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Miller S, Eizenberg-Magar I, Reich-Zeliger S, Rimer J, Zaretsky I, Reshef D, Kopitman E, Friedman N, Antebi YE. Independent and temporally separated dynamics for RORγt and Foxp3 during Th17 differentiation. Front Immunol 2025; 16:1462045. [PMID: 40356912 PMCID: PMC12066577 DOI: 10.3389/fimmu.2025.1462045] [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: 08/12/2024] [Accepted: 04/08/2025] [Indexed: 05/15/2025] Open
Abstract
T helper 17 and Regulatory T cells (Th17 and Treg, respectively) are two well-described lymphocyte subsets with opposing actions. The divergent fates of Th17 and Treg cells are accounted for, at least in part, by molecular antagonism that occurs between their respective specific transcription factors, RORγt and Foxp3. An imbalance between Th17 and Treg cells may lead to tissue inflammation and is associated with certain types of autoimmunity. In order to understand the heterogeneity and dynamics of the differentiation process, we studied Th17/Treg cell differentiation of naïve cells in vitro, using RORγtGFPFoxp3RFP dual-reporter mouse. Flow cytometry revealed the consistent emergence of a population of double positive RORγt+Foxp3+ (DP) cells during the early stages of Th17 cell differentiation. These DP cells are closely related to RORγt+ single positive (SPR) cells in terms of global gene expression. Nevertheless, for some genes, DP cells share an expression pattern with Foxp3+ single positive (SPF) Treg cells, most importantly by reducing IL17 levels. Using time-lapse microscopy, we could delineate the expression dynamics of RORγt and Foxp3 at a clonal level. While the RORγt expression level elevates early during differentiation, Foxp3 rises later and is more stable upon environmental changes. These distinct expression profiles are independent of each other. During differentiation and proliferation, individual cells transit between SPR, DP, and SPF states. Nevertheless, the differentiation of sister cells within a clone progeny was highly correlated. We further demonstrated that sorted SPR and DP populations were not significantly affected by changes in their environment, suggesting that the correlated fate decision emerged at early time points before the first division. Overall, this study provides the first quantitative analysis of differentiation dynamics during the generation of DP RORγt+Foxp3+ cells. Characterizing these dynamics and the differentiation trajectory could provide a profound understanding and be used to better define the distinct fates of T cells, critical mediators of the immune response.
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MESH Headings
- Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism
- Nuclear Receptor Subfamily 1, Group F, Member 3/genetics
- Nuclear Receptor Subfamily 1, Group F, Member 3/immunology
- Animals
- Cell Differentiation/immunology
- Th17 Cells/immunology
- Th17 Cells/cytology
- Th17 Cells/metabolism
- Forkhead Transcription Factors/metabolism
- Forkhead Transcription Factors/genetics
- Forkhead Transcription Factors/immunology
- Mice
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/cytology
- Mice, Inbred C57BL
- Mice, Transgenic
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Affiliation(s)
- Stav Miller
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
- Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | | | | | - Jacob Rimer
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Irina Zaretsky
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
- Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - Dan Reshef
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Ekaterina Kopitman
- Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot, Israel
| | - Nir Friedman
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Yaron E Antebi
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
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Paton H, Sarkar P, Gurung P. An overview of host immune responses against Leishmania spp. infections. Hum Mol Genet 2025:ddaf043. [PMID: 40287829 DOI: 10.1093/hmg/ddaf043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 03/18/2025] [Accepted: 03/24/2025] [Indexed: 04/29/2025] Open
Abstract
Leishmania spp. infections pose a significant global health challenge, affecting approximately 1 billion people across more than 88 endemic countries. This unicellular, obligate intracellular parasite causes a spectrum of diseases, ranging from localized cutaneous lesions to systemic visceral infections. Despite advancements in modern medicine and increased understanding of the parasite's etiology and associated diseases, treatment options remain limited to pentavalent antimonials, liposomal amphotericin B, and miltefosine. A deeper understanding of the interactions between immune and non-immune cells involved in the clearance of Leishmania spp. infections could uncover novel therapeutic strategies for this debilitating disease. This review highlights recent progress in elucidating how various cell types contribute to the regulation and resolution of Leishmania spp. infections.
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Affiliation(s)
- Hanna Paton
- Inflammation Program, University of Iowa, 431 Newton Road, Iowa City, IA 52242, United States
- Department of Internal Medicine, University of Iowa, 431 Newton Road, Iowa City, IA 52442, United States
- Immunology Graduate Program, University of Iowa, 431 Newton Road, Iowa City, IA 52242, United States
| | - Prabuddha Sarkar
- Inflammation Program, University of Iowa, 431 Newton Road, Iowa City, IA 52242, United States
- Department of Internal Medicine, University of Iowa, 431 Newton Road, Iowa City, IA 52442, United States
| | - Prajwal Gurung
- Inflammation Program, University of Iowa, 431 Newton Road, Iowa City, IA 52242, United States
- Department of Internal Medicine, University of Iowa, 431 Newton Road, Iowa City, IA 52442, United States
- Immunology Graduate Program, University of Iowa, 431 Newton Road, Iowa City, IA 52242, United States
- Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, 431 Newton Road, Iowa City, IA 52242, United States
- Center for Immunology and Immune Based Disease, University of Iowa, 431 Newton Road, Iowa City, IA 52242, United States
- Iowa City Veterans Affairs (VA) Medical Center, 601 US-6, Iowa City, IA 52246, United States
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Wang Y, Jiang Y, Li M, Xiao Y, Zhao Q, Zeng J, Wei S, Chen S, Zhao Y, Du F, Chen Y, Deng S, Shen J, Li X, Li W, Wang F, Sun Y, Gu L, Xiao Z, Wang S, Wu X. Rosavin derived from Rhodiola alleviates colitis in mice through modulation of Th17 differentiation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 136:156318. [PMID: 39647466 DOI: 10.1016/j.phymed.2024.156318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 09/25/2024] [Accepted: 12/04/2024] [Indexed: 12/10/2024]
Abstract
BACKGROUND Rosavin (RSV) is a naturally occurring compound isolated from Rhodiola species. While RSV has been reported with pharmacological activities of anti-oxidation, anti-inflammation, anti-stress and immunomodulation, its effect on colitis and the underlying mechanisms remain unclear. PURPOSE This study aims to investigate whether and how RSV alleviated colitis in mice. STUDY DESIGN AND METHODS The protective effect of RSV (50, 100, 200 mg/kg, p.o.) was investigated in dextran sulfate sodium (DSS) mediated mouse models of acute and chronic colitis. Alterations in fecal microbiota were evaluated by 16S rRNA sequencing. Pseudo germ-free mice achieved by antibiotics treatment were applied to assess the RSV-mediated functional role of gut microbiota in colitis. RNA sequencing was performed to determine RSV-induced colonic response. Primary T cell culture was conducted to examine the effect of RSV on Th17 and Treg differentiation. Whole blood assay, dual luciferase reporter assay, and molecular docking methods were applied to investigate the mechanisms and targets of RSV in Th17 regulation. RESULTS Oral RSV significantly relieved DSS-mediated acute and chronic colitis in mice, which recovered body weight loss, reduced disease activity index, alleviated colon injury, inhibited inflammation, suppressed the apoptosis of intestinal epithelia, and maintained intestinal barrier function. Moreover, RSV specifically regulated intestinal microbiota by recovering DSS-mediated microbial changes and elevating beneficial microbes such as Lactobacillus and Akkermansia. Antibiotics treatment experiment showed that the protective role of RSV was at least partially dependent on gut microbiota; however, in vitro incubation showed that RSV did not directly promote the growth of Lactobacillus and Akkermansia strains. Further analysis showed that RSV-mediated genetic alterations in colon were enriched in pathways related to lymphocyte regulation. Additionally, RSV regulated the balance of Th17/Treg in colitis mice. Importantly, RSV inhibited the differentiation of Th17 cell in vitro, suppressed the production of IL-17 by Th17 cells, and downregulated Rorc encoding RORγt and its downstream Il17. RSV significantly inhibited the RORγt transcription activity and bound to its ligand binding domain. CONCLUSION RSV alleviates murine colitis through regulating intestinal immunity. Notably, RSV is identified as a novel regulator of Th17 cells that inhibits RORγt-mediated Th17 differentiation. These findings potentiate the Rhodiola-derived natural chemicals as novel anti-colitis agents.
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Affiliation(s)
- Yi Wang
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646100, China; Sichuan Fifth People's Hospital, Chengdu, Sichuan 610015, China
| | - Yu Jiang
- Department of Gerontology, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, 646100, China
| | - Mingxing Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646100, China; South Sichuan Institute of Translational Medicine, Luzhou 646100, China
| | - Yaqin Xiao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
| | - Qianyun Zhao
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646100, China
| | - Jiuping Zeng
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646100, China
| | - Shulin Wei
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646100, China
| | | | - Yueshui Zhao
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646100, China; South Sichuan Institute of Translational Medicine, Luzhou 646100, China
| | - Fukuan Du
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646100, China; South Sichuan Institute of Translational Medicine, Luzhou 646100, China
| | - Yu Chen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646100, China; South Sichuan Institute of Translational Medicine, Luzhou 646100, China
| | - Shuai Deng
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646100, China; South Sichuan Institute of Translational Medicine, Luzhou 646100, China
| | - Jing Shen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646100, China; South Sichuan Institute of Translational Medicine, Luzhou 646100, China
| | - Xiaobing Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646100, China
| | - Wanping Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646100, China
| | - Fang Wang
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646100, China
| | - Yuhong Sun
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646100, China
| | - Li Gu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646100, China
| | - Zhangang Xiao
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646100, China; South Sichuan Institute of Translational Medicine, Luzhou 646100, China; Gulin County Hospital of Traditional Chinese Medicine, Luzhou 646500, China.
| | - Shengpeng Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
| | - Xu Wu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646100, China; Department of Paediatric Care, Luzhou People's Hospital, Luzhou, Sichuan 646000, China.
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Xia Y, Yang Q, Li Q, Wen J, Li M, Wu Z, Nie L, Huang Z, Wu SY, Du J. Metallothionein-1 mitigates the advancement of osteoarthritis by regulating Th17/Treg balance. Cell Immunol 2024; 405-406:104877. [PMID: 39305580 DOI: 10.1016/j.cellimm.2024.104877] [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: 07/22/2024] [Revised: 09/04/2024] [Accepted: 09/13/2024] [Indexed: 12/02/2024]
Abstract
Osteoarthritis (OA) is a chronic inflammatory joint disorder characterized by cartilage degradation and bone remodeling. This study investigated the regulatory role of metallothionein 1 (MT1) in modulating immune responses and the balance between regulatory T cells (Treg) and T helper 17 cells (Th17) in OA. Peripheral blood mononuclear cells (PBMCs) from healthy individuals and OA patients were assessed for cytokine expression linked to Treg/Th17 homeostasis. OA was induced in wild-type (WT) and Mt1 knockout (MT1KO) mice via surgical destabilization of the medial meniscus. Clinical scores, pathological features, inflammatory cytokines, and Treg/Th17 balance were evaluated. MT1KO mice showed significantly elevated Mt1, pro-inflammatory cytokines (IL-1, IL-6, TNF-α) and exacerbated OA progression, characterized by increased knee joint diameter, inflammatory infiltration, and cartilage destruction. Mechanistically, disrupted Treg/Th17 balance played a pivotal role in OA exacerbation, with MT1KO promoting Th17 differentiation and reducing Treg populations. Additionally, the compensatory elevation of anti-inflammatory interleukin-10 (IL-10) in OA patients hinted at a nuanced immune regulatory mechanism. The study illuminates intricate interactions involving MT1, Treg/Th17 cells, and pro-inflammatory cytokines in OA pathogenesis, suggesting MT1's potential as a pivotal regulatory factor and a therapeutic target for mitigating immune dysregulation in OA.
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Affiliation(s)
- Yuhao Xia
- Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen China
| | - Qiannan Yang
- Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen China
| | - Qian Li
- Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen China
| | - Jiahao Wen
- Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen China
| | - Mingyang Li
- Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen China
| | - Zhicheng Wu
- Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen China
| | - Liping Nie
- Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen China
| | - Zhong Huang
- Department of Immunology, School of Medicine, Shenzhen University, Shenzhen, China.
| | - Shang Ying Wu
- Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen China.
| | - Jing Du
- Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen China.
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5
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Chia JE, Rousseau RP, Ozturk M, Poswayo SKL, Lucas R, Brombacher F, Parihar SP. The divergent outcome of IL-4Rα signalling on Foxp3 T regulatory cells in listeriosis and tuberculosis. Front Immunol 2024; 15:1427055. [PMID: 39483462 PMCID: PMC11524857 DOI: 10.3389/fimmu.2024.1427055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 09/18/2024] [Indexed: 11/03/2024] Open
Abstract
Introduction Forkhead box P3 (Foxp3) T regulatory cells are critical for maintaining self-tolerance, immune homeostasis, and regulating the immune system. Methods We investigated interleukin-4 receptor alpha (IL-4Rα) signalling on T regulatory cells (Tregs) during Listeria monocytogenes (L. monocytogenes) infection using a mouse model on a BALB/c background, specifically with IL-4Rα knockdown in Tregs (Foxp3creIL-4Rα-/lox). Results We showed an impairment of Treg responses, along with a decreased bacterial burden and diminished tissue pathology in the liver and spleen, which translated into better survival. Mechanistically, we observed an enhancement of the Th1 signature, characterised by increased expression of the T-bet transcription factor and a greater number of effector T cells producing IFN-γ, IL-2 following ex-vivo stimulation with heat-killed L. monocytogenes in Foxp3creIL-4Rα-/lox mice. Furthermore, CD8 T cells from Foxp3creIL-4Rα-/lox mice displayed increased cytotoxicity (Granzyme-B) with higher proliferation capacity (Ki-67), better survival (Bcl-2) with concomitant reduced apoptosis (activated caspase 3). In contrast to L. monocytogenes, Foxp3creIL-4Rα-/lox mice displayed similar bacterial burdens, lung pathology and survival during Mycobacterium tuberculosis (M. tuberculosis) infection, despite increased T cell numbers and IFN-γ, TNF and IL-17 production. Conclusion Our results demonstrated that the diminished IL-4Rα signalling on Foxp3+ T regulatory cells resulted in a loss of their functionality, leading to survival benefits in listeriosis but not in tuberculosis.
