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Berzack S, Galor A. Microbiome-based therapeutics for ocular diseases. Clin Exp Optom 2025; 108:115-122. [PMID: 39617011 PMCID: PMC11875938 DOI: 10.1080/08164622.2024.2422479] [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: 09/16/2024] [Revised: 10/22/2024] [Accepted: 10/23/2024] [Indexed: 12/08/2024] Open
Abstract
The relationship between the gut microbiome and ocular health has garnered increasing attention within the scientific community. Recent research has focused on the gut-eye axis, examining whether imbalances within the gut microbiome can influence the development, progression and severity of ocular diseases, including dry eye disease, uveitis, and glaucoma. Dysbiosis within the gut microbiome is linked to immune dysregulation, chronic inflammation, and epithelial barrier dysfunction, all of which contribute to ocular pathology. This review synthesises current evidence on these associations, exploring how gut microbiome alterations drive disease mechanisms. Furthermore, it examines the therapeutic potential of microbiome-targeted interventions, including antibiotics, prebiotics, probiotics, and faecal microbiota transplantation, all of which aim to restore microbial balance and modulate immune responses. As the prevalence of these conditions continues to rise, a deeper understanding of the gut-eye axis may facilitate the development of novel, targeted therapies to address unmet needs in the management of ocular diseases.
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Affiliation(s)
- Shannan Berzack
- Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA
| | - Anat Galor
- Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
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Garcia JN, Cottam MA, Rodriguez AS, Agha AFH, Winn NC, Hasty AH. Interrupting T cell memory ameliorates exaggerated metabolic response to weight cycling. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.17.633599. [PMID: 39896598 PMCID: PMC11785015 DOI: 10.1101/2025.01.17.633599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/04/2025]
Abstract
People frequently experience cycles of weight gain and loss. This weight cycling has been demonstrated, in humans and animal models, to increase cardiometabolic disease and disrupt glucose homeostasis. Obesity itself - and to an even greater extent weight regain - causes adipose tissue inflammation, resulting in metabolic dysfunction. Studies show that even after weight loss, increased numbers of lipid associated macrophages and memory T cells persist in adipose tissue and become more inflammatory upon weight regain. These findings suggest that the immune system retains a "memory" of obesity, which may contribute to the elevated inflammation and metabolic dysfunction associated with weight cycling. Here, we show that blocking the CD70-CD27 axis, critical for formation of immunological memory, decreases the number of memory T cells and reduces T cell clonality within adipose tissue after weight loss and weight cycling. Furthermore, while mice with impaired ability to create obesogenic immune memory have similar metabolic responses as wildtype mice to stable obesity, they are protected from the worsened glucose tolerance associated with weight cycling. Our data are the first to target metabolic consequences of weight cycling through an immunomodulatory mechanism. Thus, we propose a new avenue of therapeutic intervention by which targeting memory T cells can be leveraged to minimize the adverse consequences of weight cycling. These findings are particularly timely given the increasing use of efficacious weight loss drugs, which will likely lead to more instances of human weight cycling.
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Affiliation(s)
- Jamie N. Garcia
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee, USA
- VA Tennessee Valley Healthcare System, Nashville, Tennessee, USA
| | - Matthew A. Cottam
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee, USA
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Alec S. Rodriguez
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee, USA
| | - Anwar F. Hussein Agha
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee, USA
| | - Nathan C. Winn
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee, USA
- Division of Gastroenterology, Hepatology, & Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Alyssa H. Hasty
- Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, Tennessee, USA
- VA Tennessee Valley Healthcare System, Nashville, Tennessee, USA
- University of Texas Southwestern, Dallas, Texas, USA
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Principi N, Lazzara A, Paglialonga L, Viafora F, Aurelio C, Esposito S. Recurrent pericarditis and interleukin (IL)-1 inhibitors. Int Immunopharmacol 2024; 141:113017. [PMID: 39197293 DOI: 10.1016/j.intimp.2024.113017] [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: 05/10/2024] [Revised: 07/16/2024] [Accepted: 08/22/2024] [Indexed: 09/01/2024]
Abstract
Recurrent pericarditis (RP) is defined by the European Society of Cardiology (ESC) as an instance of acute pericarditis (AP) that occurs at least 4-6 weeks after the resolution of a previous episode of the same ailment. To mitigate the risk of RP, it is advised to administer accurate and prolonged pharmacological treatment for both the initial AP and subsequent RP. ESC guidelines recommend commencing treatment for any single episode of AP, including those that contribute to RP, with non-steroidal anti-inflammatory drugs (NSAIDs) in conjunction with colchicine for several months, often followed by gradual tapering. If there is an inadequate response, corticosteroids (CS) may be introduced cautiously. However, in a minority of cases, even when NSAIDs, colchicine, and CS are administered together at the highest recommended dosages, they may prove ineffective. In such instances, treatment with immunosuppressive drugs or biologics is advised. Among biologics, interleukin (IL)-1 inhibitors have been extensively studied, although certain gaps remain. This narrative review delves into the rationale for employing IL-1 inhibitors and presents findings from existing studies regarding their efficacy, tolerability, and safety. Analysis of the literature indicates that there is currently insufficient data to ascertain the true therapeutic role of IL-1 inhibitors in managing and preventing RP. However, theoretically, drugs targeting both IL-1α and IL-1β may offer superior efficacy compared to those solely targeting IL-1β due to the significant involvement of both cytokines in inflammation. Further research is warranted to determine the comparative effectiveness of IL-1α and IL-1β inhibitors.
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Affiliation(s)
| | - Angela Lazzara
- Pediatric Clinic, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Letizia Paglialonga
- Pediatric Clinic, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Federico Viafora
- Pediatric Clinic, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Camilla Aurelio
- Pediatric Clinic, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Susanna Esposito
- Pediatric Clinic, Department of Medicine and Surgery, University of Parma, Parma, Italy.
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Franz T, Stegemann-Koniszewski S, Schreiber J, Müller A, Bruder D, Dudeck A, Boehme JD, Kahlfuss S. Metabolic and ionic control of T cells in asthma endotypes. Am J Physiol Cell Physiol 2024; 327:C1300-C1307. [PMID: 39374078 DOI: 10.1152/ajpcell.00474.2024] [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: 07/09/2024] [Revised: 09/05/2024] [Accepted: 09/16/2024] [Indexed: 10/09/2024]
Abstract
CD4+ T cells play a central role in orchestrating the immune response in asthma, with dysregulated ion channel profiles and altered metabolic signatures contributing to disease progression and severity. An important classification of asthma is based on the presence of T-helper cell type 2 (Th2) inflammation, dividing patients into Th2-high and Th2-low endotypes. These distinct endotypes have implications for disease severity, treatment response, and prognosis. By elucidating how ion channels and energy metabolism control Th cells in asthma, this review contributes to the pathophysiological understanding and the prospective development of personalized therapeutic treatment strategies for patients suffering from distinct asthma endotypes.
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Affiliation(s)
- Tobias Franz
- Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Sabine Stegemann-Koniszewski
- Experimental Pneumology, Department of Pneumology, University Hospital Magdeburg, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke University, Magdeburg, Germany
- Health Campus Immunology, Infectiology and Inflammation (GCI3), Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Jens Schreiber
- Experimental Pneumology, Department of Pneumology, University Hospital Magdeburg, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke University, Magdeburg, Germany
- Health Campus Immunology, Infectiology and Inflammation (GCI3), Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Andreas Müller
- Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Health Campus Immunology, Infectiology and Inflammation (GCI3), Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke-University, Magdeburg, Germany
| | - Dunja Bruder
- Research Group Infection Immunology, Institute of Medical Microbiology and Hospital Hygiene, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University, Magdeburg, Germany
- Research Group Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany
- Health Campus Immunology, Infectiology and Inflammation (GCI3), Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Anne Dudeck
- Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Health Campus Immunology, Infectiology and Inflammation (GCI3), Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke-University, Magdeburg, Germany
| | - Julia D Boehme
- Research Group Infection Immunology, Institute of Medical Microbiology and Hospital Hygiene, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University, Magdeburg, Germany
- Research Group Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany
- Health Campus Immunology, Infectiology and Inflammation (GCI3), Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Sascha Kahlfuss
- Institute of Molecular and Clinical Immunology, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Health Campus Immunology, Infectiology and Inflammation (GCI3), Medical Faculty, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
- Center for Health and Medical Prevention (CHaMP), Otto-von-Guericke-University, Magdeburg, Germany
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Chi Z, Jia Q, Yang H, Ren H, Jin C, He J, Wuri N, Sui Z, Zhang J, Mengke B, Zhu L, Qiqi G, Aierqing S, Wuli J, Ai D, Fan R, Herrid M. snRNA-seq of adipose tissues reveals the potential cellular and molecular mechanisms of cold and disease resistance in Mongolian cattle. BMC Genomics 2024; 25:999. [PMID: 39448899 PMCID: PMC11520132 DOI: 10.1186/s12864-024-10913-y] [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: 05/11/2024] [Accepted: 10/17/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND Mongolian cattle are local breeds in northern China with excellent adaptability to harsh environmental conditions. Adipose tissues play essential roles in tolerance to cold and disease, but the associated cellular and molecular mechanisms are unclear. METHODS Single-nucleus RNA sequencing (snRNA-seq) was performed on the adipose tissues from the subcutaneous (SAT), greater omentum (OAT) and perirenal (PAT) of 3 healthy cattle. The adipogenic trajectory was analyzed, and the functional roles of gene of interest were verified in vitro. RESULTS There were different cell subpopulations in adipose tissues. The lipid-deposition adipocytes identified by the PTGER3 marker exhibited outstanding characteristics in SAT. In PAT and OAT, aldosterone was expressed to provide clues for the differential brown adipocytes. Among the DEGs by comparing OAT with SAT and PAT with OAT, C3 was significantly expressed in most of the cell populations in SAT. G0S2, LIPE, LPIN1, PTGER3 and RGCC took part in the adipogenic trajectory from preadipocyte commitment to mature adipocytes. S100A4 expression affected Ca2+ signaling and the expression of UCP1 ~ 3, FABP4 and PTGER3. CONCLUSION The cell heterogeneity and genes expressed in adipose tissues of Mongolian cattle not only determine the endocrine and energy storage, but contribute to adapt to cold and disease resistance.
