a large set of E. coli genomes, determined to likely represent novel STEC virulence factors.
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Affiliation(s)
- Lisa M Harrison
- Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, MD, United States
| | - David W Lacher
- Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, MD, United States
| | - Mark K Mammel
- Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, MD, United States
| | - Susan R Leonard
- Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, MD, United States
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45
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Controlling leukocyte trafficking in IBD. Pharmacol Res 2020; 159:105050. [PMID: 32598943 DOI: 10.1016/j.phrs.2020.105050] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 06/24/2020] [Accepted: 06/24/2020] [Indexed: 12/11/2022]
Abstract
Inflammatory bowel disease (IBD) is characterized by the accumulation of immune cells, myeloid cells and lymphocytes in the inflamed intestine. The presence and persistence of these cells, together with the production of pro-inflammatory mediators, perpetuate intestinal inflammation in both ulcerative colitis and Crohn's disease. Thus, blockade of leukocyte migration to the intestine is a main strategy used to control the disease and alleviate symptoms. Vedolizumab is the only anti-integrin drug approved for the treatment of IBD but several other drugs also targeting integrins, chemokines or receptors involved in leukocyte intestinal trafficking are under development and investigated for their efficacy and safety in IBD. The challenge now is to better understand the specific mechanism of action underlying each drug and to identify biomarkers that would guide drug selection in the individual patient.
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46
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Yang X, Lu D, Zhuo J, Lin Z, Yang M, Xu X. The Gut-liver Axis in Immune Remodeling: New insight into Liver Diseases. Int J Biol Sci 2020; 16:2357-2366. [PMID: 32760203 PMCID: PMC7378637 DOI: 10.7150/ijbs.46405] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 06/12/2020] [Indexed: 02/07/2023] Open
Abstract
The gut microbiota consists of a dynamic multispecies community of bacteria, fungi, archaea, and protozoans, playing a fundamental role in the induction, training, and function of the host immune system. The liver is anatomically and physiologically linked to the gut microbiota via enterohepatic circulation, specifically receiving intestine-derived blood through the portal vein. The gut microbiota is crucial for maintaining immune homeostasis of the gut-liver axis. A shift in gut microbiota composition can result in activation of the mucosal immune response causing homeostasis imbalance. This imbalance results in translocation of bacteria and migration of immune cells to the liver, which is related to inflammation-mediated liver injury and tumor progression. In this review, we outline the role of the gut microbiota in modulating host immunity and summarize novel findings and recent advances in immune-based therapeutics associated with the gut-liver axis. Moving forward, a deep understanding of the microbiome-immune-liver axis will provide insight into the basic mechanisms of gut microbiota dysbiosis affecting liver diseases.
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Affiliation(s)
- Xinyu Yang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China.,NHFPC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
| | - Di Lu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China.,NHFPC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
| | - Jianyong Zhuo
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China.,NHFPC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
| | - Zuyuan Lin
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China.,NHFPC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
| | - Modan Yang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China.,NHFPC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China.,NHFPC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, 310003, China
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de Krijger M, Visseren T, Wildenberg ME, Hooijer GKJ, Verstegen MMA, van der Laan LJW, de Jonge WJ, Verheij J, Ponsioen CY. Characterization of gut-homing molecules in non-endstage livers of patients with primary sclerosing cholangitis and inflammatory bowel disease. J Transl Autoimmun 2020; 3:100054. [PMID: 32743534 PMCID: PMC7388383 DOI: 10.1016/j.jtauto.2020.100054] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 04/02/2020] [Indexed: 02/07/2023] Open
Abstract
Introduction The co-occurrence of inflammatory bowel disease (IBD) in up to 80% of patients with primary sclerosing cholangitis (PSC) suggests a relation between the gut and the liver in patients with both PSC and IBD. One hypothesis suggests that aberrantly expressed homing molecules in the liver drive infiltration of gut-homing memory T-cells that are originally primed in intestinal environment. One of the main findings supporting this hypothesis is the expression of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in PSC livers. Expression of homing molecules in early PSC remains unclear. The aim of this study was to investigate expression patterns of homing chemokines and adhesion molecules in PSC-IBD colons and livers, and to study whether changes are already present in early stages of PSC. Methods Needle biopsies from livers of 20 PSC patients with short-term PSC (PSC-IBDST) as well as explant liver biopsies of 8 patients with long-term PSC (PSC-IBDLT) were collected (median disease duration 0 and 22 years, respectively). Only patients with concomitant IBD were included (89% ulcerative colitis and 11% Crohn’s disease). Expression and distribution of MAdCAM-1, VAP-1, integrin β7, CCL25, CCL28, CXCL12, αE (CD103) and E-cadherin were assessed in both liver and colon tissue. Liver tissue collected from obstructive cholangitis in resection specimens for Klatskin tumors or resection specimens from hepatic metastasis, liver tissue of patients with hepatitis C virus (HCV) and of patients with primary biliary cholangitis (PBC) served as controls. Results MAdCAM-1 expression in livers of PSC-IBDLT patients was increased compared to controls. The proportion of CD3+ T-cells expressing integrin β7 did not differ between PSC-IBDST and control groups, but was higher in liver tissue of PSC-IBDLT patients. There was no difference in αE+ T-cells between PSC-IBDLT and control groups. The chemokine CCL28 was highly expressed in biliary epithelial cells. This intense staining pattern was more pronounced in PSC-IBDST, but overall did not significantly differ from controls. Conclusions We confirm that aberrant gut lymphocyte homing to the liver exists in PSC, linking gut and liver disease pathology in PSC-IBD. Our data suggests that this phenomenon increases over time in later stages of the disease, worsening ongoing inflammation.