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Affiliation(s)
- Julius E. Chia
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa
- Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Robert P. Rousseau
- Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Diseases and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Mumin Ozturk
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa
- Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Sibongiseni K. L. Poswayo
- Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Diseases and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Rodney Lucas
- Research Animal Facility (RAF), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Frank Brombacher
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa
- Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Diseases and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Suraj P. Parihar
- Division of Immunology, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Diseases and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Division of Medical Microbiology, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Division of Human Metabolomics, North-West University, Potchefstroom, South Africa
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Paredes-Ruiz D, Martin-Iglesias D, Amo L, Ruiz-Irastorza G. Elucidating the mechanisms and efficacy of antimalarial drugs in systemic lupus erythematosus. Expert Opin Pharmacother 2024; 25:2047-2060. [PMID: 39354741 DOI: 10.1080/14656566.2024.2412252] [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: 06/29/2024] [Revised: 09/30/2024] [Accepted: 09/30/2024] [Indexed: 10/03/2024]
Abstract
INTRODUCTION Antimalarials (AMs) are old drugs with a wide range of beneficial effects in systemic lupus erythematosus (SLE) beyond the control of activity. The most recent debate is focused on defining the optimal doses to assure the best benefit/risk ratio. AREAS COVERED We have reviewed the pharmacological basis underlying the various therapeutic effects of AMs and the beneficial and toxic effects of HCQ, also discussing the role of mepacrine not only as a substitute in cases of maculopathy, but also as a very effective therapy combined with HCQ. We searched PubMed and Embase for articles published in English at any time. We used the terms "hydroxychloroquine" or "mepacrine" or "chloroquine" or "antimalarials", "pharmacokinetics", "efficacy", "remission", "toxicity", "adherence". We reviewed original research articles, large observational studies, systematic reviews, and expert consensus statements. Additionally, studies were identified through the assessment of the reference lists of the evaluated manuscripts. EXPERT OPINION We advocate for the widespread use of HCQ at stable doses of 200 mg/d (≤4 mg/kg/d for most patients) and also for the early combination therapy with mepacrine to assure a good control of SLE activity, and also a durable and safe use of these essential drugs for the management of SLE.
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Affiliation(s)
- Diana Paredes-Ruiz
- Biobizkaia Health Research Institute, Hospital Universitario Cruces, Bizkaia, The Basque Country, Spain
| | - Daniel Martin-Iglesias
- Biobizkaia Health Research Institute, Hospital Universitario Cruces, Bizkaia, The Basque Country, Spain
- Internal Medicine Department, Hospital Universitario de Leon, Leon, Spain
| | - Laura Amo
- Immunopathology Group, Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, Spain
| | - Guillermo Ruiz-Irastorza
- Biobizkaia Health Research Institute, Hospital Universitario Cruces, Bizkaia, The Basque Country, Spain
- Department of Medicine, University of The Basque Country, UPV/EHU, Bizkaia, The Basque Country, Spain
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7
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Nouri N, Aghebati-Maleki L, Soltani-Zangbar MS, Kamrani A, Mehdizadeh A, Danaii S, Heris JA, Chakeri-Khiavi F, Yousefi M. Analysis of Th17 cell population and expression of microRNA and factors related to Th17 in patients with premature ovarian failure. J Reprod Immunol 2024; 165:104290. [PMID: 39053202 DOI: 10.1016/j.jri.2024.104290] [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: 09/27/2023] [Revised: 06/10/2024] [Accepted: 06/24/2024] [Indexed: 07/27/2024]
Abstract
Folliculogenesis is the process where follicles in the ovaries develop and eventually lead to ovulation. Any disruption to this process can cause premature ovarian failure. miR-326 is one of the microRNAs whose expression leads to Th17 production. Th17 activates the immune system to respond more vigorously, and by producing interlukins and cytokines causes inflammation and autoimmune disorders. Th17-induced inflammation and Th17/Treg imbalance can result in POF. This investigation took samples from 30 POF patients and 30 healthy people. The study utilized PCR to assess the expression levels of cytokines, specific transcription factor (ROR-γt), and miR-326. Additionally, ELISA was employed to analyze serum levels of IL-17, IL-21, IL-23. Furthermore, flow cytometry was utilized to determine the frequency of Th17. Compared to the control group, our results demonstrated a rise in the transcription factor RORɣt and a considerable rise in the frequency of Th17 cells in patients with POF. The level of inflammatory cytokines IL-17, IL-21, and IL-23 secreted in serum samples of patients with POF increased significantly compared to the control group. Results of investigating microRNA associated with Th17 cells also showed increased expression of miR-326 in females suffering from POF. The elevation of pro-inflammatory markers in women with POF contrary to the control group underscores the significant involvement of the immune system in pregnancy disorders pathogenesis. Consequently, immunological factors may serve as promising biomarkers for predicting POF likelihood in high-risk women in the future.
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Affiliation(s)
- Narjes Nouri
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mohammad Sadegh Soltani-Zangbar
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amin Kamrani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Mehdizadeh
- Hematology and Oncology Research Center,Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahla Danaii
- Gynecology Department, Eastern Azerbaijan ACECR ART center, Eastern Azerbaijan branch of ACECR, Tabriz, Iran
| | - Javad Ahmadian Heris
- Department of Allergy and Clinical Immunology, Pediatric Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mehdi Yousefi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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8
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Wenzek C, Siemes D, Hönes GS, Pastille E, Härting N, Kaiser F, Moeller LC, Engel DR, Westendorf AM, Führer D. Lack of canonical thyroid hormone receptor α signaling changes regulatory T cell phenotype in female mice. iScience 2024; 27:110547. [PMID: 39175769 PMCID: PMC11340620 DOI: 10.1016/j.isci.2024.110547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 06/17/2024] [Accepted: 07/16/2024] [Indexed: 08/24/2024] Open
Abstract
The immune system has emerged as an important target of thyroid hormones (THs); however, the role of TH in T cells has so far remained elusive. In this study, we assessed the effect of TH receptor α (TRα) signaling on activation and function of T cells. Our findings show that lack of canonical TRα action not only increased the frequency of regulatory T cells (Treg) but propelled an activated and migratory Treg phenotype and nuclear factor κB (NF-κB) activation in Treg. Conversely, canonical TRα action reduced activation of the NF-κB pathway previously shown to play a pivotal role in Treg differentiation and function. Taken together, our findings demonstrate that TRα impacts T cell differentiation and phenotype. Given the well-known interaction of inflammation, immune responses, and TH axis in e.g., severe illness, altered TH-TRα signaling may have an important role in regulating T cell responses during disease.
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Affiliation(s)
- Christina Wenzek
- Department of Endocrinology, Diabetology and Metabolism, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Devon Siemes
- Institute for Experimental Immunology and Imaging, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - G. Sebastian Hönes
- Department of Endocrinology, Diabetology and Metabolism, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Eva Pastille
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Nina Härting
- Institute for Human Genetics, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Frank Kaiser
- Institute for Human Genetics, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Lars C. Moeller
- Department of Endocrinology, Diabetology and Metabolism, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Daniel R. Engel
- Institute for Experimental Immunology and Imaging, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Astrid M. Westendorf
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
| | - Dagmar Führer
- Department of Endocrinology, Diabetology and Metabolism, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany
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9
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Kawashima N, Okiji T. Characteristics of inflammatory mediators in dental pulp inflammation and the potential for their control. FRONTIERS IN DENTAL MEDICINE 2024; 5:1426887. [PMID: 39917698 PMCID: PMC11797954 DOI: 10.3389/fdmed.2024.1426887] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 07/24/2024] [Indexed: 02/09/2025] Open
Abstract
Dental pulp is a mesenchymal connective tissue located inside the rigid encasement of the dentin. When bacteria or bacterial products invade the dental pulp, inflammation known as pulpitis is induced in this tissue. Various mediators produced during the course of pulpitis profoundly modify the pathophysiology of the inflammation. Typical mediators include cytokines, chemokines, nitric oxide, reactive oxygen species, matrix metalloproteinases, proteases, neutrophil extracellular traps, neuropeptides, and eicosanoids. Controlling these mediators may potentially lead to the healing of pulpitis and the preservation of pulp tissue. This review discusses these mediators and further explores the possibility of controlling them.
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Affiliation(s)
- Nobuyuki Kawashima
- Department of Pulp Biology and Endodontics, Division of Oral Health Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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10
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Prins CA, de Oliveira FL, de Mello Coelho V, Dos Santos Ribeiro EB, de Almeida JS, Silva NMB, Almeida FM, Martinez AMB. Galectin-3 absence alters lymphocytes populations dynamics behavior and promotes functional recovery after spinal cord injury in mice. Exp Neurol 2024; 377:114785. [PMID: 38670250 DOI: 10.1016/j.expneurol.2024.114785] [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: 11/13/2023] [Revised: 04/02/2024] [Accepted: 04/18/2024] [Indexed: 04/28/2024]
Abstract
Spinal cord injury (SCI) results from various mechanisms that damage the nervous tissue and the blood-brain barrier, leading to sensory and motor function loss below the injury site. Unfortunately, current therapeutic approaches for SCI have limited efficacy in improving patients outcomes. Galectin-3, a protein whose expression increases after SCI, influences the neuroinflammatory response by favoring pro-inflammatory M1 macrophages and microglia, while inhibiting pro-regenerative M2 macrophages and microglia, which are crucial for inflammation resolution and tissue regeneration. Previous studies with Galectin-3 knock-out mice demonstrated enhanced motor recovery after SCI. The M1/M2 balance is strongly influenced by the predominant lymphocytic profiles (Th1, Th2, T Reg, Th17) and cytokines and chemokines released at the lesion site. The present study aimed to investigate how the absence of galectin-3 impacts the adaptive immune system cell population dynamics in various lymphoid spaces following a low thoracic spinal cord compression injury (T9-T10) using a 30 g vascular clip for one minute. It also aimed to assess its influence on the functional outcome in wild-type (WT)and Galectin-3 knock-out (GALNEG) mice. Histological analysis with hematoxylin-eosin and Luxol Fast Blue staining revealed that WT and GALNEG animals exhibit similar spinal cord morphology. The absence of galectin-3 does not affect the common neuroanatomy shared between the groups prompting us to analyze outcomes between both groups. Following our crush model, both groups lost motor and sensory functions below the lesion level. During a 42-day period, GALNEG mice demonstrated superior locomotor recovery in the Basso Mouse Scale (BMS) gait analysis and enhanced motor coordination performance in the ladder rung walk test (LRW) compared to WT mice. GALNEG mice also exhibited better sensory recovery, and their electrophysiological parameters suggested a higher number of functional axons with faster nerve conduction. Seven days after injury, flow cytometry of thymus, spleen, and blood revealed an increased number of T Reg and Th2 cells, accompanied by a decrease in Th1 and Th17 cells in GALNEG mice. Immunohistochemistry conducted on the same day exhibited an increased number of Th2 and T Reg cells around the GALNEG's spinal cord lesion site. At 42-day dpi immunohistochemistry analyses displayed reduced astrogliosis and greater axon preservation in GALNEG's spinal cord seem as a reduction of GFAP immunostaining and an increase in NFH immunostaining, respectively. In conclusion, GALNEG mice exhibited better functional recovery attributed to the milder pro-inflammatory influence, compensated by a higher quantity of T Reg and Th2 cells. These findings suggest that galectin-3 plays a crucial role in the immune response after spinal cord injury and could be a potential target for clinical therapeutic interventions.
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Affiliation(s)
- Caio Andrade Prins
- Laboratório de Neurodegeneração e Reparo, Departamento de Patologia, Programa de Pós-graduação em Anatomia Patológica, Faculdade de Medicina, Hospital Universitário Clementina Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Felipe Leite de Oliveira
- Laboratório de Interações Celulares, Instituto de Ciências Biomédicas, Programa de Pós-graduação em Ciências Morfológicas, Centro de Ciências da Saúde, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Valeria de Mello Coelho
- Laboratório de lmunofisiologia, Instituto de Ciências Biomédicas, Programa de Pós-graduação em Ciências Morfológicas, Centro de Ciências da Saúde, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Emanuela Bezerra Dos Santos Ribeiro
- Laboratório de Neurodegeneração e Reparo, Departamento de Patologia, Programa de Pós-graduação em Anatomia Patológica, Faculdade de Medicina, Hospital Universitário Clementina Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Juliana Silva de Almeida
- Laboratório de Neurodegeneração e Reparo, Departamento de Patologia, Programa de Pós-graduação em Anatomia Patológica, Faculdade de Medicina, Hospital Universitário Clementina Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Natalia Moraes Bechelli Silva
- Laboratório de Neurodegeneração e Reparo, Departamento de Patologia, Programa de Pós-graduação em Anatomia Patológica, Faculdade de Medicina, Hospital Universitário Clementina Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Fernanda Martins Almeida
- Laboratório de Neurodegeneração e Reparo, Instituto de Ciências Biomédicas, Programa de Pós-graduação em Anatomia Patológica, Centro de Ciências da Saúde, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Ana Maria Blanco Martinez
- Laboratório de Neurodegeneração e Reparo, Departamento de Patologia, Programa de Pós-graduação em Anatomia Patológica, Faculdade de Medicina, Hospital Universitário Clementina Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
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11
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Li Y, Ning X, Zhao Z, He X, Xue Q, Zhou M, Li W, Li M. Core fucosylation of maternal milk N-glycans imparts early-life immune tolerance through gut microbiota-dependent regulation in RORγt + Treg cells. Food Funct 2024; 15:4140-4153. [PMID: 38445991 DOI: 10.1039/d4fo00230j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/07/2024]
Abstract
Milk glycans play key roles in shaping and maintaining a healthy infant gut microbiota. Core fucosylation catalyzed by fucosyltransferase (Fut8) is the major glycosylation pattern on human milk N-glycan, which was crucial for promoting the colonization and dominant growth of Bifidobacterium and Lactobacillus spp. in neonates. However, the influence of core-fucose in breast milk on the establishment of early-life immune tolerance remains poorly characterized. In this study, we found that the deficiency of core-fucose in the milk of maternal mice caused by Fut8 gene heterozygosity (Fut8+/-) resulted in poor immune tolerance towards the ovalbumin (OVA) challenge, accompanied by a reduced proportion of intestinal RORγt+ Treg cells and the abundance of Lactobacillus spp., especially L. reuteri and L. johnsonii, in their breast-fed neonates. The administration of the L. reuteri and L. johnsonii mixture to neonatal mice compromised the OVA-induced allergy and up-regulated the intestinal RORγt+ Treg cell proportions. However, Lactobacillus mixture supplementation did not alleviate allergic responses in RORγt+ Treg cell-deficient mice caused by Rorc gene heterozygosity (Rorc+/-) post OVA challenge, indicating that the intervention effects depend on the RORγt+ Treg cells. Interestingly, instead of L. reuteri and L. johnsonii, we found that the relative abundance of another Lactobacillus spp., L. murinus, in the gut of the offspring mice was significantly promoted by intervention, which showed enhancing effects on the proliferation of splenic and intestinal RORγt+ Treg cells in in vitro studies. The above results indicate that core fucosylation of breast milk N-glycans is beneficial for the establishment of RORγt+ Treg cell mediated early-life immune tolerance through the manipulation of symbiotic bacteria in mice.