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Affiliation(s)
- Zhiduan Chi
- College of Veterinary Medicine, Shanxi Agricultural University, Taigu, 030801, China
| | - Qiong Jia
- College of Veterinary Medicine, Shanxi Agricultural University, Taigu, 030801, China
| | - Haoyu Yang
- College of Veterinary Medicine, Shanxi Agricultural University, Taigu, 030801, China
| | - Hongrui Ren
- College of Veterinary Medicine, Shanxi Agricultural University, Taigu, 030801, China
| | - Congli Jin
- College of Veterinary Medicine, Shanxi Agricultural University, Taigu, 030801, China
| | - Jinxin He
- College of Veterinary Medicine, Shanxi Agricultural University, Taigu, 030801, China
| | - Nile Wuri
- College of Veterinary Medicine, Shanxi Agricultural University, Taigu, 030801, China
| | - Ze Sui
- College of Veterinary Medicine, Shanxi Agricultural University, Taigu, 030801, China
| | - Junzhen Zhang
- College of Animal Science, Shanxi Agricultural University, Taigu, 030801, China
| | - Bayier Mengke
- Animal Husbandry and Veterinary Technology Extension Center of Alxa League, Alxa Left Banner, 750300, China
| | - Lixian Zhu
- Animal Husbandry and Veterinary Technology Extension Center of Alxa League, Alxa Left Banner, 750300, China
| | - Ge Qiqi
- Animal Husbandry and Veterinary Technology Extension Center of Alxa League, Alxa Left Banner, 750300, China
| | - Sarengaowa Aierqing
- Animal Husbandry and Veterinary Technology Extension Center of Alxa League, Alxa Left Banner, 750300, China
| | - Ji Wuli
- Animal Husbandry and Veterinary Technology Extension Center of Alxa League, Alxa Left Banner, 750300, China
| | - Dong Ai
- Bureau of Agriculture and Animal Husbandry of Alxa League, Bayanhot, 750306, China
| | - Ruiwen Fan
- College of Veterinary Medicine, Shanxi Agricultural University, Taigu, 030801, China.
| | - Muren Herrid
- Grassland & Cattle Investment Co., Ltd, Hohhot, 011500, China.
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Morad MA, Doudar NA, Tawfeek N, Yacoub M, Azoz T, El Demerdash D. IL-4Rα (rs1801275) A>G polymorphism in Egyptian immune thrombocytopenia (ITP) patients: a single center experience. Hematol Transfus Cell Ther 2024; 46:352-359. [PMID: 37202334 PMCID: PMC11451371 DOI: 10.1016/j.htct.2023.03.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 01/12/2023] [Accepted: 03/30/2023] [Indexed: 05/20/2023] Open
Abstract
INTRODUCTION Chronic immune thrombocytopenia (cITP) is characterized by dysregulation of the immune response. Until recently, the role of Th2-related cytokine gene polymorphisms was unclear. Interleukin 4 (IL-4) exerts its functions by binding to three types of IL-4 receptor (IL-4R) complexes. We aimed to explore the potential association between the gene polymorphism of IL-4Rα and cITP. METHODS We investigated the clinical impact of the IL-4Rα (rs1801275) A>G single nucleotide polymorphism (SNP) using the polymerase chain reaction (PCR) followed by the restriction fragment length polymorphism (RFLP) method in 82 cITP patients and 60 healthy controls (HCs). RESULTS The IL-4Rα (rs1801275) A>G polymorphism analysis showed the mutant GG genotype was significantly higher in control females (p = 0.033). The wild AA genotype had a higher bleeding score (p = 0.02) in the adulthood onset group. Furthermore, the wild AA genotype in the cITP childhood onset group was significantly associated with the disease severity, as well as the response to treatment (p = 0.040). CONCLUSION The mutant G allele is protective against the susceptibility to cITP in the Egyptian females. The IL-4Rα (rs1801275) A>G polymorphism may affect the clinical severity of cITP and treatment response in the Egyptian population.
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Affiliation(s)
| | - Noha A Doudar
- Beni-Suef University Hospital, Faculty of Medicine, Beni-Suef University, Egypt
| | - Nehad Tawfeek
- Kasr Al-Ainy Hospital, Faculty of Medicine, Cairo University, Egypt
| | - Maha Yacoub
- Kasr Al-Ainy Hospital, Faculty of Medicine, Cairo University, Egypt
| | - Taha Azoz
- Faculty of Medicine, Cairo University, Egypt
| | - Doaa El Demerdash
- Kasr Al-Ainy Hospital, Faculty of Medicine, Cairo University, Egypt.
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Zeng H, Xu L, Liu J, Mo L, Li M, Song S, Xu X, Miao S, Zhao M, Yang P. Regulation of Tert methylation alleviates food allergy via regulating the Tert-IL10 signal pathway. Immunol Res 2024; 72:1018-1029. [PMID: 39034374 DOI: 10.1007/s12026-024-09504-6] [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: 03/23/2024] [Accepted: 06/03/2024] [Indexed: 07/23/2024]
Abstract
BACKGROUND The cause of food allergy (FA) is still a mystery. Telomerases are involved in the regulation of immune responses. This study aims to gain an understanding of the contribution of telomerase reverse transcriptase (TERT) to the pathogenesis of FA. METHODS A murine FA model was established with ovalbumin as the specific antigen. The role of TERT in regulating dendritic cell (DC) immune tolerogenic functions was evaluated in this murine model. RESULTS We observed that the Tert promoter was at demethylation status and the Tert expression was elevated in DCs of FA mice. The Tert expression in DCs had a positive correlation with the FA response. TERT prevented the induction of Il10 expression in DCs. The immune tolerogenic functions of DCs were diminished by TERT. The immune tolerogenic functions of DC were restored by CpG by boosting the Tert promoter methylation. Administration of CpG promoted the therapeutic effects of allergen specific immunotherapy in FA mice. CONCLUSIONS Low levels of Il10 expression and high levels of Tert expression were observed in intestinal DCs of FA mice. CpG exposure restored the expression of Il10 and increased the therapeutic benefits of allergen-specific immunotherapy.
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Affiliation(s)
- Haotao Zeng
- Department of Allergy, Longgang ENT Hospital & Shenzhen ENT Institute, Shenzhen, China
| | - Lingzhi Xu
- Department of Immunology, School of Basic Medical Sciences, Weifang Medical University, Weifang, China
| | - Jiangqi Liu
- Department of Allergy, Longgang ENT Hospital & Shenzhen ENT Institute, Shenzhen, China
| | - Lihua Mo
- State Key Laboratory of Respiratory Diseases Allergy Division, Shenzhen University and Institute of Allergy & Immunology of Shenzhen University, Room A7-509 at Lihu Campus of Shenzhen University. 1066 Xueyuan Blvd, Shenzhen, 518055, China
- Department of General Practice Medicine, Third Affiliated Hospital, Shenzhen University, Shenzhen, China
| | - Minyao Li
- State Key Laboratory of Respiratory Diseases Allergy Division, Shenzhen University and Institute of Allergy & Immunology of Shenzhen University, Room A7-509 at Lihu Campus of Shenzhen University. 1066 Xueyuan Blvd, Shenzhen, 518055, China
- Department of General Practice Medicine, Third Affiliated Hospital, Shenzhen University, Shenzhen, China
| | - Shuo Song
- State Key Laboratory of Respiratory Diseases Allergy Division, Shenzhen University and Institute of Allergy & Immunology of Shenzhen University, Room A7-509 at Lihu Campus of Shenzhen University. 1066 Xueyuan Blvd, Shenzhen, 518055, China
- Department of General Practice Medicine, Third Affiliated Hospital, Shenzhen University, Shenzhen, China
| | - Xuejie Xu
- State Key Laboratory of Respiratory Diseases Allergy Division, Shenzhen University and Institute of Allergy & Immunology of Shenzhen University, Room A7-509 at Lihu Campus of Shenzhen University. 1066 Xueyuan Blvd, Shenzhen, 518055, China
| | - Shihan Miao
- Shenzhen Senior High School Group, Shenzhen, China
| | - Miao Zhao
- Department of Allergy, Longgang ENT Hospital & Shenzhen ENT Institute, Shenzhen, China.
| | - Pingchang Yang
- State Key Laboratory of Respiratory Diseases Allergy Division, Shenzhen University and Institute of Allergy & Immunology of Shenzhen University, Room A7-509 at Lihu Campus of Shenzhen University. 1066 Xueyuan Blvd, Shenzhen, 518055, China.