MAdCAM-1 is aberrantly expressed in PSC-IBD liver compared to control liver. The proportion of beta7 positive T-cells is increased in long-term PSC livers. Biliary epithelial cells express CCL28, already in short-term PSC. Expression patterns of inflammatory cytokines in PSC-IBD colon are not distinct from IBD.
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Affiliation(s)
- Manon de Krijger
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Meibergdreef 69, 1105 BK, Amsterdam, the Netherlands.,Department of Gastroenterology and Hepatology Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands
| | - Thijmen Visseren
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center Rotterdam, Doctor Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands.,Department of Surgery, Erasmus MC-University Medical Center Rotterdam, Doctor Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands
| | - Manon E Wildenberg
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Meibergdreef 69, 1105 BK, Amsterdam, the Netherlands.,Department of Gastroenterology and Hepatology Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands
| | - Gerrit K J Hooijer
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands
| | - Monique M A Verstegen
- Department of Surgery, Erasmus MC-University Medical Center Rotterdam, Doctor Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands
| | - Luc J W van der Laan
- Department of Surgery, Erasmus MC-University Medical Center Rotterdam, Doctor Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands
| | - Wouter J de Jonge
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Meibergdreef 69, 1105 BK, Amsterdam, the Netherlands
| | - Joanne Verheij
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands
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Immunohistochemical staining with chemokine panel of non-specific colitis predicts future IBD diagnosis. Cytokine 2020; 127:154935. [PMID: 31770615 DOI: 10.1016/j.cyto.2019.154935] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 11/15/2019] [Accepted: 11/18/2019] [Indexed: 12/16/2022]
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49
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Henderson AR, Choi H, Lee E. Blood and Lymphatic Vasculatures On-Chip Platforms and Their Applications for Organ-Specific In Vitro Modeling. MICROMACHINES 2020; 11:E147. [PMID: 32013154 PMCID: PMC7074693 DOI: 10.3390/mi11020147] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 01/23/2020] [Accepted: 01/28/2020] [Indexed: 02/07/2023]
Abstract
The human circulatory system is divided into two complementary and different systems, the cardiovascular and the lymphatic system. The cardiovascular system is mainly concerned with providing nutrients to the body via blood and transporting wastes away from the tissues to be released from the body. The lymphatic system focuses on the transport of fluid, cells, and lipid from interstitial tissue spaces to lymph nodes and, ultimately, to the cardiovascular system, as well as helps coordinate interstitial fluid and lipid homeostasis and immune responses. In addition to having distinct structures from each other, each system also has organ-specific variations throughout the body and both systems play important roles in maintaining homeostasis. Dysfunction of either system leads to devastating and potentially fatal diseases, warranting accurate models of both blood and lymphatic vessels for better studies. As these models also require physiological flow (luminal and interstitial), extracellular matrix conditions, dimensionality, chemotactic biochemical gradient, and stiffness, to better reflect in vivo, three dimensional (3D) microfluidic (on-a-chip) devices are promising platforms to model human physiology and pathology. In this review, we discuss the heterogeneity of both blood and lymphatic vessels, as well as current in vitro models. We, then, explore the organ-specific features of each system with examples in the gut and the brain and the implications of dysfunction of either vasculature in these organs. We close the review with discussions on current in vitro models for specific diseases with an emphasis on on-chip techniques.
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Affiliation(s)
- Aria R. Henderson
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA;
| | - Hyoann Choi
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA;
| | - Esak Lee
- Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA;
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50
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Zhang Y, Shen B, Zhuge L, Xie Y. Identification of differentially expressed genes between the colon and ileum of patients with inflammatory bowel disease by gene co-expression analysis. J Int Med Res 2019; 48:300060519887268. [PMID: 31822145 PMCID: PMC7251957 DOI: 10.1177/0300060519887268] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE We aimed to identify differentially expressed genes (DEG) in patients with inflammatory bowel disease (IBD). METHODS RNA-seq data were obtained from the Array Express database. DEG were identified using the edgeR package. A co-expression network was constructed and key modules with the highest correlation with IBD inflammatory sites were identified for analysis. The Cytoscape MCODE plugin was used to identify key sub-modules of the protein-protein interaction (PPI) network. The genes in the sub-modules were considered hub genes, and functional enrichment analysis was performed. Furthermore, we constructed a drug-gene interaction network. Finally, we visualized the hub gene expression pattern between the colon and ileum of IBD using the ggpubr package and analyzed it using the Wilcoxon test. RESULTS DEG were identified between the colon and ileum of IBD patients. Based on the co-expression network, the green module had the highest correlation with IBD inflammatory sites. In total, 379 DEG in the green module were identified for the PPI network. Nineteen hub genes were differentially expressed between the colon and ileum. The drug-gene network identified these hub genes as potential drug targets. CONCLUSION Nineteen DEG were identified between the colon and ileum of IBD patients.
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Affiliation(s)
- Yuting Zhang
- Institute of Gastroenterology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, P. R. China.,Department of Liver Diseases, People's Hospital of Yichun City, Yichun, Jiangxi Province, P. R. China
| | - Bo Shen
- Department of Hepatobiliary Surgery, People's Hospital of Yichun City, Yichun, Jiangxi Province, P R China
| | - Liya Zhuge
- Institute of Gastroenterology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, P. R. China
| | - Yong Xie
- Institute of Gastroenterology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, P. R. China.,Department of Gastroenterology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, P R China
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