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Affiliation(s)
- Yuyuan Li
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China.
| | - Xixi Ning
- College of Basic Medical Science, Dalian Medical University, Dalian, China.
| | - Zihui Zhao
- Pelvic Floor Repair Center, Dalian Women and Children's Medical Group, Dalian, China
| | - Xi He
- College of Basic Medical Science, Dalian Medical University, Dalian, China.
| | - Qidi Xue
- College of Basic Medical Science, Dalian Medical University, Dalian, China.
| | - Manlin Zhou
- College of Basic Medical Science, Dalian Medical University, Dalian, China.
| | - Wenzhe Li
- Shantou University Medical College, Shantou, Guangdong, China.
| | - Ming Li
- College of Basic Medical Science, Dalian Medical University, Dalian, China.
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12
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Maloney E, Duffy D. Deciphering the relationship between temperature and immunity. DISCOVERY IMMUNOLOGY 2024; 3:kyae001. [PMID: 38567294 PMCID: PMC10917241 DOI: 10.1093/discim/kyae001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 12/01/2023] [Accepted: 01/29/2024] [Indexed: 04/04/2024]
Abstract
Fever is a hallmark symptom of disease across the animal kingdom. Yet, despite the evidence linking temperature fluctuation and immune response, much remains to be discovered about the molecular mechanisms governing these interactions. In patients with rheumatoid arthritis, for instance, it is clinically accepted that joint temperature can predict disease progression. But it was only recently demonstrated that the mitochondria of stimulated T cells can rise to an extreme 50°C, potentially indicating a cellular source of these localized 'fevers'. A challenge to dissecting these mechanisms is a bidirectional interplay between temperature and immunity. Heat shock response is found in virtually all organisms, activating protective pathways when cells are exposed to elevated temperatures. However, the temperature threshold that activates these pathways can vary within the same organism, with human immune cells, in particular, demonstrating differential sensitivity to heat. Such inter-cellular variation may be clinically relevant given the small but significant temperature differences seen between tissues, ages, and sexes. Greater understanding of how such small temperature perturbations mediate immune responses may provide new explanations for persistent questions in disease such as sex disparity in disease prevalence. Notably, the prevalence and severity of many maladies are rising with climate change, suggesting temperature fluctuations can interact with disease on multiple levels. As global temperatures are rising, and our body temperatures are falling, questions regarding temperature-immune interactions are increasingly critical. Here, we review this aspect of environmental interplay to better understand temperature's role in immune variation and subsequent risk of disease.
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Affiliation(s)
- Elizabeth Maloney
- Translational Immunology Unit, Institut Pasteur, Université Paris Cité, Paris, France
- Frontiers of Innovation in Research and Education PhD Program, LPI Doctoral School, Paris, France
| | - Darragh Duffy
- Translational Immunology Unit, Institut Pasteur, Université Paris Cité, Paris, France
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13
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Borna Š, Lee E, Nideffer J, Ramachandran A, Wang B, Baker J, Mavers M, Lakshmanan U, Narula M, Garrett AKH, Schulze J, Olek S, Marois L, Gernez Y, Bhatia M, Chong HJ, Walter J, Kitcharoensakkul M, Lang A, Cooper MA, Bertaina A, Roncarolo MG, Meffre E, Bacchetta R. Identification of unstable regulatory and autoreactive effector T cells that are expanded in patients with FOXP3 mutations. Sci Transl Med 2023; 15:eadg6822. [PMID: 38117899 PMCID: PMC11070150 DOI: 10.1126/scitranslmed.adg6822] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 11/17/2023] [Indexed: 12/22/2023]
Abstract
Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (Tregs) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and Treg stability in vivo and compared T cell abnormalities in patients with IPEX with those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). To study Tregs independently of their phenotype and to analyze T cell autoreactivity, we combined Treg-specific demethylation region analyses, single-cell multiomic profiling, and bulk TCR sequencing. We found that patients with IPEX, unlike patients with APECED, have expanded autoreactive T cells originating from both autoreactive effector T cells (Teffs) and Tregs. In addition, a fraction of the expanded Tregs from patients with IPEX lost their phenotypic and functional markers, including CD25 and FOXP3. Functional experiments with CRISPR-Cas9-mediated FOXP3 knockout Tregs and Tregs from patients with IPEX indicated that the patients' Tregs gain a TH2-skewed Teff-like function, which is consistent with immune dysregulation observed in these patients. Analyses of FOXP3 mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation indicated that Tregs expressing nonmutated FOXP3 prevent the accumulation of autoreactive Teffs and unstable Tregs. These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.
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Affiliation(s)
- Šimon Borna
- Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Esmond Lee
- Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Jason Nideffer
- Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Akshaya Ramachandran
- Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Bing Wang
- Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Jeanette Baker
- Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Melissa Mavers
- Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Uma Lakshmanan
- Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Mansi Narula
- Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Amy Kang-hee Garrett
- Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | | | - Sven Olek
- Ivana Turbachova Laboratory for Epigenetics, Precision for Medicine GmbH, Berlin, 12489, Germany
| | - Louis Marois
- Department of Medicine, Immunology and Allergy Service, CHU de Québec – Laval University, Quebec, G1V 4G2, Canada
| | - Yael Gernez
- Department of Pediatrics, Division of Allergy, Rheumatology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Monica Bhatia
- Columbia University Irving Medical Center, NY, NY 10032, USA
| | - Hey Jin Chong
- Division of Allergy and Immunology, University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh, Pittsburgh, 15224, Pa, USA
| | - Jolan Walter
- Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins All Children’s Hospital, University of South Florida, St. Petersburg, 33701, FL, USA
| | - Maleewan Kitcharoensakkul
- Divisions of Rheumatology/Immunology, and Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University in St. Louis, St. Louis, Missouri, 63110, USA
| | - Abigail Lang
- Department of Pediatrics, Division of Allergy and Immunology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, 60611, USA
- Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
| | - Megan A. Cooper
- Department of pediatrics, division of Rheumatology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, 63110, USA
| | - Alice Bertaina
- Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Center for Definitive and Curative Medicine (CDCM), Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Maria Grazia Roncarolo
- Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Center for Definitive and Curative Medicine (CDCM), Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Eric Meffre
- Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, 269 Campus Drive West, Stanford, CA 94305, USA
| | - Rosa Bacchetta
- Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Center for Definitive and Curative Medicine (CDCM), Stanford University School of Medicine, Stanford, CA 94305, USA
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14
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Chang YH, Hsing CH, Chiu CJ, Wu YR, Hsu SM, Hsu YH. Protective role of IL-17-producing γδ T cells in a laser-induced choroidal neovascularization mouse model. J Neuroinflammation 2023; 20:279. [PMID: 38007487 PMCID: PMC10676594 DOI: 10.1186/s12974-023-02952-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 11/07/2023] [Indexed: 11/27/2023] Open
Abstract
BACKGROUND Vision loss in patients with wet/exudative age-related macular degeneration (AMD) is associated with choroidal neovascularization (CNV), and AMD is the leading cause of irreversible vision impairment in older adults. Interleukin-17A (IL-17A) is a component of the microenvironment associated with some autoimmune diseases. Previous studies have indicated that wet AMD patients have elevated serum IL-17A levels. However, the effect of IL-17A on AMD progression needs to be better understood. We aimed to investigate the role of IL-17A in a laser-induced CNV mouse model. METHODS We established a laser-induced CNV mouse model in wild-type (WT) and IL-17A-deficient mice and then evaluated the disease severity of these mice by using fluorescence angiography. We performed enzyme-linked immunosorbent assay (ELISA) and fluorescence-activated cell sorting (FACS) to analyze the levels of IL-17A and to investigate the immune cell populations in the eyes of WT and IL-17A-deficient mice. We used ARPE-19 cells to clarify the effect of IL-17A under oxidative stress. RESULTS In the laser-induced CNV model, the CNV lesions were larger in IL-17A-deficient mice than in WT mice. The numbers of γδ T cells, CD3+CD4+RORγt+ T cells, Treg cells, and neutrophils were decreased and the number of macrophages was increased in the eyes of IL-17A-deficient mice compared with WT mice. In WT mice, IL-17A-producing γδ T-cell numbers increased in a time-dependent manner from day 7 to 28 after laser injury. IL-6 levels increased and IL-10, IL-24, IL-17F, and GM-CSF levels decreased in the eyes of IL-17A-deficient mice after laser injury. In vitro, IL-17A inhibited apoptosis and induced the expression of the antioxidant protein HO-1 in ARPE-19 cells under oxidative stress conditions. IL-17A facilitated the repair of oxidative stress-induced barrier dysfunction in ARPE-19 cells. CONCLUSIONS Our findings provide new insight into the protective effect of IL-17A in a laser-induced CNV model and reveal a novel regulatory role of IL-17A-producing γδ T cells in the ocular microenvironment in wet AMD.
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Affiliation(s)
- Yu-Hsien Chang
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chung-Hsi Hsing
- Department of Anesthesiology, Chi Mei Medical Center, Tainan, Taiwan
- Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan
| | - Chiao-Juno Chiu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Rou Wu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Sheng-Min Hsu
- Department of Ophthalmology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Hsiang Hsu
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Antibody New Drug Research Center, National Cheng Kung University, Tainan, Taiwan.
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15
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Banerjee S, Nahar U, Dahiya D, Gupta R, Mukherjee S, Sachdeva N, Sood A, Dey P, Radotra B, Bhansali A. IL-17 A correlates with disease progression in papillary thyroid carcinoma. Diagn Pathol 2023; 18:93. [PMID: 37563607 PMCID: PMC10413719 DOI: 10.1186/s13000-023-01362-4] [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: 02/21/2023] [Accepted: 06/05/2023] [Indexed: 08/12/2023] Open
Abstract
BACKGROUND Cancer progression can be promoted by chronic inflammation. Local immune response may be associated with favourable or unfavourable prognosis of Papillary Thyroid Carcinoma (PTC). Regulatory T (Treg) cells and T helper 17 (Th17) cells exert opposing function and their balance may have a vital role in promotion of tumor growth. Treg cells in tumor microenvironment (TME) may promote tumor progression and reduced survival of patients. Whereas, Th17 cells can promote or inhibit tumor progression depending on phenotypic characteristics of tumor. In this study, we aimed to analyse the kind of immune response developed and its prognostic impact in future therapeutics. METHODS Cytometric Bead Array (CBA) analysis of pro and anti-inflammatory cytokines (IFN-gamma, IL-2, IL-6, IL-17 A, TNF-alpha and IL-4, IL-10) was done in 15 PTC irrespective of Lymphocytic Thyroiditis (LT) and 16 Hashimoto's Thyroiditis (HT) cases. Immunohistochemical expression of FoxP3 and IL-17 A was studied in 27 cases of PTC with LT. Whereas, quantitative gene expression of both was analysed in 10 cases. RESULTS All the pro-inflammatory cytokines showed mild elevation in PTC with LT. On IHC, IL-17 A expression was observed in 74% PTC with LT. Whereas, FoxP3 was present in only 40% cases. Also, IL-17 A expression was significantly associated with age group (> 45 years), tumor size ≤ 1 cm and disease progression. CONCLUSIONS Increased expression of cytokines suggested correlation between inflammatory factors and progression of thyroid tumors. Along with this, the balance between IL-17 A and FoxP3 may play an important role in PTC development, prognosis and future management.
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Affiliation(s)
- Sohini Banerjee
- Department of Histopathology, Post Graduate Institute of Medical Education and Research Chandigarh, 160012, Chandigarh, India
| | - Uma Nahar
- Department of Histopathology, Post Graduate Institute of Medical Education and Research Chandigarh, 160012, Chandigarh, India.
| | - Divya Dahiya
- Department of General Surgery, Post Graduate Institute of Medical Education and Research Chandigarh, 160012, Chandigarh, India
| | - Rijuneeta Gupta
- Department of Otolaryngology (ENT), Post Graduate Institute of Medical Education and Research Chandigarh, 160012, Chandigarh, India
| | - Soham Mukherjee
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research Chandigarh, 160012, Chandigarh, India
| | - Naresh Sachdeva
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research Chandigarh, 160012, Chandigarh, India
| | - Ashwani Sood
- Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India
| | - Pranab Dey
- Department of Cytology and Gynaecological Pathology, Post Graduate Institute of Medical Education and Research Chandigarh, 160012, Chandigarh, India
| | - Bishan Radotra
- Department of Histopathology, Post Graduate Institute of Medical Education and Research Chandigarh, 160012, Chandigarh, India
| | - Anil Bhansali
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research Chandigarh, 160012, Chandigarh, India
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16
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Čēma I, Kakar J, Dzudzilo M, Murovska M. Immunological Aspects of EBV and Oral Mucosa Interactions in Oral Lichen Planus. APPLIED SCIENCES 2023; 13:6735. [DOI: 10.3390/app13116735] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Oral lichen planus (OLP) is considered a T cell-mediated chronic inflammatory process activated by an unknown antigen, making basal keratinocytes vulnerable to a cytotoxic cell mediated immune response. The aim of this review is to summarize information on the role and pathways of Epstein–Barr virus (EBV) and immune cells in inducing OLP as an autoimmune lesion. The pathogenesis of OLP is analyzed from immunological aspects of interactions between EBV and oral mucosa. The results of the available studies allow us to assume that EBV can act both as an exogenous and an endogenous antigen in the pathogenesis of OLP. We emphasized the role of antigen-presenting cells (APC), such as dendritic cells (Langerhans cells, LC), in detecting and capturing antigens and modulating the adaptive immune response. Although EBV shows tropism for B cells and epithelial cells, under certain conditions it can infect monocytes, LCs, NK, and T lymphocytes. It means that under some circumstances of the chronic inflammatory process, EBV particles can react as endogenous agents. During the development of the autoimmune process, a decisive role is played by the loss of immune tolerance. Factors like the activity of cytokines, chemokines, and autoantibodies secreted by EBV-positive plasma cells, autoantigens formed due to virus protein mimicry of human proteins, new self-peptides released from damaged tissues, self-reactive B and T cells, dysregulation of LC function, the anti-apoptotic effect of EBV early lytic antigens, and an imbalance between inflammatory and anti-inflammatory immune cells facilitate the development of an autoimmune process.