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Dadfar S, Yazdanpanah E, Pazoki A, Nemati MH, Eslami M, Haghmorad D, Oksenych V. The Role of Mesenchymal Stem Cells in Modulating Adaptive Immune Responses in Multiple Sclerosis. Cells 2024; 13:1556. [PMID: 39329740 PMCID: PMC11430382 DOI: 10.3390/cells13181556] [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: 09/02/2024] [Revised: 09/12/2024] [Accepted: 09/14/2024] [Indexed: 09/28/2024] Open
Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, leading to significant disability through neurodegeneration. Despite advances in the understanding of MS pathophysiology, effective treatments remain limited. Mesenchymal stem cells (MSCs) have gained attention as a potential therapeutic option due to their immunomodulatory and regenerative properties. This review examines MS pathogenesis, emphasizing the role of immune cells, particularly T cells, in disease progression, and explores MSCs' therapeutic potential. Although preclinical studies in animal models show MSC efficacy, challenges such as donor variability, culture conditions, migratory capacity, and immunological compatibility hinder widespread clinical adoption. Strategies like genetic modification, optimized delivery methods, and advanced manufacturing are critical to overcoming these obstacles. Further research is needed to validate MSCs' clinical application in MS therapy.
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Affiliation(s)
- Sepehr Dadfar
- Student Research Committee, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Esmaeil Yazdanpanah
- Student Research Committee, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Alireza Pazoki
- Student Research Committee, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Mohammad Hossein Nemati
- Student Research Committee, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Majid Eslami
- Cancer Research Center, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
- Department of Bacteriology and Virology, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Dariush Haghmorad
- Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
- Cancer Research Center, Semnan University of Medical Sciences, Semnan 35147-99442, Iran
| | - Valentyn Oksenych
- Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway
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Rogozynski NP, Dixon B. The Th1/Th2 paradigm: A misrepresentation of helper T cell plasticity. Immunol Lett 2024; 268:106870. [PMID: 38788801 DOI: 10.1016/j.imlet.2024.106870] [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: 05/02/2024] [Accepted: 05/21/2024] [Indexed: 05/26/2024]
Abstract
For decades, the Th1/2 paradigm has been used to classify immune responses as either Th1 or Th2-biased. However, in recent years, a staggering amount of evidence has emerged to support rejection of the classical Th1/Th2 paradigm, such as the discoveries of new helper T cell subsets, helper T cell plasticity and protective mixed-Th1/Th2 responses. This opinion piece investigates the shortcomings of classical Th1/Th2 paradigm in the context of recent works, with the goal of facilitating the development of newer models to represent the diversity of Th cells.
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Affiliation(s)
| | - Brian Dixon
- Department of Biology, University of Waterloo, Waterloo, Canada.
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10
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Seida I, Al Shawaf M, Mahroum N. Fecal microbiota transplantation in autoimmune diseases - An extensive paper on a pathogenetic therapy. Autoimmun Rev 2024; 23:103541. [PMID: 38593970 DOI: 10.1016/j.autrev.2024.103541] [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: 01/11/2024] [Revised: 03/31/2024] [Accepted: 04/04/2024] [Indexed: 04/11/2024]
Abstract
The role of infections in the pathogenesis of autoimmune diseases has long been recognized and reported. In addition to infectious agents, the internal composition of the "friendly" living bacteria, (microbiome) and its correlation to immune balance and dysregulation have drawn the attention of researchers for decades. Nevertheless, only recently, scientific papers regarding the potential role of transferring microbiome from healthy donor subjects to patients with autoimmune diseases has been proposed. Fecal microbiota transplantation or FMT, carries the logic of transferring microorganisms responsible for immune balance from healthy donors to individuals with immune dysregulation or more accurately for our paper, autoimmune diseases. Viewing the microbiome as a pathogenetic player allows us to consider FMT as a pathogenetic-based treatment. Promising results alongside improved outcomes have been demonstrated in patients with different autoimmune diseases following FMT. Therefore, in our current extensive review, we aimed to highlight the implication of FMT in various autoimmune diseases, such as inflammatory bowel disease, autoimmune thyroid and liver diseases, systemic lupus erythematosus, and type 1 diabetes mellitus, among others. Presenting all the aspects of FMT in more than 12 autoimmune diseases in one paper, to the best of our knowledge, is the first time presented in medical literature. Viewing FMT as such could contribute to better understanding and newer application of the model in the therapy of autoimmune diseases, indeed.
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Affiliation(s)
- Isa Seida
- International School of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Maisam Al Shawaf
- International School of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Naim Mahroum
- International School of Medicine, Istanbul Medipol University, Istanbul, Turkey.
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11
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Huang X, Huang J, Li X, Fan J, Zhou D, Qu HQ, Glessner JT, Ji D, Jia Q, Ding Z, Wang N, Wei W, Lyu X, Li MJ, Liu Z, Liu W, Wei Y, Hakonarson H, Xia Q, Li J. Target genes regulated by CLEC16A intronic region associated with common variable immunodeficiency. J Allergy Clin Immunol 2024; 153:1668-1680. [PMID: 38191060 DOI: 10.1016/j.jaci.2023.12.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 12/25/2023] [Accepted: 12/29/2023] [Indexed: 01/10/2024]
Abstract
BACKGROUND CLEC16A intron 19 has been identified as a candidate locus for common variable immunodeficiency (CVID). OBJECTIVES This study sought to elucidate the molecular mechanism by which variants at the CLEC16A intronic locus may contribute to the pathogenesis of CVID. METHODS The investigators performed fine-mapping of the CLEC16A locus in a CVID cohort, then deleted the candidate functional SNP in T-cell lines by the CRISPR-Cas9 technique and conducted RNA-sequencing to identify target gene(s). The interactions between the CLEC16A locus and its target genes were identified using circular chromosome conformation capture. The transcription factor complexes mediating the chromatin interactions were determined by proteomic approach. The molecular pathways regulated by the CLEC16A locus were examined by RNA-sequencing and reverse phase protein array. RESULTS This study showed that the CLEC16A locus is an enhancer regulating expression of multiple target genes including a distant gene ATF7IP2 through chromatin interactions. Distinct transcription factor complexes mediate the chromatin interactions in an allele-specific manner. Disruption of the CLEC16A locus affects the AKT signaling pathway, as well as the molecular response of CD4+ T cells to immune stimulation. CONCLUSIONS Through multiomics and targeted experimental approaches, this study elucidated the underlying target genes and signaling pathways involved in the genetic association of CLEC16A with CVID, and highlighted plausible molecular targets for developing novel therapeutics.
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Affiliation(s)
- Xubo Huang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Jinxia Huang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Xiumei Li
- Department of Cell Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Tianjin Institute of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Jingxian Fan
- Department of Cell Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Tianjin Institute of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China; Department of Bioinformatics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Desheng Zhou
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Hui-Qi Qu
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pa
| | - Joseph T Glessner
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pa; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pa; Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa
| | - Dandan Ji
- Department of Cell Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Tianjin Institute of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Qi Jia
- International School of Information Science Engineering, Dalian University of Technology, Dalian, China
| | - Zhiyong Ding
- Mills Institute for Personalized Cancer Care, Fynn Biotechnologies Ltd, Jinan, China
| | - Nan Wang
- Mills Institute for Personalized Cancer Care, Fynn Biotechnologies Ltd, Jinan, China
| | - Wei Wei
- Department of Rheumatology and Immunology, Tianjin Medical University General Hospital, Tianjin, China
| | - Xing Lyu
- Department of Rheumatology and Immunology, Tianjin Medical University General Hospital, Tianjin, China
| | - Mulin Jun Li
- Department of Bioinformatics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Zhe Liu
- Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
| | - Wei Liu
- Tianjin Children's Hospital (Tianjin University Children's Hospital), Tianjin, China; Tianjin Key Laboratory of Birth Defects for Prevention and Treatment, Tianjin, China
| | - Yongjie Wei
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Hakon Hakonarson
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pa; Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pa; Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa
| | - Qianghua Xia
- Department of Cell Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Tianjin Institute of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China; Department of Bioinformatics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
| | - Jin Li
- Department of Cell Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Tianjin Institute of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China; Department of Rheumatology and Immunology, Tianjin Medical University General Hospital, Tianjin, China.
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12
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Ullah A, Jiao W, Shen B. The role of proinflammatory cytokines and CXC chemokines (CXCL1-CXCL16) in the progression of prostate cancer: insights on their therapeutic management. Cell Mol Biol Lett 2024; 29:73. [PMID: 38745115 PMCID: PMC11094955 DOI: 10.1186/s11658-024-00591-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 05/06/2024] [Indexed: 05/16/2024] Open
Abstract
Reproductive cancers are malignancies that develop in the reproductive organs. One of the leading cancers affecting the male reproductive system on a global scale is prostate cancer (PCa). The negative consequences of PCa metastases endure and are severe, significantly affecting mortality and life quality for those who are affected. The association between inflammation and PCa has captured interest for a while. Inflammatory cells, cytokines, CXC chemokines, signaling pathways, and other elements make up the tumor microenvironment (TME), which is characterized by inflammation. Inflammatory cytokines and CXC chemokines are especially crucial for PCa development and prognosis. Cytokines (interleukins) and CXC chemokines such as IL-1, IL-6, IL-7, IL-17, TGF-β, TNF-α, CXCL1-CXCL6, and CXCL8-CXCL16 are thought to be responsible for the pleiotropic effects of PCa, which include inflammation, progression, angiogenesis, leukocyte infiltration in advanced PCa, and therapeutic resistance. The inflammatory cytokine and CXC chemokines systems are also promising candidates for PCa suppression and immunotherapy. Therefore, the purpose of this work is to provide insight on how the spectra of inflammatory cytokines and CXC chemokines evolve as PCa develops and spreads. We also discussed recent developments in our awareness of the diverse molecular signaling pathways of these circulating cytokines and CXC chemokines, as well as their associated receptors, which may one day serve as PCa-targeted therapies. Moreover, the current status and potential of theranostic PCa therapies based on cytokines, CXC chemokines, and CXC receptors (CXCRs) are examined.
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Affiliation(s)
- Amin Ullah
- Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine and Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Wang Jiao
- Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine and Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Bairong Shen
- Joint Laboratory of Artificial Intelligence for Critical Care Medicine, Department of Critical Care Medicine and Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
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13
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Yazdanpanah E, Dadfar S, Shadab A, Orooji N, Nemati M, Pazoki A, Esmaeili S, Baharlou R, Haghmorad D. Berberine: A natural modulator of immune cells in multiple sclerosis. Immun Inflamm Dis 2024; 12:e1213. [PMID: 38477663 PMCID: PMC10936236 DOI: 10.1002/iid3.1213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 02/26/2024] [Accepted: 03/01/2024] [Indexed: 03/14/2024] Open
Abstract
Berberine is a benzylisoquinoline alkaloid found in such plants as Berberis vulgaris, Berberis aristata, and others, revealing a variety of pharmacological properties as a result of interacting with different cellular and molecular targets. Recent studies have shown the immunomodulatory effects of Berberine which result from its impacts on immune cells and immune response mediators such as diverse T lymphocyte subsets, dendritic cells (DCs), and different inflammatory cytokines. Multiple sclerosis (MS) is a chronic disabling and neurodegenerative disease of the central nervous system (CNS) characterized by the recruitment of autoreactive T cells into the CNS causing demyelination, axonal damage, and oligodendrocyte loss. There have been considerable changes discovered in MS regards to the function and frequency of T cell subsets such as Th1 cells, Th17 cells, Th2 cells, Treg cells, and DCs. In the current research, we reviewed the outcomes of in vitro, experimental, and clinical investigations concerning the modulatory effects that Berberine provides on the function and numbers of T cell subsets and DCs, as well as important cytokines that are involved in MS.
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Affiliation(s)
| | - Sepehr Dadfar
- Department of Immunology, School of MedicineSemnan University of Medical SciencesSemnanIran
| | - Alireza Shadab
- Department of Immunology, School of MedicineSemnan University of Medical SciencesSemnanIran
| | - Niloufar Orooji
- Department of Immunology, School of MedicineSemnan University of Medical SciencesSemnanIran
| | - MohammadHossein Nemati
- Department of Immunology, School of MedicineSemnan University of Medical SciencesSemnanIran
| | - Alireza Pazoki
- Department of Immunology, School of MedicineSemnan University of Medical SciencesSemnanIran
| | | | - Rasoul Baharlou
- Department of Immunology, School of MedicineSemnan University of Medical SciencesSemnanIran
- Cancer Research CenterSemnan University of Medical SciencesSemnanIran
| | - Dariush Haghmorad
- Department of Immunology, School of MedicineSemnan University of Medical SciencesSemnanIran
- Cancer Research CenterSemnan University of Medical SciencesSemnanIran
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14
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Pahwa P, Vyas AK, Sevak JK, Singh R, Maras JS, Patra S, Sarin SK, Trehanpati N. Modulation of CD8 +T cells, NK cells and Th1cytokines by metabolic milieu in decline of HBV-viremia in pregnant women treated with tenofovir-disoproxil from second trimester of pregnancy. J Reprod Immunol 2024; 162:104208. [PMID: 38367478 DOI: 10.1016/j.jri.2024.104208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 01/04/2024] [Accepted: 01/24/2024] [Indexed: 02/19/2024]
Abstract
High HBV DNA levels predispose to mother to child transmission (MTCT) of HBV. Early nucleotide analogue (NA) therapy can reduce HBV DNA and minimize MTCT. We analysed immune-metabolic profile in pregnant mothers who received NA from 2nd trimester compared with untreated mothers. In 2nd trimester, there was no difference in immune profiles between Gr.1 and Gr.2 but high viral load women had downregulated pyruvate, NAD+ metabolism but in 3rd trimester, Gr.1 had significant reduction in HBV-DNA, upregulated pyruvate and NAD with increased IFN-2αA, CD8Tcells, NK cells and decreased Tregs, IL15, IL18, IL29, TGFβ3 compared to Gr.2. In Gr.1, three eAg-ve women showed undetectable DNA and HBsAg. At delivery, Gr.1 showed no MTCT, with undetectable HBV DNA, HBsAg, high CD8 and NK cells in two women. We conclude, that starting NA from second trimester, reduces HBV load and MTCT, modulates NAD, induces immunity and suggest use of NA in early gestation in future trials.
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Affiliation(s)
- Prabhjyoti Pahwa
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ashish Kumar Vyas
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Jayesh Kumar Sevak
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ravinder Singh
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Jaswinder Singh Maras
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sharda Patra
- Department of Obstetrics and Gynaecology, Lady Harding Medical College, New Delhi, India
| | - Shiv K Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
| | - Nirupama Trehanpati
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.
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15
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Hromić-Jahjefendić A, Lundstrom K, Adilović M, Aljabali AAA, Tambuwala MM, Serrano-Aroca Á, Uversky VN. Autoimmune response after SARS-CoV-2 infection and SARS-CoV-2 vaccines. Autoimmun Rev 2024; 23:103508. [PMID: 38160960 DOI: 10.1016/j.autrev.2023.103508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 12/19/2023] [Indexed: 01/03/2024]
Abstract
The complicated relationships between autoimmunity, COVID-19, and COVID-19 vaccinations are described, giving insight into their intricacies. Antinuclear antibodies (ANA), anti-Ro/SSA, rheumatoid factor, lupus anticoagulant, and antibodies against interferon (IFN)-I have all been consistently found in COVID-19 patients, indicating a high prevalence of autoimmune reactions following viral exposure. Furthermore, the discovery of human proteins with structural similarities to SARS-CoV-2 peptides as possible autoantigens highlights the complex interplay between the virus and the immune system in initiating autoimmunity. An updated summary of the current status of COVID-19 vaccines is presented. We present probable pathways underpinning the genesis of COVID-19 autoimmunity, such as bystander activation caused by hyperinflammatory conditions, viral persistence, and the creation of neutrophil extracellular traps. These pathways provide important insights into the development of autoimmune-related symptoms ranging from organ-specific to systemic autoimmune and inflammatory illnesses, demonstrating the wide influence of COVID-19 on the immune system.
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Affiliation(s)
- Altijana Hromić-Jahjefendić
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Hrasnicka cesta 15, 71000 Sarajevo, Bosnia and Herzegovina.
| | | | - Muhamed Adilović
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, International University of Sarajevo, Hrasnicka cesta 15, 71000 Sarajevo, Bosnia and Herzegovina.
| | - Alaa A A Aljabali
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Yarmouk University, P.O. Box 566, Irbid 21163, Jordan.
| | - Murtaza M Tambuwala
- Lincoln Medical School, Brayford Pool Campus, University of Lincoln, Lincoln LN6 7TS, UK.
| | - Ángel Serrano-Aroca
- Biomaterials and Bioengineering Laboratory, Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia San Vicente Mártir, c/Guillem de Castro 94, 46001, Valencia, Spain.
| | - Vladimir N Uversky
- Department of Molecular Medicine and USF Health Byrd Alzheimer's Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA.
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16
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Imperiale BR, Gamberale A, Yokobori N, García A, Bartoletti B, Aidar O, López B, Cruz V, González Montaner P, Palmero DJ, de la Barrera S. Transforming growth factor-β, Interleukin-23 and interleukin-1β modulate TH22 response during active multidrug-resistant tuberculosis. Immunology 2024; 171:45-59. [PMID: 37715690 DOI: 10.1111/imm.13698] [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: 01/23/2023] [Accepted: 09/08/2023] [Indexed: 09/18/2023] Open
Abstract
We previously reported that patients with multidrug-resistant tuberculosis (MDR-TB) showed low systemic and Mtb-induced Th22 responses associated to high sputum bacillary load and severe lung lesions suggesting that Th22 response could influence the ability of these patients to control bacillary growth and tissue damage. In MDR-TB patients, the percentage of IL-22+ cells inversely correlates with the proportion of senescent PD-1+ T cells. Herein, we aimed to evaluate the pathways involved on the regulation of systemic and Mtb-induced Th22 response in MDR-TB and fully drug-susceptible TB patients (S-TB) and healthy donors. Our results show that while IL-1β and IL-23 promote Mtb-induced IL-22 secretion and expansion of IL-22+ cells, TGF-β inhibits this response. Systemic and in vitro Mtb-induced Th22 response inversely correlates with TGF-β amounts in plasma and in PBMC cultures respectively. The number of circulating PD-1+ T cells directly correlates with plasmatic TGF-β levels and blockade of PD-1/PD-L1 signalling enhances in vitro Mtb-induced expansion of IL-22+ cells. Thus, TGF-β could also inhibit Th22 response through upregulation of PD-1 expression in T cells. Higher percentage of IL-23+ monocytes was observed in TB patients. In contrast, the proportion of IL-1β+ monocytes was lower in TB patients with bilateral lung cavities (BCC) compared to those patients with unilateral cavities (UCC). Interestingly, TB patients with BCC showed higher plasmatic and Mtb-induced TGF-β secretion than patients with UCC. Thus, high TGF-β secretion and subtle differences in IL-23 and IL-1β expression could diminish systemic and in vitro Mtb-induced Th22 response along disease progression in TB patients.