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Affiliation(s)
- Ingrīda Čēma
- Department of Maxillo-Facial Surgery and Oral Medicine, Rīga Stradiņš University, 16 Dzirciema Str., LV-1007 Rīga, Latvia
| | - Jagriti Kakar
- Department of Maxillo-Facial Surgery and Oral Medicine, Rīga Stradiņš University, 16 Dzirciema Str., LV-1007 Rīga, Latvia
- Doctoral Study Department, Rīga Stradiņš University, 16 Dzirciema Str., LV-1007 Rīga, Latvia
| | - Madara Dzudzilo
- Department of Maxillo-Facial Surgery and Oral Medicine, Rīga Stradiņš University, 16 Dzirciema Str., LV-1007 Rīga, Latvia
| | - Modra Murovska
- Institute of Microbiology and Virology, Rīga Stradiņš University, 5 Rātsupītes Str., LV-1067 Rīga, Latvia
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17
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Piovani D, Brunetta E, Bonovas S. UV radiation and air pollution as drivers of major autoimmune conditions. ENVIRONMENTAL RESEARCH 2023; 224:115449. [PMID: 36764434 DOI: 10.1016/j.envres.2023.115449] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 01/18/2023] [Accepted: 02/07/2023] [Indexed: 06/18/2023]
Abstract
Autoimmune diseases comprise a very heterogeneous group of disorders characterized by disruptive immune responses against self-antigens, chronic morbidity and increased mortality. The incidence and prevalence of major autoimmune conditions are particularly high in the western world, at northern latitudes, and in industrialized countries. This study will mainly focus on five major autoimmune conditions, namely type 1 diabetes, multiple sclerosis, inflammatory bowel diseases, rheumatoid arthritis, and autoimmune thyroid disorders. Epidemiological and experimental evidence suggests a protective role of sunlight exposure on the etiology of major autoimmune conditions mediated by the endogenous production of vitamin D and nitric oxide. A historical perspective shows how the rise of anthropogenic air pollutants is temporally associated with dramatic increases in incidence of these conditions. The scattering caused by ambient particulate matter and the presence of tropospheric ozone can reduce the endogenous production of vitamin D and nitric oxide, which are implicated in maintaining the immune homeostasis. Air pollutants have direct detrimental effects on the human body and are deemed responsible of an increasingly higher portion of the annual burden of human morbidity and mortality. Air pollution contributes in systemic inflammation, activates oxidative pathways, induces epigenetic alterations, and modulates the function and phenotype of dendritic cells, Tregs, and T-cells. In this review, we provide epidemiological and mechanistic insights regarding the role of UV-mediated effects in immunity and how anthropic-derived air pollution may affect major autoimmune conditions through direct and indirect mechanisms.
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Affiliation(s)
- Daniele Piovani
- Department of Biomedical Sciences, Humanitas University, 20072, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, 20089, Rozzano, Milan, Italy.
| | - Enrico Brunetta
- Department of Biomedical Sciences, Humanitas University, 20072, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, 20089, Rozzano, Milan, Italy
| | - Stefanos Bonovas
- Department of Biomedical Sciences, Humanitas University, 20072, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, 20089, Rozzano, Milan, Italy
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Stroukov W, Mastronicola D, Albany CJ, Catak Z, Lombardi G, Scottà C. OMIP-090: A 20-parameter flow cytometry panel for rapid analysis of cell diversity and homing capacity in human conventional and regulatory T cells. Cytometry A 2023; 103:362-367. [PMID: 36740883 PMCID: PMC10952450 DOI: 10.1002/cyto.a.24720] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 01/11/2023] [Accepted: 01/21/2023] [Indexed: 02/07/2023]
Abstract
The panel was developed and optimized for monitoring changes in homing capacity and functional diversity of human CD4+ conventional and regulatory T cell subsets. The analysis was based on expression of only surface markers in freshly isolated peripheral blood mononuclear cells (PBMCs) to reduce at minimum any alteration due to permeabilization or freezing/thawing procedures. We included markers to assess the distribution of naïve and memory populations based on the expression of CD45RA, CCR7, CD25, CD28 and CD95 in both conventional and regulatory T cells. The identification of major functional subsets was performed using CCR4, CCR6, CCR10, CXCR3 and CXCR5. Homing capacity of these subsets to skin, airway tract, gut and inflammatory lesions could finally be assessed with the markers CLA, CCR3, CCR5 and integrin β7. The panel was tested on freshly isolated PBMCs from healthy donors and patients with allergic rhinitis or autoimmune disorders.
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Affiliation(s)
- Wladislaw Stroukov
- “Peter Gorer” Department of Immunobiology, School of Immunology & Microbiological SciencesKing's College LondonLondonUK
| | - Daniela Mastronicola
- “Peter Gorer” Department of Immunobiology, School of Immunology & Microbiological SciencesKing's College LondonLondonUK
| | - Caraugh Jane Albany
- “Peter Gorer” Department of Immunobiology, School of Immunology & Microbiological SciencesKing's College LondonLondonUK
- British Heart Foundation Centre, School of Cardiovascular Medicine and SciencesKing's College LondonLondonUK
| | - Zeynep Catak
- “Peter Gorer” Department of Immunobiology, School of Immunology & Microbiological SciencesKing's College LondonLondonUK
| | - Giovanna Lombardi
- “Peter Gorer” Department of Immunobiology, School of Immunology & Microbiological SciencesKing's College LondonLondonUK
| | - Cristiano Scottà
- “Peter Gorer” Department of Immunobiology, School of Immunology & Microbiological SciencesKing's College LondonLondonUK
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Ma X, Ma R, Zhang M, Qian B, Wang B, Yang W. Recent Progress in Multiple Sclerosis Treatment Using Immune Cells as Targets. Pharmaceutics 2023; 15:pharmaceutics15030728. [PMID: 36986586 PMCID: PMC10057470 DOI: 10.3390/pharmaceutics15030728] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 02/02/2023] [Accepted: 02/16/2023] [Indexed: 02/24/2023] Open
Abstract
Multiple sclerosis (MS) is an autoimmune-mediated demyelinating disease of the central nervous system. The main pathological features are inflammatory reaction, demyelination, axonal disintegration, reactive gliosis, etc. The etiology and pathogenesis of the disease have not been clarified. The initial studies believed that T cell-mediated cellular immunity is the key to the pathogenesis of MS. In recent years, more and more evidence has shown that B cells and their mediated humoral immune and innate immune cells (such as microglia, dendritic cells, macrophages, etc.) also play an important role in the pathogenesis of MS. This article mainly reviews the research progress of MS by targeting different immune cells and analyzes the action pathways of drugs. The types and mechanisms of immune cells related to the pathogenesis are introduced in detail, and the mechanisms of drugs targeting different immune cells are discussed in depth. This article aims to clarify the pathogenesis and immunotherapy pathway of MS, hoping to find new targets and strategies for the development of therapeutic drugs for MS.
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Affiliation(s)
- Xiaohong Ma
- Department of Neuroscience, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China
- The First Clinical Medical School, Henan University of Chinese Medicine, Zhengzhou 450046, China
| | - Rong Ma
- School of Pharmaceutical Sciences, Henan Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou University, Zhengzhou 450001, China
| | - Mengzhe Zhang
- School of Pharmaceutical Sciences, Henan Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou University, Zhengzhou 450001, China
| | - Baicheng Qian
- Department of Neuroscience, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China
| | - Baoliang Wang
- Department of Neuroscience, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China
- Correspondence: (B.W.); (W.Y.)
| | - Weijing Yang
- School of Pharmaceutical Sciences, Henan Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou University, Zhengzhou 450001, China
- Correspondence: (B.W.); (W.Y.)
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20
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Chen C, Wang Z, Ding Y, Qin Y. Tumor microenvironment-mediated immune evasion in hepatocellular carcinoma. Front Immunol 2023; 14:1133308. [PMID: 36845131 PMCID: PMC9950271 DOI: 10.3389/fimmu.2023.1133308] [Citation(s) in RCA: 108] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 02/02/2023] [Indexed: 02/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is the third leading cause of tumor-related mortality worldwide. In recent years, the emergency of immune checkpoint inhibitor (ICI) has revolutionized the management of HCC. Especially, the combination of atezolizumab (anti-PD1) and bevacizumab (anti-VEGF) has been approved by the FDA as the first-line treatment for advanced HCC. Despite great breakthrough in systemic therapy, HCC continues to portend a poor prognosis owing to drug resistance and frequent recurrence. The tumor microenvironment (TME) of HCC is a complex and structured mixture characterized by abnormal angiogenesis, chronic inflammation, and dysregulated extracellular matrix (ECM) remodeling, collectively contributing to the immunosuppressive milieu that in turn prompts HCC proliferation, invasion, and metastasis. The tumor microenvironment coexists and interacts with various immune cells to maintain the development of HCC. It is widely accepted that a dysfunctional tumor-immune ecosystem can lead to the failure of immune surveillance. The immunosuppressive TME is an external cause for immune evasion in HCC consisting of 1) immunosuppressive cells; 2) co-inhibitory signals; 3) soluble cytokines and signaling cascades; 4) metabolically hostile tumor microenvironment; 5) the gut microbiota that affects the immune microenvironment. Importantly, the effectiveness of immunotherapy largely depends on the tumor immune microenvironment (TIME). Also, the gut microbiota and metabolism profoundly affect the immune microenvironment. Understanding how TME affects HCC development and progression will contribute to better preventing HCC-specific immune evasion and overcoming resistance to already developed therapies. In this review, we mainly introduce immune evasion of HCC underlying the role of immune microenvironment, describe the dynamic interaction of immune microenvironment with dysfunctional metabolism and the gut microbiome, and propose therapeutic strategies to manipulate the TME in favor of more effective immunotherapy.
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Affiliation(s)
| | | | | | - Yanru Qin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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21
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Xu Y, Liang J, Gao W, Sun Y, Zhang Y, Shan F, Ge J, Xia Q. Peripheral blood cytokines as potential diagnostic biomarkers of suicidal ideation in patients with first-episode drug-naïve major depressive disorder. Front Public Health 2022; 10:1021309. [PMID: 36420006 PMCID: PMC9678225 DOI: 10.3389/fpubh.2022.1021309] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 10/24/2022] [Indexed: 11/09/2022] Open
Abstract
Objective Major Depressive Disorder (MDD) is a leading cause of disability, with a high risk of suicidal ideation (SI). Few studies have evaluated the potential of multiple cytokines as biomarkers for SI in patients with MDD. In the present study, we examined the serum levels of multiple cytokines in patients with first-episode drug-naïve MDD, with the aim to discover and identify serum cytokines-based biomarkers for identification of SI in MDD. Methods A total of 55 patients with first-episode drug-naïve MDD were enrolled and divided into two groups: 26 MDD patients without SI and 29 MDD patients with SI. Beck Scale for Suicide Ideation was used to estimate SI. A total of 37 cytokines were measured using Multiplex Luminex Assays. The levels of serum cytokines between MDD patients without SI and MDD patients with SI were compared and diagnostic values of different cytokines were evaluated using the receiver operating characteristic (ROC) curve method for discriminating MDD patients with SI from MDD patients without SI. The relationship between the group and the abnormal cytokines were investigated in multiple linear regression models, with adjustments for age, gender, BMI, smoking, and Hamilton Depression Rating Scale-24 (HAMD-24) scores. Results The levels of CCL26 and VEGF in MDD patients with SI were significantly lower than those in MDD patients without SI (all P < 0.05). On the contrary, the levels of IL-17C, CXCL10, and TNF-β in MDD patients with SI were significantly higher than those in MDD patients without SI (all P < 0.05). Moreover, the results of multiple linear regression revealed that group was a significant independent predictor of serum IL-17C, CCL-26, VEGF, and TNF-β levels (all P < 0.05). In terms of CXC10, group was also likely to be a significant independent predictor (β = 0.257, P = 0.063). Furthermore, the AUC values of IL-17C and TNF-β were 0.728 and 0.732, respectively. Additionally, a combined panel of IL-17C and TNF-β achieved a high accuracy in discriminating MDD patients with SI from MDD patients without SI (AUC = 0.848, sensitivity = 75.9%, specificity = 72.7%). Conclusions These results suggested that circulating IL-17C and TNF-β may hold promise in the discovery of biomarkers for identification of SI in MDD.
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Affiliation(s)
- Yayun Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, China,The Key Laboratory of Anti-Inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Jun Liang
- Affiliated Psychological Hospital of Anhui Medical University, Hefei, China,Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China,Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, China,Anhui Clinical Research Center for Mental Disorders, Hefei, China
| | - Wenfan Gao
- Affiliated Psychological Hospital of Anhui Medical University, Hefei, China,Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China,Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, China,Anhui Clinical Research Center for Mental Disorders, Hefei, China
| | - Yanhong Sun
- Affiliated Psychological Hospital of Anhui Medical University, Hefei, China,Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China,Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, China,Anhui Clinical Research Center for Mental Disorders, Hefei, China
| | - Yuanyuan Zhang
- Affiliated Psychological Hospital of Anhui Medical University, Hefei, China,Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China,Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, China,Anhui Clinical Research Center for Mental Disorders, Hefei, China
| | - Feng Shan
- Affiliated Psychological Hospital of Anhui Medical University, Hefei, China,Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China,Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, China,Anhui Clinical Research Center for Mental Disorders, Hefei, China
| | - Jinfang Ge
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, China,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Anhui Medical University, Hefei, China,School of Pharmacy, Anhui Medical University, Hefei, China,*Correspondence: Jinfang Ge
| | - Qingrong Xia
- Affiliated Psychological Hospital of Anhui Medical University, Hefei, China,Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China,Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, China,Anhui Clinical Research Center for Mental Disorders, Hefei, China,Qingrong Xia
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22
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Singh PK, Das S, Rai G, Ansari MA, Dar SA, Singh T, Pandhi D. A Snapshot of T Cell Subset Cytokines in Pemphigus Vulgaris: A Cross-Sectional Study. Cureus 2022; 14:e29890. [PMID: 36348826 PMCID: PMC9630798 DOI: 10.7759/cureus.29890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/02/2022] [Indexed: 11/07/2022] Open
Abstract
Objective: The purpose of this study was to assess the serum levels of cytokines produced by the Th1 (IFN‐γ, IL-12), Th2 (IL‐4), Th17 (IL-6, IL‐17A, IL‐23), and Treg (IL‐10 and TGF-β) pathways in individuals with active pemphigus vulgaris (PV) and to determine whether these levels were correlated with the severity of the disease condition. Patients and methods: This study was conducted with 90 individuals, of which 50 were PV patients and 40 healthy individuals (age and gender-matched) as controls. Serum samples were collected and tested for cytokine levels by ELISA (enzyme-linked immunosorbent assay). The cytokine levels in the serum of PV patients and healthy controls were compared statistically using the Mann-Whitney test for nonparametric samples. The strength of the association between the variables was evaluated using the Spearman correlation test. Results: The mean serum levels of IFN- γ (p < 0.001), IL-6 (p < 0.001), IL-10 (p < 0.001), IL-12 (p < 0.05), and IL-17 (p < 0.001) were significantly higher and TGF-β were significantly low in the PV patients than those observed in the control group. The mean concentration of serum IL-4 in patients with PV did not differ from those in the control group. Conclusions: In active PV, the Th1 and Th17 pathways are involved in the development and progression of the disease, whereas the Th2 pathway is blocked. Both of these pathways play a significant role in the disease. It is possible that the Treg pathway acts as an antagonist to the Th1 and Th17 pathways, which would cause the disease to become more localised. This study lays the foundation for a better understanding of the aetiology of PV and implies that cytokines could be used as potential therapeutic targets and disease activity biomarkers.
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De Lorenzo S, Tovoli F, Trevisani F. Mechanisms of Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Patients with Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:4616. [PMID: 36230538 PMCID: PMC9564277 DOI: 10.3390/cancers14194616] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 09/20/2022] [Accepted: 09/21/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver cancer and a relevant global health problem. Immune checkpoint inhibitors (ICIs) represent the most effective systemic treatment for HCC. However, due to primary resistance, approximately 40% of HCC patients do not achieve a disease control with ICIs. Moreover, a similar proportion will experience disease progression after an initial response caused by secondary resistance. This review describes the mechanisms of primary and secondary resistance and reports the ongoing therapeutic strategies to overcome these obstacles.
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Affiliation(s)
| | - Francesco Tovoli
- Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Franco Trevisani
- Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
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24
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Lu Y, Feng N, Du Y, Yu R. Nanoparticle-Based Therapeutics to Overcome Obstacles in the Tumor Microenvironment of Hepatocellular Carcinoma. NANOMATERIALS (BASEL, SWITZERLAND) 2022; 12:nano12162832. [PMID: 36014696 PMCID: PMC9414814 DOI: 10.3390/nano12162832] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 05/09/2023]
Abstract
Hepatocellular carcinoma (HCC) is still a main health concern around the world, with a rising incidence and high mortality rate. The tumor-promoting components of the tumor microenvironment (TME) play a vital role in the development and metastasis of HCC. TME-targeted therapies have recently drawn increasing interest in the treatment of HCC. However, the short medication retention time in TME limits the efficiency of TME modulating strategies. The nanoparticles can be elaborately designed as needed to specifically target the tumor-promoting components in TME. In this regard, the use of nanomedicine to modulate TME components by delivering drugs with protection and prolonged circulation time in a spatiotemporal manner has shown promising potential. In this review, we briefly introduce the obstacles of TME and highlight the updated information on nanoparticles that modulate these obstacles. Furthermore, the present challenges and future prospects of TME modulating nanomedicines will be briefly discussed.
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Affiliation(s)
- Yuanfei Lu
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou 310009, China
| | - Na Feng
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou 310009, China
| | - Yongzhong Du
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China
- Correspondence: (Y.D.); (R.Y.); Tel.: +86-571-88208435 (Y.D.); +86-571-87783925 (R.Y.)
| | - Risheng Yu
- Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou 310009, China
- Correspondence: (Y.D.); (R.Y.); Tel.: +86-571-88208435 (Y.D.); +86-571-87783925 (R.Y.)
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Qing J, Hu X, Li C, Song W, Tirichen H, Yaigoub H, Li Y. Fucose as a potential therapeutic molecule against the immune-mediated inflammation in IgA nepharopathy: An unrevealed link. Front Immunol 2022; 13:929138. [PMID: 36059518 PMCID: PMC9428610 DOI: 10.3389/fimmu.2022.929138] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/24/2022] [Indexed: 11/29/2022] Open
Abstract
Background IgA nephropathy (IgAN) is an autoimmune disease that affects people of any age and is an important cause of end-stage renal disease. However, the pathogenesis and pathophysiology of IgAN is not clear. This article aimed to explore the immune-mediated inflammation and genetic mechanisms in IgAN. Methods The transcriptome sequencing data of IgAN glomeruli in the Gene Expression Omnibus database were downloaded. Single-sample gene set enrichment analysis was used to estimate the immune microenvironment of the merged microarray data and GSE141295. IgAN samples were divided into two clusters by cluster analysis. “limma” and “DEseq2” package in R were used to identify differentially expressed genes (DEGs). The weighted gene co-expression network analysis (WGCNA) was used to identify the co-expression modules related to inflammation in IgAN. R software package “clusterProfiler” was used for enrichment analysis, whereas Short Time-Series Expression Miner (STEM) analysis was used to identify the trend of gene expression. Machine-learn (ML) was performed using the shiny app. Finally, Drug Signatures Database (DSigDB) was used to identify potential molecules for treating IgAN. Results The infiltration of macrophages in IgAN glomeruli was increased, whereas CD4+ T cells, especially inducedregulatory T cells (iTregs) were decreased. A total of 1,104 common DEGs were identified from the merged data and GSE141295. Brown module was identified to have the highest inflammatory correlation with IgAN using WGCNA, and 15 hub genes were screened from this module. Among these 15 hub genes, 14 increased with the severity of IgAN inflammation based on STEM analysis. Neural network (nnet) is considered as the best model to predict the severity of IgAN. Fucose identified from DSigDB has a potential biological activity to treat IgAN. Conclusion The increase of macrophages and the decrease of iTregs in glomeruli represent the immune-mediated inflammation of IgAN, and fucose may be a potential therapeutic molecule against IgAN because it affects genes involved in the severe inflammation of IgAN.
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Affiliation(s)
- Jianbo Qing
- The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, China
- Department of Nephrology, Shanxi Provincial People’s Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China
| | - Xueli Hu
- School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Changqun Li
- The Fifth Clinical Medical College of Shanxi Medical University, Taiyuan, China
| | - Wenzhu Song
- School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Hasna Tirichen
- Institutes of Biomedical Sciences, Shanxi University, Taiyuan, China
| | - Hasnaa Yaigoub
- Institutes of Biomedical Sciences, Shanxi University, Taiyuan, China
| | - Yafeng Li
- Department of Nephrology, Shanxi Provincial People’s Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China
- Core Laboratory , Shanxi Provincial People’s Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China
- Shanxi Provincial Key Laboratory of Kidney Disease, Taiyuan, China
- Academy of Microbial Ecology, Shanxi Medical University, Taiyuan, China
- *Correspondence: Yafeng Li,
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Sukri A, Hanafiah A, Kosai NR. The Roles of Immune Cells in Gastric Cancer: Anti-Cancer or Pro-Cancer? Cancers (Basel) 2022; 14:cancers14163922. [PMID: 36010915 PMCID: PMC9406374 DOI: 10.3390/cancers14163922] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 08/05/2022] [Accepted: 08/07/2022] [Indexed: 12/03/2022] Open
Abstract
Simple Summary Gastric cancer is still one of the leading causes of death caused by cancer in developing countries. The emerging role of immunotherapy in cancer treatment has led to more research to elucidate the roles of essential immune cells in gastric cancer prognosis. We reviewed the roles of immune cells including T cells, B cells, dendritic cells, macrophages and natural killer cells in gastric cancer. Although the studies conducted on the roles of immune cells in gastric cancer pathogenesis produced conflicting results, understanding the roles of immune cells in gastric cancer will help us to harness them for application in immunotherapy for better prognosis and management of gastric cancer patients. Abstract Despite the fact that the incidence of gastric cancer has declined over the last decade, it is still the world’s leading cause of cancer-related death. The diagnosis of early gastric cancer is difficult, as symptoms of this cancer only manifest at a late stage of cancer progression. Thus, the prognosis of gastric cancer is poor, and the current treatment for improving patients’ outcomes involves the application of surgery and chemotherapy. Immunotherapy is one of the most recent therapies for gastric cancer, whereby the immune system of the host is programmed to combat cancer cells, and the therapy differs based upon the patient’s immune system. However, an understanding of the role of immune cells, namely the cell-mediated immune response and the humoral immune response, is pertinent for applications of immunotherapy. The roles of immune cells in the prognosis of gastric cancer have yielded conflicting results. This review discusses the roles of immune cells in gastric cancer pathogenesis, specifically, T cells, B cells, macrophages, natural killer cells, and dendritic cells, as well as the evidence presented thus far. Understanding how cancer cells interact with immune cells is of paramount importance in designing treatment options for gastric cancer immunotherapy.
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Affiliation(s)
- Asif Sukri
- Integrative Pharmacogenomics Institute (iPROMISE), Universiti Teknologi MARA (UiTM), Bandar Puncak Alam, Shah Alam 43200, Malaysia
| | - Alfizah Hanafiah
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
- Correspondence:
| | - Nik Ritza Kosai
- Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
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Ruan S, Huang Y, He M, Gao H. Advanced Biomaterials for Cell-Specific Modulation and Restore of Cancer Immunotherapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2200027. [PMID: 35343112 PMCID: PMC9165523 DOI: 10.1002/advs.202200027] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 02/18/2022] [Indexed: 05/09/2023]
Abstract
The past decade has witnessed the explosive development of cancer immunotherapies. Nevertheless, low immunogenicity, limited specificity, poor delivery efficiency, and off-target side effects remain to be the major limitations for broad implementation of cancer immunotherapies to patient bedside. Encouragingly, advanced biomaterials offering cell-specific modulation of immunological cues bring new solutions for improving the therapeutic efficacy while relieving side effect risks. In this review, focus is given on how functional biomaterials can enable cell-specific modulation of cancer immunotherapy within the cancer-immune cycle, with particular emphasis on antigen-presenting cells (APCs), T cells, and tumor microenvironment (TME)-resident cells. By reviewing the current progress in biomaterial-based cancer immunotherapy, here the aim is to provide a better understanding of biomaterials' role in targeting modulation of antitumor immunity step-by-step and guidelines for rationally developing targeting biomaterials for more personalized cancer immunotherapy. Moreover, the current challenge and future perspective regarding the potential application and clinical translation will also be discussed.
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Affiliation(s)
- Shaobo Ruan
- Advanced Research Institute of Multidisciplinary ScienceBeijing Institute of TechnologyBeijing100081China
| | - Yuanyu Huang
- Advanced Research Institute of Multidisciplinary ScienceBeijing Institute of TechnologyBeijing100081China
| | - Mei He
- College of PharmacyUniversity of FloridaGainesvilleFL32610USA
| | - Huile Gao
- West China School of PharmacySichuan UniversityChengdu610041China
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Bilvayeh S, Mortazavi SH, Salari F, Gorginkaraji A. Glucocorticoids Decreased GATA-3 Expression but Increased FOXP3 Expression in Allergic Rhinitis Patients. TURKISH JOURNAL OF IMMUNOLOGY 2022. [DOI: 10.4274/tji.galenos.2022.35220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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29
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Unleashing cell-penetrating peptide applications for immunotherapy. Trends Mol Med 2022; 28:482-496. [DOI: 10.1016/j.molmed.2022.03.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 03/24/2022] [Accepted: 03/25/2022] [Indexed: 12/31/2022]
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30
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Karimi E, Azari H, Tahmasebi A, Nikpoor AR, Negahi AA, Sanadgol N, Shekari M, Mousavi P. LncRNA-miRNA network analysis across the Th17 cell line reveals biomarker potency of lncRNA NEAT1 and KCNQ1OT1 in multiple sclerosis. J Cell Mol Med 2022; 26:2351-2362. [PMID: 35266286 PMCID: PMC8995444 DOI: 10.1111/jcmm.17256] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 02/08/2022] [Accepted: 02/12/2022] [Indexed: 12/11/2022] Open
Abstract
Differentiation of CD4+ T cells into Th17 cells is an important factor in the onset and progression of multiple sclerosis (MS) and Th17/Treg imbalance. Little is known about the role of lncRNAs in the differentiation of CD4+ cells from Th17 cells. This study aimed to analyse the lncRNA‐miRNAs network involved in MS disease and its role in the differentiation of Th17 cells. The lncRNAs in Th17 differentiation were obtained from GSE66261 using the GEO datasets. Differential expression of lncRNAs in Th17 primary cells compared to Th17 effector cells was investigated by RNA‐seq analysis. Next, the most highlighted lncRNAs in autoimmune diseases were downloaded from the lncRNAs disease database, and the most critical miRNA was extracted by literature search. Then, the lncRNA‐miRNA interaction was achieved by the Starbase database, and the ceRNA network was designed by Cytoscape. Finally, using the CytoHubba application, two hub lncRNAs with the most interactions with miRNAs were identified by the MCODE plug‐in. The expression level of genes was measured by qPCR, and the plasma level of cytokines was analysed by ELISA kits. The results showed an increase in the expression of NEAT1, KCNQ1OT1 and RORC and a decrease in the expression of FOXP3. In plasma, an upregulation of IL17 and a downregulation of TGFB inflammatory cytokines were detected. The dysregulated expression of these genes could be attributed to relapsing‐remitting MS (RR‐MS) patients and help us understand MS pathogenesis better.
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Affiliation(s)
- Elham Karimi
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Hanieh Azari
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | | | - Amin Reza Nikpoor
- Sciences Research Center for Molecular Medicine, Hormozgan University of Medical, Hormozgan, Iran
| | - Ahmad Agha Negahi
- Department of Internal Medicine, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Nima Sanadgol
- Institute of Neuroanatomy, RWTH University Hospital Aachen, Aachen, Germany
| | - Mohammad Shekari
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.,Sciences Research Center for Molecular Medicine, Hormozgan University of Medical, Hormozgan, Iran
| | - Pegah Mousavi
- Department of Medical Genetics, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.,Sciences Research Center for Molecular Medicine, Hormozgan University of Medical, Hormozgan, Iran
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31
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Purohit V, Wagner A, Yosef N, Kuchroo VK. Systems-based approaches to study immunometabolism. Cell Mol Immunol 2022; 19:409-420. [PMID: 35121805 PMCID: PMC8891302 DOI: 10.1038/s41423-021-00783-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 09/17/2021] [Indexed: 02/06/2023] Open
Abstract
Technical advances at the interface of biology and computation, such as single-cell RNA-sequencing (scRNA-seq), reveal new layers of complexity in cellular systems. An emerging area of investigation using the systems biology approach is the study of the metabolism of immune cells. The diverse spectra of immune cell phenotypes, sparsity of immune cell numbers in vivo, limitations in the number of metabolites identified, dynamic nature of cellular metabolism and metabolic fluxes, tissue specificity, and high dependence on the local milieu make investigations in immunometabolism challenging, especially at the single-cell level. In this review, we define the systemic nature of immunometabolism, summarize cell- and system-based approaches, and introduce mathematical modeling approaches for systems interrogation of metabolic changes in immune cells. We close the review by discussing the applications and shortcomings of metabolic modeling techniques. With systems-oriented studies of metabolism expected to become a mainstay of immunological research, an understanding of current approaches toward systems immunometabolism will help investigators make the best use of current resources and push the boundaries of the discipline.