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Affiliation(s)
- Belén R Imperiale
- Institute of Experimental Medicine (IMEX)-CONICET, National Academy of Medicine, Buenos Aires City, Argentina
| | - Ana Gamberale
- Dr. Francisco Javier Muñiz Hospital, Buenos Aires City, Argentina
| | - Noemí Yokobori
- National Institute of Infectious Diseases, ANLIS Carlos G. Malbrán, Buenos Aires City, Argentina
| | - Ana García
- Dr. Francisco Javier Muñiz Hospital, Buenos Aires City, Argentina
| | - Bruno Bartoletti
- Dr. Francisco Javier Muñiz Hospital, Buenos Aires City, Argentina
| | - Omar Aidar
- Dr. Francisco Javier Muñiz Hospital, Buenos Aires City, Argentina
| | - Beatriz López
- National Institute of Infectious Diseases, ANLIS Carlos G. Malbrán, Buenos Aires City, Argentina
| | - Victor Cruz
- Dr. Francisco Javier Muñiz Hospital, Buenos Aires City, Argentina
| | - Pablo González Montaner
- Dr. Francisco Javier Muñiz Hospital, Buenos Aires City, Argentina
- Vaccareza Institute, Buenos Aires City, Argentina
| | - Domingo J Palmero
- Dr. Francisco Javier Muñiz Hospital, Buenos Aires City, Argentina
- Vaccareza Institute, Buenos Aires City, Argentina
| | - Silvia de la Barrera
- Institute of Experimental Medicine (IMEX)-CONICET, National Academy of Medicine, Buenos Aires City, Argentina
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17
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Carlsson E, Cowell-McGlory T, Hedrich CM. cAMP responsive element modulator α promotes effector T cells in systemic autoimmune diseases. Immunology 2023; 170:470-482. [PMID: 37435993 DOI: 10.1111/imm.13680] [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: 04/15/2023] [Accepted: 07/01/2023] [Indexed: 07/13/2023] Open
Abstract
T lymphocytes play a crucial role in adaptive immunity. Dysregulation of T cell-derived inflammatory cytokine expression and loss of self-tolerance promote inflammation and tissue damage in several autoimmune/inflammatory diseases, including systemic lupus erythematosus (SLE) and psoriasis. The transcription factor cAMP responsive element modulator α (CREMα) plays a key role in the regulation of T cell homeostasis. Increased expression of CREMα is a hallmark of the T cell-mediated inflammatory diseases SLE and psoriasis. Notably, CREMα regulates the expression of effector molecules through trans-regulation and/or the co-recruitment of epigenetic modifiers, including DNA methyltransferases (DNMT3a), histone-methyltransferases (G9a) and histone acetyltransferases (p300). Thus, CREMα may be used as a biomarker for disease activity and/or target for future targeted therapeutic interventions.
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Affiliation(s)
- Emil Carlsson
- Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Taylor Cowell-McGlory
- Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Christian M Hedrich
- Department of Women's and Children's Health, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
- Department of Rheumatology, Alder Hey Children's NHS Foundation Trust Hospital, Liverpool, UK
- Paediatric Excellence Initiative, NIHR Great Ormond Street Biomedical Research Centre, Alder Hey Children's NHS Foundation Trust Hospital, Liverpool, UK
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18
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Kim A, Xie F, Abed OA, Moon JJ. Vaccines for immune tolerance against autoimmune disease. Adv Drug Deliv Rev 2023; 203:115140. [PMID: 37980949 PMCID: PMC10757742 DOI: 10.1016/j.addr.2023.115140] [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: 09/22/2023] [Revised: 11/06/2023] [Accepted: 11/10/2023] [Indexed: 11/21/2023]
Abstract
The high prevalence and rising incidence of autoimmune diseases have become a prominent public health issue. Autoimmune disorders result from the immune system erroneously attacking the body's own healthy cells and tissues, causing persistent inflammation, tissue injury, and impaired organ function. Existing treatments primarily rely on broad immunosuppression, leaving patients vulnerable to infections and necessitating lifelong treatments. To address these unmet needs, an emerging frontier of vaccine development aims to restore immune equilibrium by inducing immune tolerance to autoantigens, offering a potential avenue for a cure rather than mere symptom management. We discuss this burgeoning field of vaccine development against inflammation and autoimmune diseases, with a focus on common autoimmune disorders, including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus. Vaccine-based strategies provide a new pathway for the future of autoimmune disease therapeutics, heralding a new era in the battle against inflammation and autoimmunity.
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Affiliation(s)
- April Kim
- Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Fang Xie
- Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA
| | - Omar A Abed
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - James J Moon
- Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA; Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor 48109, USA.
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19
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Dallaston MC, Birtles G, Araujo RP, Jenner AL. The effect of chemotaxis on T-cell regulatory dynamics. J Math Biol 2023; 87:84. [PMID: 37947884 DOI: 10.1007/s00285-023-02017-0] [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: 01/16/2023] [Revised: 10/17/2023] [Accepted: 10/17/2023] [Indexed: 11/12/2023]
Abstract
Autoimmune diseases, such as Multiple Sclerosis, are often modelled through the dynamics of T-cell interactions. However, the spatial aspect of such diseases, and how dynamics may result in spatially heterogeneous outcomes, is often overlooked. We consider the effects of diffusion and chemotaxis on T-cell regulatory dynamics using a three-species model of effector and regulator T-cell populations, along with a chemical signalling agent. While diffusion alone cannot lead to instability and spatial patterning, the inclusion of chemotaxis can result in multiple forms of instability that produce highly complicated spatiotemporal behaviour. The parameter regimes in which different instabilities occur are determined through linear stability analysis and the full dynamics is explored through numerical simulation.
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Affiliation(s)
- Michael C Dallaston
- School of Mathematical Sciences, Queensland University of Technology, George St, Brisbane, QLD, 4000, Australia.
| | - Geneva Birtles
- School of Mathematical Sciences, Queensland University of Technology, George St, Brisbane, QLD, 4000, Australia
| | - Robyn P Araujo
- School of Mathematical Sciences, Queensland University of Technology, George St, Brisbane, QLD, 4000, Australia
| | - Adrianne L Jenner
- School of Mathematical Sciences, Queensland University of Technology, George St, Brisbane, QLD, 4000, Australia
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20
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Zhang T, Dong S, Zhai Y, Naatz L, Zhou Z, Chen M. Diphtheria toxin-derived, anti-PD-1 immunotoxin, a potent and practical tool to selectively deplete PD-1 + cells. Protein Sci 2023; 32:e4741. [PMID: 37515422 PMCID: PMC10443333 DOI: 10.1002/pro.4741] [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: 02/04/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 07/30/2023]
Abstract
Programmed death-1 (PD-1), an immune checkpoint receptor, is expressed on activated lymphocytes, macrophages, and some types of tumor cells. While PD-1+ cells have been implicated in outcomes of cancer immunity, autoimmunity, and chronic infections, the exact roles of these cells in various physiological and pathological processes remain elusive. Molecules that target and deplete PD-1+ cells would be instrumental in defining the roles unambiguously. Previously, an immunotoxin has been generated for the depletion of PD-1+ cells though its usage is impeded by its low production yield. Thus, a more practical molecular tool is desired to deplete PD-1+ cells and to examine functions of these cells. We designed and generated a novel anti-PD1 diphtheria immunotoxin, termed PD-1 DIT, targeting PD-1+ cells. PD-1 DIT is comprised of two single chain variable fragments (scFv) derived from an anti-PD-1 antibody, coupled with the catalytic and translocation domains of the diphtheria toxin. PD-1 DIT was produced using a yeast expression system that has been engineered to efficiently produce protein toxins. The yield of PD-1 DIT reached 1-2 mg/L culture, which is 10 times higher than the previously reported immunotoxin. Flow cytometry and confocal microscopy analyses confirmed that PD-1 DIT specifically binds to and enters PD-1+ cells. The binding avidities between PD-1 DIT and two PD-1+ cell lines are approximately 25 nM. Moreover, PD-1 DIT demonstrated potent cytotoxicity toward PD-1+ cells, with a half maximal effective concentration (EC50 ) value of 1 nM. In vivo experiments further showed that PD-1 DIT effectively depleted PD-1+ cells and enabled mice inoculated with PD-1+ tumor cells to survive throughout the study. Our findings using PD-1 DIT revealed the critical role of pancreatic PD-1+ T cells in the development of type-1 diabetes (T1D). Additionally, we observed that PD-1 DIT treatment ameliorated relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE), a mouse model of relapsing-remitting multiple sclerosis (RR-MS). Lastly, we did not observe significant hepatotoxicity in mice treated with PD-1 DIT, which had been reported for other immunotoxins derived from the diphtheria toxin. With its remarkable selective and potent cytotoxicity toward PD-1+ cells, coupled with its high production yield, PD-1 DIT emerges as a powerful biotechnological tool for elucidating the physiological roles of PD-1+ cells. Furthermore, the potential of PD-1 DIT to be developed into a novel therapeutic agent becomes evident.