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Affiliation(s)
- Vinee Purohit
- Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
| | - Allon Wagner
- Department of Electrical Engineering and Computer Science, University of California, Berkeley, CA, 94720, USA
- Center for Computational Biology, University of California, Berkeley, CA, 94720, USA
| | - Nir Yosef
- Department of Electrical Engineering and Computer Science, University of California, Berkeley, CA, 94720, USA
- Center for Computational Biology, University of California, Berkeley, CA, 94720, USA
| | - Vijay K Kuchroo
- Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
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32
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Qin Y, Gao C, Luo J. Metabolism Characteristics of Th17 and Regulatory T Cells in Autoimmune Diseases. Front Immunol 2022; 13:828191. [PMID: 35281063 PMCID: PMC8913504 DOI: 10.3389/fimmu.2022.828191] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 02/07/2022] [Indexed: 12/12/2022] Open
Abstract
The abnormal number and functional deficiency of immune cells are the pathological basis of various diseases. Recent years, the imbalance of Th17/regulatory T (Treg) cell underlies the occurrence and development of inflammation in autoimmune diseases (AID). Currently, studies have shown that material and energy metabolism is essential for maintaining cell survival and normal functions and the altered metabolic state of immune cells exists in a variety of AID. This review summarizes the biology and functions of Th17 and Treg cells in AID, with emphasis on the advances of the roles and regulatory mechanisms of energy metabolism in activation, differentiation and physiological function of Th17 and Treg cells, which will facilitate to provide targets for the treatment of immune-mediated diseases.
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Affiliation(s)
- Yan Qin
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Chong Gao
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Jing Luo
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
- *Correspondence: Jing Luo,
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33
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Cyanidin restores Th17/Treg balance and inhibits T follicular helper cell differentiation via modulation of ROCK2 signaling in an experimental model of rheumatoid arthritis. Int Immunopharmacol 2021; 101:108359. [PMID: 34863656 DOI: 10.1016/j.intimp.2021.108359] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 10/10/2021] [Accepted: 11/07/2021] [Indexed: 01/02/2023]
Abstract
Disturbed Th17/Treg balance is a critical pathological event in the disease progression of rheumatoid arthritis (RA). Recently, emerging studies have demonstrated that CD4 + T helper follicular (Tfh) cells exacerbates the pathogenic manifestations of RA. Contrarily, our previous report has shown that cyanidin, a flavonoid compound, attenuates disease severity of RA. Howbeit, this study investigated the therapeutic efficacy of cyanidin in relation to Th17/Treg balance and pathogenic Tfh cells in RA. Onto results, cyanidin inhibited increased Th17 cell differentiation and reciprocally improved FoxP3 + Treg cells both in-vivo and in-vitro. Concomitantly, cyanidin abated the detrimental effects of IL-17 via restoration of IL-10 secretion in adjuvant induced arthritic (AIA) rats. Furthermore, cyanidin reduced Tfh cells proportion and IgG levels in AIA rats, thus rectifying Tfh and follicular regulatory T (Tfr) cell ratio. Mechanistically, the restoring effect of cyanidin was associated with blunted activation of ROCK2/STAT3 signaling axis and reciprocal increase in the level of STAT-5 activity. Notwithstanding, cyanidin therapeutic efficacy correlated with specific oral ROCK2 inhibitor KD025 in-vitro. Collectively, these results demonstrate a dual promising therapeutic role of cyanidin via regulating Th17/Treg ratio and Tfh cell differentiation in an experimental model of RA.
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34
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Prado DS, Cattley RT, Shipman CW, Happe C, Lee M, Boggess WC, MacDonald ML, Hawse WF. Synergistic and additive interactions between receptor signaling networks drive the regulatory T cell versus T helper 17 cell fate choice. J Biol Chem 2021; 297:101330. [PMID: 34688667 PMCID: PMC8645459 DOI: 10.1016/j.jbc.2021.101330] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 10/09/2021] [Accepted: 10/11/2021] [Indexed: 12/04/2022] Open
Abstract
CD4+ T cells differentiate into subsets that promote immunity or minimize damage to the host. T helper 17 cells (Th17) are effector cells that function in inflammatory responses. T regulatory cells (Tregs) maintain tolerance and prevent autoimmunity by secreting immunosuppressive cytokines and expressing check point receptors. While the functions of Th17 and Treg cells are different, both cell fate trajectories require T cell receptor (TCR) and TGF-β receptor (TGF-βR) signals, and Th17 polarization requires an additional IL-6 receptor (IL-6R) signal. Utilizing high-resolution phosphoproteomics, we identified that both synergistic and additive interactions between TCR, TGF-βR, and IL-6R shape kinase signaling networks to differentially regulate key pathways during the early phase of Treg versus Th17 induction. Quantitative biochemical analysis revealed that CD4+ T cells integrate receptor signals via SMAD3, which is a mediator of TGF-βR signaling. Treg induction potentiates the formation of the canonical SMAD3/4 trimer to activate a negative feedback loop through kinases PKA and CSK to suppress TCR signaling, phosphatidylinositol metabolism, and mTOR signaling. IL-6R signaling activates STAT3 to bind SMAD3 and block formation of the SMAD3/4 trimer during the early phase of Th17 induction, which leads to elevated TCR and PI3K signaling. These data provide a biochemical mechanism by which CD4+ T cells integrate TCR, TGF-β, and IL-6 signals via generation of alternate SMAD3 complexes that control the development of early signaling networks to potentiate the choice of Treg versus Th17 cell fate.
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Affiliation(s)
- Douglas S Prado
- Department of Immunology and Center for Systems Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Richard T Cattley
- Department of Immunology and Center for Systems Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Corey W Shipman
- Department of Immunology and Center for Systems Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Cassandra Happe
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Mijoon Lee
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA
| | - William C Boggess
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA
| | - Matthew L MacDonald
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - William F Hawse
- Department of Immunology and Center for Systems Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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35
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Sakai K, Sakurai T, De Velasco MA, Nagai T, Chikugo T, Ueshima K, Kura Y, Takahama T, Hayashi H, Nakagawa K, Kudo M, Nishio K. Intestinal Microbiota and Gene Expression Reveal Similarity and Dissimilarity Between Immune-Mediated Colitis and Ulcerative Colitis. Front Oncol 2021; 11:763468. [PMID: 34778085 PMCID: PMC8578892 DOI: 10.3389/fonc.2021.763468] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 10/11/2021] [Indexed: 12/30/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) have become the standard of care for several cancers. However, ICI therapy has also been associated with various immune-related adverse events (irAEs). Clinical manifestations of immune-related colitis resemble those of inflammatory bowel diseases such as ulcerative colitis (UC). The composition of the bowel microflora is thought to influence the development of inflammatory bowel disease and irAE colitis. We profiled the gene expressions and microbe compositions of colonic mucosa from patients with solid cancers receiving anti-PD-L1 antibody treatment; we then compared the expression profiles associated with irAE colitis with those associated with UC. The pathway enrichment analysis revealed functional similarities between inflamed regions of irAE colitis and UC. The common enriched pathways included leukocyte extravasation and immune responses, whereas non-inflamed mucosa from patients with irAE colitis was distinct from patients with UC and was characterized by the recruitment of immune cells. A similarity between the microbiota profiles was also identified. A decreased abundance of Bacteroides species was observed in inflamed regions from both irAE colitis and UC based on a microbiota composition analysis of 16S rDNA sequencing. Pathways associated with molecule transport systems, including fatty acids, were enriched in inflamed and non-inflamed irAE colitis and inflamed UC, similar to Piphillin-inferred KEGG pathways. While UC is characterized by local regions of inflammation, ICI treatment extends to non-inflammatory regions of the colonial mucosa where immune cells are reconstituted. This analysis of the similarity and heterogeneity of irAE colitis and UC provides important information for the management of irAE colitis.
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Affiliation(s)
- Kazuko Sakai
- Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Toshiharu Sakurai
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Marco A De Velasco
- Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Tomoyuki Nagai
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Takaaki Chikugo
- Department of Diagnostic Pathology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Kazuomi Ueshima
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Yurie Kura
- Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Takayuki Takahama
- Department of Medical Oncology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Hidetoshi Hayashi
- Department of Medical Oncology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Kazuhiko Nakagawa
- Department of Medical Oncology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Kazuto Nishio
- Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka, Japan
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36
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Xue W, Li JJ, Zou Y, Zou B, Wei L. Microbiota and Ocular Diseases. Front Cell Infect Microbiol 2021; 11:759333. [PMID: 34746029 PMCID: PMC8566696 DOI: 10.3389/fcimb.2021.759333] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 10/06/2021] [Indexed: 12/12/2022] Open
Abstract
Recent advances have identified significant associations between the composition and function of the gut microbiota and various disorders in organ systems other than the digestive tract. Utilizing next-generation sequencing and multiomics approaches, the microbial community that possibly impacts ocular disease has been identified. This review provides an overview of the literature on approaches to microbiota analysis and the roles of commensal microbes in ophthalmic diseases, including autoimmune uveitis, age-related macular degeneration, glaucoma, and other ocular disorders. In addition, this review discusses the hypothesis of the "gut-eye axis" and evaluates the therapeutic potential of targeting commensal microbiota to alleviate ocular inflammation.
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Affiliation(s)
- Wei Xue
- State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China
| | - Jing Jing Li
- State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China
| | - Yanli Zou
- State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China.,Department of Ophthalmology, Affiliated Foshan Hospital, Southern Medical University, Foshan, China
| | - Bin Zou
- State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China
| | - Lai Wei
- State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou, China
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37
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Bentley ER, Little SR. Local delivery strategies to restore immune homeostasis in the context of inflammation. Adv Drug Deliv Rev 2021; 178:113971. [PMID: 34530013 PMCID: PMC8556365 DOI: 10.1016/j.addr.2021.113971] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 09/05/2021] [Accepted: 09/07/2021] [Indexed: 12/13/2022]
Abstract
Immune homeostasis is maintained by a precise balance between effector immune cells and regulatory immune cells. Chronic deviations from immune homeostasis, driven by a greater ratio of effector to regulatory cues, can promote the development and propagation of inflammatory diseases/conditions (i.e., autoimmune diseases, transplant rejection, etc.). Current methods to treat chronic inflammation rely upon systemic administration of non-specific small molecules, resulting in broad immunosuppression with unwanted side effects. Consequently, recent studies have developed more localized and specific immunomodulatory approaches to treat inflammation through the use of local biomaterial-based delivery systems. In particular, this review focuses on (1) local biomaterial-based delivery systems, (2) common materials used for polymeric-delivery systems and (3) emerging immunomodulatory trends used to treat inflammation with increased specificity.
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Affiliation(s)
- Elizabeth R Bentley
- Department of Bioengineering, University of Pittsburgh, 302 Benedum Hall, 3700 O'Hara Street, Pittsburgh, PA 15260, United States.
| | - Steven R Little
- Department of Bioengineering, University of Pittsburgh, 302 Benedum Hall, 3700 O'Hara Street, Pittsburgh, PA 15260, United States; Department of Chemical Engineering, University of Pittsburgh, 940 Benedum Hall, 3700 O'Hara Street, Pittsburgh, PA 15213, United States; Department of Clinical and Translational Science, University of Pittsburgh, Forbes Tower, Suite 7057, Pittsburgh, PA 15213, United States; McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive, Suite 300, Pittsburgh, PA 15219, United States; Department of Immunology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, United States; Department of Pharmaceutical Sciences, University of Pittsburgh, 3501 Terrace Street, Pittsburgh, PA 15213, United States; Department of Ophthalmology, University of Pittsburgh, 203 Lothrop Street, Pittsburgh, PA 15213, United States.
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38
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Pessoa Rodrigues C, Chatterjee A, Wiese M, Stehle T, Szymanski W, Shvedunova M, Akhtar A. Histone H4 lysine 16 acetylation controls central carbon metabolism and diet-induced obesity in mice. Nat Commun 2021; 12:6212. [PMID: 34707105 PMCID: PMC8551339 DOI: 10.1038/s41467-021-26277-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 09/21/2021] [Indexed: 12/26/2022] Open
Abstract
Noncommunicable diseases (NCDs) account for over 70% of deaths world-wide. Previous work has linked NCDs such as type 2 diabetes (T2D) to disruption of chromatin regulators. However, the exact molecular origins of these chronic conditions remain elusive. Here, we identify the H4 lysine 16 acetyltransferase MOF as a critical regulator of central carbon metabolism. High-throughput metabolomics unveil a systemic amino acid and carbohydrate imbalance in Mof deficient mice, manifesting in T2D predisposition. Oral glucose tolerance testing (OGTT) reveals defects in glucose assimilation and insulin secretion in these animals. Furthermore, Mof deficient mice are resistant to diet-induced fat gain due to defects in glucose uptake in adipose tissue. MOF-mediated H4K16ac deposition controls expression of the master regulator of glucose metabolism, Pparg and the entire downstream transcriptional network. Glucose uptake and lipid storage can be reconstituted in MOF-depleted adipocytes in vitro by ectopic Glut4 expression, PPARγ agonist thiazolidinedione (TZD) treatment or SIRT1 inhibition. Hence, chronic imbalance in H4K16ac promotes a destabilisation of metabolism triggering the development of a metabolic disorder, and its maintenance provides an unprecedented regulatory epigenetic mechanism controlling diet-induced obesity.
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Affiliation(s)
- Cecilia Pessoa Rodrigues
- Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, 79108, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Schaenzlestrasse 1, 79104, Freiburg, Germany
- International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB), Freiburg, Germany
| | - Aindrila Chatterjee
- Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, 79108, Freiburg, Germany
- European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117, Heidelberg, Germany
| | - Meike Wiese
- Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, 79108, Freiburg, Germany
| | - Thomas Stehle
- Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, 79108, Freiburg, Germany
| | - Witold Szymanski
- Proteomics Facility, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Maria Shvedunova
- Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, 79108, Freiburg, Germany
| | - Asifa Akhtar
- Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, 79108, Freiburg, Germany.
- Faculty of Biology, University of Freiburg, Schaenzlestrasse 1, 79104, Freiburg, Germany.
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39
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Fratzke AP, Gregory AE, van Schaik EJ, Samuel JE. Coxiella burnetii Whole Cell Vaccine Produces a Th1 Delayed-Type Hypersensitivity Response in a Novel Sensitized Mouse Model. Front Immunol 2021; 12:754712. [PMID: 34616410 PMCID: PMC8488435 DOI: 10.3389/fimmu.2021.754712] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 09/06/2021] [Indexed: 12/22/2022] Open
Abstract
Q-VAX®, a whole cell, formalin-inactivated vaccine, is the only vaccine licensed for human use to protect against Coxiella burnetii, the cause of Q fever. Although this vaccine provides long-term protection, local and systemic reactogenic responses are common in previously sensitized individuals which prevents its use outside of Australia. Despite the importance of preventing these adverse reactions to develop widely accepted, novel vaccines against C. burnetii, little is understood about the underlying cellular mechanisms. This is mostly attributed to the use of a guinea pig reactogenicity model where complex cellular analysis is limited. To address this, we compared three different mouse strains develop a model of C. burnetii whole cell vaccine reactogenic responses. SKH1 and C57Bl/6, but not BALBc mice, develop local granulomatous reactions after either infection- or vaccine-induced sensitization. We evaluated local and systemic responses by measuring T cell populations from the vaccination site and spleen during elicitation using flow cytometry. Local reaction sites showed influx of IFNγ+ and IL17a+ CD4 T cells in sensitized mice compared with controls and a reduction in IL4+ CD4 T cells. Additionally, sensitized mice showed a systemic response to elicitation by an increase in IFNγ+ and IL17a+ CD4 T cells in the spleen. These results indicate that local and systemic C. burnetii reactogenic responses are consistent with a Th1 delayed-type hypersensitivity. Our experiments provide insights into the pathophysiology of C. burnetii whole cell vaccine reactogenicity and demonstrate that C57Bl/6 and SKH1 mice can provide a valuable model for evaluating the reactogenicity of novel C. burnetii vaccine candidates.
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Affiliation(s)
- Alycia P. Fratzke
- Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, United States
- Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University, Bryan, TX, United States
| | - Anthony E. Gregory
- Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University, Bryan, TX, United States
- Department of Physiology & Biophysics, School of Medicine, University of California Irvine, Irvine, CA, United States
| | - Erin J. van Schaik
- Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University, Bryan, TX, United States
| | - James E. Samuel
- Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, United States
- Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University, Bryan, TX, United States
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40
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Wagner A, Wang C, Fessler J, DeTomaso D, Avila-Pacheco J, Kaminski J, Zaghouani S, Christian E, Thakore P, Schellhaass B, Akama-Garren E, Pierce K, Singh V, Ron-Harel N, Douglas VP, Bod L, Schnell A, Puleston D, Sobel RA, Haigis M, Pearce EL, Soleimani M, Clish C, Regev A, Kuchroo VK, Yosef N. Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. Cell 2021; 184:4168-4185.e21. [PMID: 34216539 PMCID: PMC8621950 DOI: 10.1016/j.cell.2021.05.045] [Citation(s) in RCA: 276] [Impact Index Per Article: 69.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 02/15/2021] [Accepted: 05/27/2021] [Indexed: 12/11/2022]
Abstract
Metabolism is a major regulator of immune cell function, but it remains difficult to study the metabolic status of individual cells. Here, we present Compass, an algorithm to characterize cellular metabolic states based on single-cell RNA sequencing and flux balance analysis. We applied Compass to associate metabolic states with T helper 17 (Th17) functional variability (pathogenic potential) and recovered a metabolic switch between glycolysis and fatty acid oxidation, akin to known Th17/regulatory T cell (Treg) differences, which we validated by metabolic assays. Compass also predicted that Th17 pathogenicity was associated with arginine and downstream polyamine metabolism. Indeed, polyamine-related enzyme expression was enhanced in pathogenic Th17 and suppressed in Treg cells. Chemical and genetic perturbation of polyamine metabolism inhibited Th17 cytokines, promoted Foxp3 expression, and remodeled the transcriptome and epigenome of Th17 cells toward a Treg-like state. In vivo perturbations of the polyamine pathway altered the phenotype of encephalitogenic T cells and attenuated tissue inflammation in CNS autoimmunity.
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Affiliation(s)
- Allon Wagner
- Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA 94720, USA; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Chao Wang
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada.
| | - Johannes Fessler
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA
| | - David DeTomaso
- Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA
| | | | - James Kaminski
- Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Sarah Zaghouani
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Elena Christian
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | | | - Brandon Schellhaass
- Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA 94720, USA
| | - Elliot Akama-Garren
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Kerry Pierce
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | | | - Noga Ron-Harel
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Biology, Technion, Israel Institute of Technology, Haifa 3200003, Israel
| | - Vivian Paraskevi Douglas
- Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA
| | - Lloyd Bod
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Alexandra Schnell
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Daniel Puleston
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany
| | - Raymond A Sobel
- Palo Alto Veteran's Administration Health Care System and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Marcia Haigis
- Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA
| | - Erika L Pearce
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany
| | - Manoocher Soleimani
- Department of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87121, USA
| | - Clary Clish
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Aviv Regev
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02140, USA
| | - Vijay K Kuchroo
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
| | - Nir Yosef
- Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA 94720, USA; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Chan-Zuckerberg Biohub, San Francisco, CA 94158, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
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Lotfy A, Elgamal A, Burdzinska A, Swelum AA, Soliman R, Hassan AA, Shiha G. Stem cell therapies for autoimmune hepatitis. Stem Cell Res Ther 2021; 12:386. [PMID: 34233726 PMCID: PMC8262021 DOI: 10.1186/s13287-021-02464-w] [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: 04/09/2021] [Accepted: 05/14/2021] [Indexed: 12/12/2022] Open
Abstract
Autoimmune hepatitis is a chronic inflammatory hepatic disorder which may cause liver fibrosis. Appropriate treatment of autoimmune hepatitis is therefore important. Adult stem cells have been investigated as therapies for a variety of disorders in latest years. Hematopoietic stem cells (HSCs) were the first known adult stem cells (ASCs) and can give rise to all of the cell types in the blood and immune system. Originally, HSC transplantation was served as a therapy for hematological malignancies, but more recently researchers have found the treatment to have positive effects in autoimmune diseases such as multiple sclerosis. Mesenchymal stem cells (MSCs) are ASCs which can be extracted from different tissues, such as bone marrow, adipose tissue, umbilical cord, and dental pulp. MSCs interact with several immune response pathways either by direct cell-to-cell interactions or by the secretion of soluble factors. These characteristics make MSCs potentially valuable as a therapy for autoimmune diseases. Both ASC and ASC-derived exosomes have been investigated as a therapy for autoimmune hepatitis. This review aims to summarize studies focused on the effects of ASCs and their products on autoimmune hepatitis.
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Affiliation(s)
- Ahmed Lotfy
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, Beni-Suef, 62511, Egypt.
| | - Aya Elgamal
- Department of Animal Histology and Anatomy, Faculty of Veterinary Medicine, Badr University in Cairo (BUC), Cairo, Egypt
| | - Anna Burdzinska
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006, Warsaw, Poland
| | - Ayman A Swelum
- Department of Theriogenology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44511, Egypt
- Department of Animal Production, College of Food and Agriculture Sciences, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Reham Soliman
- Tropical Medicine Department, Faculty of Medicine, Port Said University, Port Said, Egypt
- Egyptian Liver Research Institute and Hospital (ELRIAH), Mansoura, Egypt
| | - Ayman A Hassan
- Egyptian Liver Research Institute and Hospital (ELRIAH), Mansoura, Egypt
| | - Gamal Shiha
- Egyptian Liver Research Institute and Hospital (ELRIAH), Mansoura, Egypt.
- Hepatology and Gastroenterology Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
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42
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Ghezzi L, Cantoni C, Pinget GV, Zhou Y, Piccio L. Targeting the gut to treat multiple sclerosis. J Clin Invest 2021; 131:e143774. [PMID: 34196310 DOI: 10.1172/jci143774] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The gut-brain axis (GBA) refers to the complex interactions between the gut microbiota and the nervous, immune, and endocrine systems, together linking brain and gut functions. Perturbations of the GBA have been reported in people with multiple sclerosis (pwMS), suggesting a possible role in disease pathogenesis and making it a potential therapeutic target. While research in the area is still in its infancy, a number of studies revealed that pwMS are more likely to exhibit altered microbiota, altered levels of short chain fatty acids and secondary bile products, and increased intestinal permeability. However, specific microbes and metabolites identified across studies and cohorts vary greatly. Small clinical and preclinical trials in pwMS and mouse models, in which microbial composition was manipulated through the use of antibiotics, fecal microbiota transplantation, and probiotic supplements, have provided promising outcomes in preventing CNS inflammation. However, results are not always consistent, and large-scale randomized controlled trials are lacking. Herein, we give an overview of how the GBA could contribute to MS pathogenesis, examine the different approaches tested to modulate the GBA, and discuss how they may impact neuroinflammation and demyelination in the CNS.
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Affiliation(s)
- Laura Ghezzi
- Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.,University of Milan, Milan, Italy
| | - Claudia Cantoni
- Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Gabriela V Pinget
- Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
| | - Yanjiao Zhou
- Department of Medicine, School of Medicine, UConn Health, Farmington, Connecticut, USA
| | - Laura Piccio
- Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.,Brain and Mind Centre, School of Medical Sciences, University of Sydney, Sydney, New South Wales, Australia.,Hope Center for Neurological Disorders, Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
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Kim G, Kim W, Lim S, Lee H, Koo J, Nam K, Kim S, Park S, Choi J. In Vivo Induction of Regulatory T Cells Via CTLA-4 Signaling Peptide to Control Autoimmune Encephalomyelitis and Prevent Disease Relapse. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2004973. [PMID: 34306974 PMCID: PMC8292875 DOI: 10.1002/advs.202004973] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 04/01/2021] [Indexed: 05/22/2023]
Abstract
Regulatory T cells play a key role in immune tolerance to self-antigens, thereby preventing autoimmune diseases. However, no drugs targeting Treg cells have been approved for clinical trials yet. Here, a chimeric peptide is generated by conjugation of the cytoplasmic domain of CTLA-4 (ctCTLA-4) with dNP2 for intracellular delivery, dNP2-ctCTLA-4, and evaluated Foxp3 expression during Th0, Th1, Treg, and Th17 differentiation dependent on TGF-β. The lysine motif of ctCTLA-4, not tyrosine motif, is required for Foxp3 expression for Treg induction and amelioration of experimental autoimmune encephalomyelitis (EAE). Transcriptome analysis reveals that dNP2-ctCTLA-4-treated T cells express Treg transcriptomic patterns with properties of suppressive functions. In addition, the molecular interaction between the lysine motif of ctCTLA-4 and PKC-η is critical for Foxp3 expression. Although both CTLA-4-Ig and dNP2-ctCTLA-4 treatment in vivo ameliorated EAE progression, only dNP2-ctCTLA-4 requires Treg cells for inhibition of disease progression and prevention of relapse. Furthermore, the CTLA-4 signaling peptide is able to induce human Tregs in vitro and in vivo as well as from peripheral blood mononuclear cells (PBMCs) of multiple sclerosis patients. These results collectively suggest that the chimeric CTLA-4 signaling peptide can be used for successful induction of regulatory T cells in vivo to control autoimmune diseases, such as multiple sclerosis.
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Affiliation(s)
- Gil‐Ran Kim
- Department of Life ScienceCollege of Natural SciencesHanyang UniversityResearch institute for Natural SciencesHanyang UniversitySeoul04763Republic of Korea
| | - Won‐Ju Kim
- Department of Life ScienceCollege of Natural SciencesHanyang UniversityResearch institute for Natural SciencesHanyang UniversitySeoul04763Republic of Korea
| | - Sangho Lim
- Hubrecht Institute for Developmental Biology and Stem Cell Research‐KNAW, University Medical Centre UtrechtUtrecht3584 CTNetherland
| | - Hong‐Gyun Lee
- Department of Life ScienceCollege of Natural SciencesHanyang UniversityResearch institute for Natural SciencesHanyang UniversitySeoul04763Republic of Korea
| | - Ja‐Hyun Koo
- Department of Life ScienceCollege of Natural SciencesHanyang UniversityResearch institute for Natural SciencesHanyang UniversitySeoul04763Republic of Korea
| | - Kyung‐Ho Nam
- Department of Life ScienceCollege of Natural SciencesHanyang UniversityResearch institute for Natural SciencesHanyang UniversitySeoul04763Republic of Korea
| | - Sung‐Min Kim
- Department of NeurologyCollege of MedicineSeoul National UniversitySeoul National University HospitalSeoul03080Republic of Korea
| | - Sung‐Dong Park
- Department of Life ScienceCollege of Natural SciencesHanyang UniversityResearch institute for Natural SciencesHanyang UniversitySeoul04763Republic of Korea
| | - Je‐Min Choi
- Department of Life ScienceCollege of Natural SciencesHanyang UniversityResearch institute for Natural SciencesResearch Institute for Convergence of Basic SciencesHanyang UniversitySeoul04763Republic of Korea
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Mechanisms Driving Immune-Related Adverse Events in Cancer Patients Treated with Immune Checkpoint Inhibitors. Curr Cardiol Rep 2021; 23:98. [PMID: 34196833 DOI: 10.1007/s11886-021-01530-2] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/14/2021] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW In the past decade, immune checkpoint inhibitors (ICIs) have revolutionized the field of cancer treatment. With the continuing rise in the number of cancer patients eligible for ICIs, a corresponding rise in immune-related adverse events (irAEs) is occurring. IrAEs are inflammatory reactions against normal, healthy tissue that occur due to ICI-induced activation of the immune system. Although the exact immune pathogenesis driving irAE development remains unknown, we review the main proposed mechanisms, highlighting how they may inform irAE prediction and treatment. RECENT FINDINGS IrAEs are common and diverse, varying in incidence, timing, and severity. The possible mechanisms driving irAEs include (1) activation of cytotoxic T cells; (2) activation of B cells and increased autoantibody production; (3) direct molecular mimicry and off-target toxicity; (4) activation of intracellular signaling and pro-inflammatory cytokine production; and (5) environmental modifiers of immune system activation, including composition of the host gut microbiome. These mechanisms may help identify predictive biomarkers and targeted treatment strategies. IrAEs are driven by multiple components of the immune system. More research is needed to understand their immunopathogenesis so that clinicians across all specialties may more effectively monitor and manage these increasingly common conditions.