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Affiliation(s)
- Tianxiao Zhang
- Department of Molecular PharmaceuticsUniversity of UtahSalt Lake CityUtahUSA
| | - Shuyun Dong
- Department of Molecular PharmaceuticsUniversity of UtahSalt Lake CityUtahUSA
| | - Yujia Zhai
- Department of Molecular PharmaceuticsUniversity of UtahSalt Lake CityUtahUSA
| | - Lauren Naatz
- Department of Molecular PharmaceuticsUniversity of UtahSalt Lake CityUtahUSA
| | - Zemin Zhou
- Department of PathologyUniversity of UtahSalt Lake CityUtahUSA
| | - Mingnan Chen
- Department of Molecular PharmaceuticsUniversity of UtahSalt Lake CityUtahUSA
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21
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Sumbayev VV, Gibbs BF, Fasler-Kan E. Editorial: Pathological reactions of cytotoxic lymphoid cells as universal therapeutic targets in cancer and autoimmune disease. Front Med (Lausanne) 2023; 10:1186318. [PMID: 37181378 PMCID: PMC10167279 DOI: 10.3389/fmed.2023.1186318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 04/10/2023] [Indexed: 05/16/2023] Open
Affiliation(s)
- Vadim V. Sumbayev
- Medway School of Pharmacy, Universities of Kent and Greenwich, Chatham Maritime, United Kingdom
| | - Bernhard F. Gibbs
- Department of Human Medicine, University of Oldenburg, Oldenburg, Germany
| | - Elizaveta Fasler-Kan
- Department of Pediatric Surgery, Children's Hospital, Inselspital Bern, University of Bern, Bern, Switzerland
- Department of Biomedical Research, University of Bern, Bern, Switzerland
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22
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Leng S, Xu W, Wu L, Liu L, Du J, Yang F, Huang D, Zhang L. NLRP3 Disturbs Treg/Th17 Cell Balance to Aggravate Apical Periodontitis. J Dent Res 2023; 102:656-666. [PMID: 36883625 DOI: 10.1177/00220345231151692] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023] Open
Abstract
Apical periodontitis is an inflammatory condition that is considered an immunological reaction of the periapical tissue to invading bacteria and their pathogenic components. Recent research has revealed that NLR family pyrin domain containing 3 (NLRP3) is crucial to the pathogenesis of apical periodontitis and serves as a link between innate and adaptive immunity. The balance between regulatory T-cell (Treg) and T helper cell 17 (Th17 cell) determines the direction of the inflammatory response. Therefore, this study aimed to investigate whether NLRP3 exacerbated periapical inflammation by disturbing Treg/Th17 balance and the underlying regulatory mechanisms. In the present study, NLRP3 was raised in apical periodontitis tissues as opposed to healthy pulp tissues. Low NLRP3 expression in dendritic cells (DCs) increased transforming growth factor β secretion while decreasing interleukin (IL)-1β and IL-6 production. The Treg ratio and IL-10 secretion rose when CD4+ T cells were cocultured with DCs primed with IL-1β neutralizing antibody (anti-IL-1β) and specific small interfering RNA (siRNA) targeting NLRP3 (siRNA NLRP3), but the proportion of Th17 cells and IL-17 release dropped. Furthermore, siRNA NLRP3-mediated suppression of NLRP3 expression aided Treg differentiation and elevated Foxp3 expression as well as IL-10 production in CD4+ T cells. Inhibition of NLRP3 activity by MCC950 boosted the percentage of Tregs while decreasing the ratio of Th17 cells, leading to reduced periapical inflammation and bone resorption. Nigericin administration, however, exacerbated periapical inflammation and bone destruction with an unbalanced Treg/Th17 response. These findings demonstrate that NLRP3 is a pivotal regulator by regulating the release of inflammatory cytokines from DCs or directly suppressing Foxp3 expression to disturb Treg/Th17 balance, thus exacerbating apical periodontitis.
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Affiliation(s)
- S Leng
- Department of Operative Dentistry and Endodontics, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - W Xu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key laboratory of Oral Biomedical Research of Zhejiang Province Cancer Center of Zhejiang University, Hangzhou, China
| | - L Wu
- Department of Geriatric Stomatology, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - L Liu
- Department of Operative Dentistry and Endodontics, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - J Du
- Department of Health Care (Department of General Dentistry II), School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, China
| | - F Yang
- Department of Operative Dentistry and Endodontics, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - D Huang
- Department of Operative Dentistry and Endodontics, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - L Zhang
- Department of Operative Dentistry and Endodontics, State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Disease, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Gholami H, Chmiel JA, Burton JP, Maleki Vareki S. The Role of Microbiota-Derived Vitamins in Immune Homeostasis and Enhancing Cancer Immunotherapy. Cancers (Basel) 2023; 15:1300. [PMID: 36831641 PMCID: PMC9954268 DOI: 10.3390/cancers15041300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 02/15/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Not all cancer patients who receive immunotherapy respond positively and emerging evidence suggests that the gut microbiota may be linked to treatment efficacy. Though mechanisms of microbial contributions to the immune response have been postulated, one likely function is the supply of basic co-factors to the host including selected vitamins. Bacteria, fungi, and plants can produce their own vitamins, whereas humans primarily obtain vitamins from exogenous sources, yet despite the significance of microbial-derived vitamins as crucial immune system modulators, the microbiota is an overlooked source of these nutrients in humans. Microbial-derived vitamins are often shared by gut bacteria, stabilizing bioenergetic pathways amongst microbial communities. Compositional changes in gut microbiota can affect metabolic pathways that alter immune function. Similarly, the immune system plays a pivotal role in maintaining the gut microbiota, which parenthetically affects vitamin biosynthesis. Here we elucidate the immune-interactive mechanisms underlying the effects of these microbially derived vitamins and how they can potentially enhance the activity of immunotherapies in cancer.
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Affiliation(s)
- Hasti Gholami
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
| | - John A. Chmiel
- Department of Microbiology and Immunology, Western University, London, ON N6A 3K7, Canada
- Canadian Research and Development Centre for Probiotics, Lawson Research Health Research Institute, London, ON N6A 5W9, Canada
| | - Jeremy P. Burton
- Department of Microbiology and Immunology, Western University, London, ON N6A 3K7, Canada
- Canadian Research and Development Centre for Probiotics, Lawson Research Health Research Institute, London, ON N6A 5W9, Canada
- Division of Urology, Department of Surgery, Western University, London, ON N6A 3K7, Canada
| | - Saman Maleki Vareki
- Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada
- London Regional Cancer Program, Lawson Health Research Institute, London, ON N6A 5W9, Canada
- Department of Oncology, Western University, London, ON N6A 3K7, Canada
- Department of Medical Biophysics, Western University, London, ON N6A 3K7, Canada
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24
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Yang W, Yu T, Zhou G, Yao S, Wakamiya M, Hu H, Paessler S, Sun J, Cong Y. Intrinsic STING Switches off Pathogenetic Programs of Th1 Cells to Inhibit Colitis. Cell Mol Gastroenterol Hepatol 2023; 15:1161-1179. [PMID: 36736893 PMCID: PMC10040963 DOI: 10.1016/j.jcmgh.2023.01.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 02/05/2023]
Abstract
BACKGROUND & AIMS T helper 1 (Th1) effector cells are implicated in inflammatory bowel disease. The stimulator of interferon genes (STING), an intracellular DNA sensor, has been shown to regulate infection and various cancers. However, whether and how intrinsic STING signaling in Th1 cells regulates colitis is still unknown. METHODS Dextran sodium sulfate-induced colitis and wild-type/STING-deficient CD4+T cell adoptive transfer models were used to analyze the role of STING in regulating colitis. The effect of STING on Th1 cells was determined by flow cytometry, RNA sequencing, metabolic assays, and mitochondrial functions. 16S ribosomal RNA sequencing and germ-free mice were used to investigate whether the microbiota were involved. The in vivo effect of STING agonist in murine colitis was determined. The expression and role of STING in human T cells were also determined. RESULTS Activation of STING transformed proinflammatory IFNγ+Th1 cells into IL-10+IFNγ+Th1 cells, which were dramatically less pathogenic in inducing colitis. STING promoted Th1 interleukin (IL)-10 production by inducing STAT3 translocation into nuclear and mitochondria, which promoted Blimp1 expression and mitochondrial oxidation, respectively. Blockade of glucose or glutamine-derived oxidation, but not lipid-derived oxidation, suppressed STING induction of IL-10. Gut microbiota were changed in STING-/- mice, but the altered microbiota did not mediate STING effects on intestinal CD4+T cell production of IL-10. Translationally, STING agonists suppressed both acute and chronic colitis. Intestinal STING+ CD4+T cells were increased in inflammatory bowel disease patients, and STING agonists upregulated IL-10 production in human CD4+T cells. CONCLUSIONS These findings establish a crucial role of T cell-intrinsic STING in switching off the pathogenic programs of Th1 cells in intestinal inflammation.
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Affiliation(s)
- Wenjing Yang
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas; Sealy Center for Microbiome Research, University of Texas Medical Branch, Galveston, Texas
| | - Tianming Yu
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas; Sealy Center for Microbiome Research, University of Texas Medical Branch, Galveston, Texas
| | - Guangxi Zhou
- Department of Gastroenterology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, P.R. China
| | - Suxia Yao
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas
| | - Maki Wakamiya
- Germ-free Mouse Facility, University of Texas Medical Branch, Galveston, Texas
| | - Haitao Hu
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas
| | - Slobodan Paessler
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas
| | - Jiaren Sun
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas; Department of Pathology, University of Texas Medical Branch, Galveston, Texas
| | - Yingzi Cong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas; Sealy Center for Microbiome Research, University of Texas Medical Branch, Galveston, Texas.
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25
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Meitei HT, Lal G. T cell receptor signaling in the differentiation and plasticity of CD4 + T cells. Cytokine Growth Factor Rev 2023; 69:14-27. [PMID: 36028461 DOI: 10.1016/j.cytogfr.2022.08.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 08/17/2022] [Indexed: 02/07/2023]
Abstract
CD4+ T cells are critical components of the adaptive immune system. The T cell receptor (TCR) and co-receptor signaling cascades shape the phenotype and functions of CD4+ T cells. TCR signaling plays a crucial role in T cell development, antigen recognition, activation, and differentiation upon recognition of foreign- or auto-antigens. In specific autoimmune conditions, altered TCR repertoire is reported and can predispose autoimmunity with organ-specific inflammation and tissue damage. TCR signaling modulates various signaling cascades and regulates epigenetic and transcriptional regulation during homeostasis and disease conditions. Understanding the mechanism by which coreceptors and cytokine signals control the magnitude of TCR signal amplification will aid in developing therapeutic strategies to treat inflammation and autoimmune diseases. This review focuses on the role of the TCR signaling cascade and its components in the activation, differentiation, and plasticity of various CD4+ T cell subsets.
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Affiliation(s)
| | - Girdhari Lal
- National Centre for Cell Science, SPPU campus, Ganeshkhind, Pune, MH 411007, India.
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26
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Wang Z, Dai R, Ahmed SA. MicroRNA-183/96/182 cluster in immunity and autoimmunity. Front Immunol 2023; 14:1134634. [PMID: 36891312 PMCID: PMC9986322 DOI: 10.3389/fimmu.2023.1134634] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 02/09/2023] [Indexed: 02/22/2023] Open
Abstract
MicroRNAs (miRNAs) are crucial post-transcriptional regulators of gene expression in ubiquitous biological processes, including immune-related pathways. This review focuses on the miR-183/96/182 cluster (miR-183C), which contains three miRNAs, miR-183, -96, and -182, having almost identical seed sequences with minor differences. The similarity among seed sequences allows these three miRNAs to act cooperatively. In addition, their minor differences permit them to target distinct genes and regulate unique pathways. The expression of miR-183C was initially identified in sensory organs. Subsequently, abnormal expression of miR-183C miRNAs in various cancers and autoimmune diseases has been reported, implying their potential role in human diseases. The regulatory effects of miR-183C miRNAs on the differentiation and function of both innate and adaptive immune cells have now been documented. In this review, we have discussed the complex role of miR-183C in the immune cells in both normal and autoimmune backgrounds. We highlighted the dysregulation of miR-183C miRNAs in several autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis (MS), and ocular autoimmune disorders, and discussed the potential for utilizing miR-183C as biomarkers and therapeutic targets of specific autoimmune diseases.
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Affiliation(s)
- Zhuang Wang
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine (VMCVM), Virginia Tech, Blacksburg, VA, United States
| | - Rujuan Dai
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine (VMCVM), Virginia Tech, Blacksburg, VA, United States
| | - Sattar Ansar Ahmed
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine (VMCVM), Virginia Tech, Blacksburg, VA, United States
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27
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Liu FL, Chen CL, Huang CH. Preparation of fermented oat milk and evaluation of its modulatory effect on antigen-specific immune responses in ovalbumin-sensitized mice. FOOD AGR IMMUNOL 2022. [DOI: 10.1080/09540105.2022.2120851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Fang-Ling Liu
- Department of Food Science, National Taiwan Ocean University, Keelung, Taiwan
| | - Chien-Li Chen
- Department of Food Science, National Taiwan Ocean University, Keelung, Taiwan
| | - Chung-Hsiung Huang
- Department of Food Science, National Taiwan Ocean University, Keelung, Taiwan
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28
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Moudgil KD, Venkatesha SH. The Anti-Inflammatory and Immunomodulatory Activities of Natural Products to Control Autoimmune Inflammation. Int J Mol Sci 2022; 24:95. [PMID: 36613560 PMCID: PMC9820125 DOI: 10.3390/ijms24010095] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/04/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022] Open
Abstract
Inflammation is an integral part of autoimmune diseases, which are caused by dysregulation of the immune system. This dysregulation involves an imbalance between pro-inflammatory versus anti-inflammatory mediators. These mediators include various cytokines and chemokines; defined subsets of T helper/T regulatory cells, M1/M2 macrophages, activating/tolerogenic dendritic cells, and antibody-producing/regulatory B cells. Despite the availability of many anti-inflammatory/immunomodulatory drugs, the severe adverse reactions associated with their long-term use and often their high costs are impediments in effectively controlling the disease process. Accordingly, suitable alternatives are being sought for these conventional drugs. Natural products offer promising adjuncts/alternatives in this regard. The availability of specific compounds isolated from dietary/medicinal plant extracts have permitted rigorous studies on their disease-modulating activities and the mechanisms involved therein. Here, we describe the basic characteristics, mechanisms of action, and preventive/therapeutic applications of 5 well-characterized natural product compounds (Resveratrol, Curcumin, Boswellic acids, Epigallocatechin-3-gallate, and Triptolide). These compounds have been tested extensively in animal models of autoimmunity as well as in limited clinical trials in patients having the corresponding diseases. We have focused our description on predominantly T cell-mediated diseases, such as rheumatoid arthritis, multiple sclerosis, Type 1 diabetes, ulcerative colitis, and psoriasis.
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Affiliation(s)
- Kamal D. Moudgil
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Baltimore VA Medical Center, Baltimore, MD 21201, USA
| | - Shivaprasad H. Venkatesha
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
- Vita Therapeutics, Baltimore, MD 21201, USA
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29
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Reyes VE. Helicobacter pylori Immune Response in Children Versus Adults. MEDICAL RESEARCH ARCHIVES 2022; 10:3370. [PMID: 37936946 PMCID: PMC10629867 DOI: 10.18103/mra.v10i12.3370] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/09/2023]
Abstract
H. pylori is perhaps the most prevalent human pathogen worldwide and infects almost half of the world's population. Despite the decreasing prevalence of infection overall, it is significant in developing countries. Most infections are acquired in childhood and persist for a lifetime unless treated. Children are often asymptomatic and often develop a tolerogenic immune response that includes T regulatory cells and their products, immunosuppressive cytokines, such as interleukin (IL)-10, and transforming growth factor-β (TGF-β). This contrasts to the gastric immune response seen in H. pylori-infected adults, where the response is mainly inflammatory, with predominant Th1 and Th17 cells, as well as, inflammatory cytokines, such as TNF-α, IFN-γ, IL-1, IL-6, IL-8, and IL-17. Therefore, compared to adults, infected children generally have limited gastric inflammation and peptic ulcer disease. H. pylori surreptitiously subverts immune defenses to persist in the human gastric mucosa for decades. The chronic infection might result in clinically significant diseases in adults, such as peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. This review compares the infection in children and adults and highlights the H. pylori virulence mechanisms responsible for the pathogenesis and immune evasion.
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Affiliation(s)
- Victor E. Reyes
- Department of Pediatrics, Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd. Galveston, TX 77555-0372 USA
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30
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Cheng X, Shen X, Wang M, Li J, Li G. TNFAIP8 modulates the survival and immune activity of Th17 cells via p53/ p21/ MDM2 pathway after acute insult. Cytokine X 2022; 4:100062. [PMID: 35128379 PMCID: PMC8803581 DOI: 10.1016/j.cytox.2022.100062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 09/26/2021] [Accepted: 01/13/2022] [Indexed: 10/25/2022] Open
Abstract
Th17 cells induced immunosuppression plays a vital role in sepsis. As a member of the tumor necrosis factor α induced protein 8 (TNFAIP8) family, TNFAIP8 is associated with different physiopathological conditions with immunological responses. However, its potential roles in regulating Th17 cells after the acute insult have not been fully elucidated. In this study, sepsis was induced by cecal ligation and puncture (CLP) in the male adult C57BL/6 mice. The stable TNFAIP8 knockdown (KD) Th17 cells were established by infecting with lentivirus carrying TNFAIP8-specific shRNA. CCK-8 assay was conducted to evaluate Th17 cell proliferation, and Annexin V/7-AAD assay was applied for apoptosis measurement by flow cytometry. The alterations of p53/ p21/ MDM2 pathway were assessed by Western blot. We observed that a high TNFAIP8 expression level was related to acute injury in septic mice. TNFAIP8 silencing suppressed Th17 cell proliferation and cytokine production in vivo and in vitro. In addition, TNFAIP8 KD increased Th17 cell apoptosis in septic mice. Furthermore, TNFAIP8 seems to affect the immune function of Th17 cells by regulating p53/ p21/ MDM2 signaling processes. We found that TNFAIP8 KD caused the up-regulation of P21 and MDM2, and also elevated p53 protein level during sepsis. Pharmacological inhibition of p53 partially rescued cell proliferation and apoptotic effects of TNFAIP8 KD. In summary, our work suggests that TNFAIP8 modulates the survival and immune function of Th17 cells after acute insult, which was possibly mediated through the p53/ p21/ MDM2 pathway.
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Affiliation(s)
- Xiaobin Cheng
- Department of Intensive Care Unit, Hubei Provincial Hospital of Traditional Chinese Medicine, China
| | - Xiaocheng Shen
- Department of Intensive Care Unit, Wuxi Fifth People's Hospital, China
| | - Min Wang
- Department of Intensive Care Unit, Hubei Provincial Hospital of Traditional Chinese Medicine, China
| | - Jing Li
- Department of Intensive Care Unit, Hubei Provincial Hospital of Traditional Chinese Medicine, China
| | - Gang Li
- Department of Intensive Care Unit, Hubei Provincial Hospital of Traditional Chinese Medicine, China
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31
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Guerreiro VA, Carvalho D, Freitas P. Obesity, Adipose Tissue, and Inflammation Answered in Questions. J Obes 2022; 2022:2252516. [PMID: 35321537 PMCID: PMC8938152 DOI: 10.1155/2022/2252516] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 12/19/2021] [Accepted: 01/03/2022] [Indexed: 12/27/2022] Open
Abstract
Background. Obesity is a global health problem of epidemic proportions, which is characterized by increased adipose tissue (AT) mass and significant repercussions in different body apparati and systems. AT is a special connective tissue, which contains several types of cells, in addition to adipocytes, and is a highly active endocrine and immune organ, which directly modulates many processes, including energy balance, metabolism, and inflammation. Summary. In this paper, the authors list and attempt to answer in a brief and simple way several questions regarding the complex relationships between obesity, adipose tissue, and inflammation, with the objective to provide an easy way to understand the main changes that occur in this pathological state. The questions are the following: Is adipose tissue only made up of adipocytes? Are adipocytes just a reservoir of free fatty acids? Do different types of fatty tissue exist? If so, which types? Can we further subcategorize the types of adipose tissue? Is it possible to form new adipocytes during adulthood? What is the role of inflammation? What is the role of macrophages? Are macrophages central mediators of obesity-induced adipose tissue inflammation and insulin resistance? What causes macrophage infiltration into adipose tissue? What is the role of hypoxia in AT alterations? Is there cross talk between adipocytes and immune cells? What other changes occur in AT in obesity? Does metabolically healthy obesity really exist? Is this a benign condition? Key messages. Obesity is a complex disease with numerous metabolic consequences, which are mainly the result of dysfunction that occurs in the adipose tissue of patients with this pathology. Understanding the pathophysiology of AT and the changes that occur in obesity would contribute to a better approach to patients with obesity, with the inherent medical implications that could result from this.