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Childhood maltreatment correlates with higher concentration of transforming growth factor beta (TGF-β) in adult patients with major depressive disorder. Psychiatry Res 2021; 301:113987. [PMID: 34023675 DOI: 10.1016/j.psychres.2021.113987] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 05/04/2021] [Indexed: 12/29/2022]
Abstract
Transforming growth factor beta (TGF-β), which has a role as a regulatory cytokine, has not been widely investigated in patients with major depressive disorder (MDD) who experienced childhood trauma. The aim of our study was to investigate the differences in circulating TGF-β levels between the patients with major depressive disorder (MDD) with and without child maltreatment (CM) history, and to compare them to the corresponding control subjects' groups (with or without CM). Blood samples were obtained from 55 patients, fulfilling DSM-IV-R criteria for a current MDD episode without psychotic symptoms, and 45 healthy controls, matched for age and gender. Participants were administered the Childhood Trauma Questionnaire (CTQ). Serum TGF-β concentration was determined by enzyme-linked immunosorbent assay. The concentration of TGF-β was significantly higher in patients with MDD with CM history, compared to MDD patients with no CM, as well as both control groups. Furthermore, we have shown that the combined effect of CM history and MDD affected TGF-β levels in adulthood, which was not observed in the control group with CM. These results indicate that MDD patients with the experience of CM have altered immune-regulatory response, and they may constitute a specific subtype within this heterogenic disorder (ecophenotype).
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Qin X, He L, Fan D, Liang W, Wang Q, Fang J. Targeting the resolution pathway of inflammation using Ac2-26 peptide-loaded PEGylated lipid nanoparticles for the remission of rheumatoid arthritis. Asian J Pharm Sci 2021; 16:483-493. [PMID: 34703497 PMCID: PMC8520054 DOI: 10.1016/j.ajps.2021.03.001] [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] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/03/2021] [Accepted: 03/05/2021] [Indexed: 12/29/2022] Open
Abstract
Rheumatoid arthritis (RA) is a common autoimmune disease characterized by joint inflammation and immune dysfunction. Although various therapeutic approaches have been utilized for the treatment of RA in clinical applications, the low responsiveness of RA patients and undesired systemic toxicity are still unresolved problems. Targeting the resolution pathway of inflammation with pro-resolving mediators would evoke the protective actions of patient for combating the inflammation. Ac2-26, a 25-amino acid peptide derived from Annexin A (a pro-resolving mediator), has shown good efficacy in the treatment of inflammatory disorders. However, the low bioavailability of Ac2-26 peptides hinders their efficacy in vivo. In this paper, we formed PEGylated lipid nanoparticles (LDNPs) by the co-assembly of l-ascorbyl palmitate (L-AP) and N-(carbonyl methoxypolyethylene glycol-2000)-1,2-distearoyl-sn‑glycero-3-phosphoethanolamine (DSPE-PEG2k) to encapsulate and deliver Ac2-26 peptides to the arthritic rats. They showed good stability and biocompatibility. After being intravenously administrated, Ac2-26 peptide-loaded PEGylated lipid nanoparticles (ADNPs) showed the prolonged in vivo circulation time and enhanced accumulation in inflamed sites. In vivo therapeutic evaluations revealed that ADNPs could attenuate synovial inflammation and improve joint pathology. Therefore, the pro-resolving therapeutic strategy using ADNPs is effective in RA treatment.
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Affiliation(s)
- Xianyan Qin
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education and School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Liming He
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education and School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Donghao Fan
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education and School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Wenlang Liang
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education and School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Qin Wang
- Key Laboratory of Advanced Technologies of Materials, Ministry of Education and School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Jiyu Fang
- Advanced Materials Processing and Analysis Center and Department of Materials Science and Engineering, University of Central Florida, Florida 32816, United State
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Abdulla OA, Neamah W, Sultan M, Alghetaa HK, Singh N, Busbee PB, Nagarkatti M, Nagarkatti P. The Ability of AhR Ligands to Attenuate Delayed Type Hypersensitivity Reaction Is Associated With Alterations in the Gut Microbiota. Front Immunol 2021; 12:684727. [PMID: 34267755 PMCID: PMC8277436 DOI: 10.3389/fimmu.2021.684727] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/09/2021] [Indexed: 12/20/2022] Open
Abstract
Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates T cell function. The aim of this study was to investigate the effects of AhR ligands, 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), and 6-Formylindolo[3,2-b]carbazole (FICZ), on gut-associated microbiota and T cell responses during delayed-type hypersensitivity (DTH) reaction induced by methylated bovine serum albumin (mBSA) in a mouse model. Mice with DTH showed significant changes in gut microbiota including an increased abundance of Bacteroidetes and decreased Firmicutes at the phylum level. Also, there was a decrease in Clostridium cluster XIV and IV, which promote anti-inflammatory responses, and an increase in Prevotella copri that facilitates pro-inflammatory responses. Interestingly, treatment of mice with TCDD attenuated the DTH response, induced Tregs, suppressed Th17 cells in the mesenteric lymph nodes (MLNs), and reversed the gut microbiota composition toward normalcy. In contrast, FICZ exacerbated the DTH response, induced heightened Th17 cells, and failed to cause a major shift in gut microbiota. Furthermore, TCDD but not FICZ caused an increase in the levels of short-chain fatty acids (SCFA), n-butyric acid, and acetic acid. Administration of sodium butyrate into mice with DTH suppressed the response, increased Tregs, and reduced Th17 cells IL17. Butyrate also caused an increase in the abundance of Clostridium and a decrease in Prevotella. Lastly, TCDD, as well as butyrate but not FICZ, were able to inhibit proinflammatory Histone deacetylases (HDACs) class I and II. Together, our data suggest that AhR ligands, such as TCDD that suppress DTH response, may mediate this effect by reversing the gut dysbiosis induced during this inflammatory response, while FICZ may fail to suppress the DTH response because of its inability to overturn the dysbiosis.
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MESH Headings
- Animals
- Basic Helix-Loop-Helix Transcription Factors/agonists
- Basic Helix-Loop-Helix Transcription Factors/metabolism
- Butyric Acid/pharmacology
- Carbazoles/toxicity
- Cytokines/genetics
- Cytokines/metabolism
- Disease Models, Animal
- Female
- Gastrointestinal Microbiome/drug effects
- Hypersensitivity, Delayed/genetics
- Hypersensitivity, Delayed/immunology
- Hypersensitivity, Delayed/metabolism
- Hypersensitivity, Delayed/prevention & control
- Ligands
- Mice
- Mice, Inbred C57BL
- Polychlorinated Dibenzodioxins/toxicity
- Receptors, Aryl Hydrocarbon/agonists
- Receptors, Aryl Hydrocarbon/metabolism
- T-Lymphocytes, Regulatory/drug effects
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- Th17 Cells/drug effects
- Th17 Cells/immunology
- Th17 Cells/metabolism
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Affiliation(s)
| | | | | | | | | | | | | | - Prakash Nagarkatti
- Department of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States
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48
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Wei C, Huang L, Zheng Y, Cai X. Selective activation of cannabinoid receptor 2 regulates Treg/Th17 balance to ameliorate neutrophilic asthma in mice. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1015. [PMID: 34277815 PMCID: PMC8267324 DOI: 10.21037/atm-21-2778] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 06/09/2021] [Indexed: 12/12/2022]
Abstract
Background The cannabinoid receptor 2 (CNR2) plays a critical role in relieving asthma, with the mechanism still unclear. We aimed to investigate the mechanism of the CNR2 agonist (β-caryophyllene, β-Car) in regulating the balance of regulatory T cells (Treg) and T helper cell 17 (Th17) and thus its role in asthma. Methods The study group of 50 pathogen-free female BALB/c mice were randomly divided at 6–8 weeks old into five groups of Control, Asthma, Asthma + β-Car (10 mg/kg), Asthma + β-Car + SR144528 (specific CNR2 antagonist, 3 mg/kg), and Asthma + β-Car + CMD178 (inhibitor of Treg cell, 10 mg/kg). ELISA was conducted to evaluate the main inflammatory cytokines [interleukin (IL)-6, IL-8, and tumor necrosis factor-α], and those secreted by Treg (transforming growth factor-β and IL-10), and Th17 (IL-17A and IL-22). Markers of Treg and Th17 cells were assessed by flow cytometry. In vitro, the CD4+ T cells were sorted and directed to differentiate to Treg and Th17 cells. The expression levels of CNR2, STAT5 and JNK1/2 were investigated by western blot and immunofluorescence assay. Results β-Car relieved neutrophilic asthma severity in mice by elevating the marker genes’ expression of Treg and inhibiting those of Th17, causing an increased proportion of Treg to Th17. β-Car also promoted the directed differentiation of CD4+ T cells into Treg, but not Th17. Activation of the CNR2 regulated the Treg/Th17 balance and relieved neutrophilic asthma possibly through promotion of phosphorylation of STAT5 and JNK1/2. Conclusions The effect of the selective CNR2 agonist activating STAT5 and JNK1/2 signaling was to change the Treg/Th17 balance and reduce the inflammatory reaction, thus ameliorating neutrophilic asthma in a mouse model.
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Affiliation(s)
- Chaochao Wei
- Department of Pulmonary and Critical Care Medicine, Hainan General Hospital, Haikou, China
| | - Linhui Huang
- Department of Pulmonary and Critical Care Medicine, Hainan General Hospital, Haikou, China
| | - Yamei Zheng
- Department of Pulmonary and Critical Care Medicine, Hainan General Hospital, Haikou, China
| | - Xingjun Cai
- Department of Pulmonary and Critical Care Medicine, Hainan General Hospital, Haikou, China
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49
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Rana J, Perry DJ, Kumar SRP, Muñoz-Melero M, Saboungi R, Brusko TM, Biswas M. CAR- and TRuC-redirected regulatory T cells differ in capacity to control adaptive immunity to FVIII. Mol Ther 2021; 29:2660-2676. [PMID: 33940160 PMCID: PMC8417451 DOI: 10.1016/j.ymthe.2021.04.034] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 04/14/2021] [Accepted: 04/27/2021] [Indexed: 12/11/2022] Open
Abstract
Regulatory T cells (Tregs) control immune responses in autoimmune disease, transplantation, and enable antigen-specific tolerance induction in protein-replacement therapies. Tregs can exert a broad array of suppressive functions through their T cell receptor (TCR) in a tissue-directed and antigen-specific manner. This capacity can now be harnessed for tolerance induction by "redirecting" polyclonal Tregs to overcome low inherent precursor frequencies and simultaneously augment suppressive functions. With the use of hemophilia A as a model, we sought to engineer antigen-specific Tregs to suppress antibody formation against the soluble therapeutic protein factor (F)VIII in a major histocompatibility complex (MHC)-independent fashion. Surprisingly, high-affinity chimeric antigen receptor (CAR)-Treg engagement induced a robust effector phenotype that was distinct from the activation signature observed for endogenous thymic Tregs, which resulted in the loss of suppressive activity. Targeted mutations in the CD3ζ or CD28 signaling motifs or interleukin (IL)-10 overexpression were not sufficient to restore tolerance. In contrast, complexing TCR-based signaling with single-chain variable fragment (scFv) recognition to generate TCR fusion construct (TRuC)-Tregs delivered controlled antigen-specific signaling via engagement of the entire TCR complex, thereby directing functional suppression of the FVIII-specific antibody response. These data suggest that cellular therapies employing engineered receptor Tregs will require regulation of activation thresholds to maintain optimal suppressive function.
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Affiliation(s)
- Jyoti Rana
- Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN 46202, USA
| | - Daniel J Perry
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Sandeep R P Kumar
- Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN 46202, USA
| | - Maite Muñoz-Melero
- Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN 46202, USA
| | - Rania Saboungi
- College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Todd M Brusko
- Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Department of Pediatrics, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Moanaro Biswas
- Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN 46202, USA.
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50
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Zhang L, Ma X, Liu P, Ge W, Hu L, Zuo Z, Xiao H, Liao W. Treatment and mechanism of fecal microbiota transplantation in mice with experimentally induced ulcerative colitis. Exp Biol Med (Maywood) 2021; 246:1563-1575. [PMID: 33926254 DOI: 10.1177/15353702211006044] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Restoring intestinal microbiota dysbiosis with fecal microbiota transplantation is considered as a promising treatment for ulcerative colitis. However, the mechanisms underlying its relieving effects remain unclear. Ulcerative colitis pathogenesis is associated with the involvement of immune cells and inflammatory cytokines. Here, we aimed to investigate the effect of fecal microbiota transplantation on T cell cytokines in a dextran sulfate sodium-induced ulcerative colitis mouse model. Five-aminosalicylic acid (5-ASA) was used as the positive control. Male C57BL/6 mice were randomly assigned to control, model (UC), UC + FMT, and UC + 5-ASA groups. Each group consisted of five mice. The establishment of the mouse model was verified by fecal occult-blood screening and hematoxylin-eosin staining. Results showed that fecal microbiota transplantation reduced colonic inflammation, significantly decreased T helper (Th)1 and Th17 cells, interferon-gamma, interleukin-2 and interleukin-17, as well as significantly increased Th2 and regulatory T (Treg) cells, interleukin-4, interleukin-10, and transforming growth factor-beta, and improved routine blood count. Furthermore, 16S rRNA gene-sequencing analysis showed a significant increase in the relative abundance of genus Akkermansia and a significant decrease in the relative abundance of genus Helicobacter in the ulcerative colitis group. Fecal microbiota transplantation restored the profile of the intestinal microbiota to that of the control group. These findings demonstrated the capability of fecal microbiota transplantation in controlling experimentally induced ulcerative colitis by improving Th1/Th2 and Th17/Treg imbalance through the regulation of intestinal microbiota.
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Affiliation(s)
- Leichang Zhang
- Department of Anorectal, The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, P.R. China
| | - Xiaofei Ma
- Department of Anorectal, Department of Postgraduate Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, P.R. China
| | - Peng Liu
- Department of Anorectal, Department of Postgraduate Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, P.R. China
| | - Wei Ge
- Department of Anorectal, The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, P.R. China
| | - Lixia Hu
- Department of Traditional Chinese Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, P.R. China
| | - Zhengyun Zuo
- Formula-Pattern Research Center, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, P.R. China
| | - Huirong Xiao
- Department of Anorectal, The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, P.R. China
| | - Wu Liao
- Department of Anorectal, The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, P.R. China
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