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Affiliation(s)
- Vanessa A. Guerreiro
- Department of Endocrinology Diabetes and Metabolism, Centro Hospitalar e Universitário de São João, Porto 4200-319, Portugal
- Faculty of Medicine, Universidade do Porto, Porto 4200-319, Portugal
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal
| | - Davide Carvalho
- Department of Endocrinology Diabetes and Metabolism, Centro Hospitalar e Universitário de São João, Porto 4200-319, Portugal
- Faculty of Medicine, Universidade do Porto, Porto 4200-319, Portugal
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal
| | - Paula Freitas
- Department of Endocrinology Diabetes and Metabolism, Centro Hospitalar e Universitário de São João, Porto 4200-319, Portugal
- Faculty of Medicine, Universidade do Porto, Porto 4200-319, Portugal
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto 4200-135, Portugal
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32
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Tang W, Dong M, Teng F, Cui J, Zhu X, Wang W, Wuniqiemu T, Qin J, Yi L, Wang S, Dong J, Wei Y. Environmental allergens house dust mite-induced asthma is associated with ferroptosis in the lungs. Exp Ther Med 2021; 22:1483. [PMID: 34765024 PMCID: PMC8576623 DOI: 10.3892/etm.2021.10918] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 09/09/2021] [Indexed: 12/15/2022] Open
Abstract
Previous studies have indicated that allergens such as house dust mites (HDM) in the environment can induce allergic asthma. Ferroptosis is a newly discovered form of regulatory cell death characterized by aberrant lipid peroxidation and the accumulation of reactive oxygen species (ROS) in cells. However, whether ferroptosis participates in the pathological process of asthma remains to be elucidated. The present study used a HDM-induced mouse asthma model to determine the effect of HDM exposure on allergic asthma and its underlying mechanisms. Female BALB/c mice were intranasally exposed to HDM to induce allergic asthma. Airway hyperresponsiveness (AHR), lung inflammation, mucus secretion, IgE levels, cytokine levels and inflammatory cell counts in bronchoalveolar lavage fluid (BALF) were investigated. In addition, the morphological changes of mitochondria, ROS levels, glutathione (GSH) levels and changes in ferroptosis pathway proteins were also determined in murine lungs. As a result, HDM exposure significantly increased AHR, inflammatory cell infiltration and mucus secretion around the airways. Furthermore, elevated IgE levels in the BALF, lung eosinophilia and a concomitant increase in IL-13 and IL-5 levels in BALF were observed. HDM inhalation increased ROS and decreased GSH levels in the lungs. HDM inhalation induced dysmorphic small mitochondria with decreased crista, as well as condensed, ruptured outer membranes. Western blotting demonstrated that the activities of glutathione peroxidase 4 and catalytic subunit solute carrier family 7 member 11 were significantly decreased, and that protein expression levels of acyl-CoA synthetase long-chain family member 4 and 15 lipoxygenase 1 were upregulated compared with mice in the normal control group. Overall, these results indicated that the AHR, airway inflammation, lipid peroxidation and ROS levels increased in HDM-induced asthma, and that HDM inhalation induced ferroptosis in the lungs, which helped to form an improved understanding of the pathogenesis of allergic asthma.
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Affiliation(s)
- Weifeng Tang
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China.,Cell and Molecular Biology Laboratory, Institutes of Integrative Medicine, Fudan University, Shanghai 200040, P.R. China
| | - Ming Dong
- Department of Acupuncture and Orthopedics, Gumei Community Health Center, Shanghai 201102, P.R. China
| | - Fangzhou Teng
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China.,Cell and Molecular Biology Laboratory, Institutes of Integrative Medicine, Fudan University, Shanghai 200040, P.R. China
| | - Jie Cui
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China.,Cell and Molecular Biology Laboratory, Institutes of Integrative Medicine, Fudan University, Shanghai 200040, P.R. China
| | - Xueyi Zhu
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China.,Cell and Molecular Biology Laboratory, Institutes of Integrative Medicine, Fudan University, Shanghai 200040, P.R. China
| | - Wenqian Wang
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China.,Cell and Molecular Biology Laboratory, Institutes of Integrative Medicine, Fudan University, Shanghai 200040, P.R. China
| | - Tulake Wuniqiemu
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China.,Cell and Molecular Biology Laboratory, Institutes of Integrative Medicine, Fudan University, Shanghai 200040, P.R. China
| | - Jingjing Qin
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China.,Cell and Molecular Biology Laboratory, Institutes of Integrative Medicine, Fudan University, Shanghai 200040, P.R. China
| | - La Yi
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China.,Cell and Molecular Biology Laboratory, Institutes of Integrative Medicine, Fudan University, Shanghai 200040, P.R. China
| | - Shiyuan Wang
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China.,Cell and Molecular Biology Laboratory, Institutes of Integrative Medicine, Fudan University, Shanghai 200040, P.R. China
| | - Jingcheng Dong
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China.,Cell and Molecular Biology Laboratory, Institutes of Integrative Medicine, Fudan University, Shanghai 200040, P.R. China
| | - Ying Wei
- Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China.,Cell and Molecular Biology Laboratory, Institutes of Integrative Medicine, Fudan University, Shanghai 200040, P.R. China
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Li H, Wang Y, Wang J. Th17/Treg cells regulated by interleukin 6 in the pathogenesis of chronic rhinosinusitis with nasal polyps. Eur Arch Otorhinolaryngol 2021; 279:3493-3501. [PMID: 34761301 DOI: 10.1007/s00405-021-07163-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 10/27/2021] [Indexed: 10/19/2022]
Abstract
PURPOSE To be investigated whether Th17/Treg cells regulated by Interleukin-6 in the pathogenesis of chronic rhinosinusitis with nasal polyps. METHODS The distributions of Th17 and Treg cells in peripheral blood mononuclear cells (PBMCs) and tissues got from 46 CRSwNP patients and 14 controls were evaluated. Th17 and Treg cells and cells-related cytokines in serum were assessed in means of cytometric bead array (CBA) multiplex assays and enzyme-linked immunosorbent assays (ELISAs). Spleen cells were isolated from spleen of 20 normal BALB/c mice (male), isolated and purified with CD4 antibody immunomagnetic bead kit. CD4+ cells were divided into three groups, including TGF-β1, TGF-β1+ IL-6 and control (PBS). Treg and Th17 cells and cells related cytokines were detected by flow cytometry (FCM) after collecting spleen cells. The level of IL-10 and IL-17 in supernatant was measured by ELISA. RESULTS Th17/Treg ratio and the level of IL-6 in both ECRSwNP (P < 0.05) and non-ECRSwNP (P < 0.05) were significantly increased when compared with control group, these were consistent with the previous findings. Experiments in vitro suggested that the level of Th17 cells in IL-6+ TGF-β1 group was significantly increased than TGF-β1 group and control group (P < 0.05). The ratio of cells expressed RoRγt in IL-6+ TGF-β1 group was much higher than TGF-β1 group (P < 0.05). CONCLUSION IL-6 might regulate the function of Th17 and Treg cells and the Th17/Treg ratio and have a role in the pathogenesis of CRSwNP.
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Affiliation(s)
- Haiyang Li
- Department of Otorhinolaryngology, Head and Neck Surgery, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongti South Road, Chaoyang District, Beijing, 100020, People's Republic of China
| | - Yongle Wang
- Department of Otorhinolaryngology, Head and Neck Surgery, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongti South Road, Chaoyang District, Beijing, 100020, People's Republic of China
| | - Jianting Wang
- Department of Otorhinolaryngology, Head and Neck Surgery, Beijing Chaoyang Hospital, Capital Medical University, No. 8 Gongti South Road, Chaoyang District, Beijing, 100020, People's Republic of China.
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Muller K, Xiao J, Putra J, Rothstein R, McCourt C, Konnikova L, Lisovsky M. Lymphocytic Esophagitis With Predominance of CD4 T Cells and Expansion of Th1 Cells Is Associated With Achalasia. Am J Clin Pathol 2021; 156:278-287. [PMID: 33609026 DOI: 10.1093/ajcp/aqaa239] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES Although histologic features in biopsies suggesting a possibility of achalasia would be helpful diagnostically, such features remain unknown. The goal of this study was to explore the prevalence, histologic features, and immunophenotype of lymphocytic esophagitis (LyE) in achalasia biopsies. METHODS The study group consisted of 57 patients with achalasia. Controls comprised 52 patients with severe gastroesophageal reflux disease (GERD) and normal esophageal motility. CD4/CD8 immunophenotype of lymphocytes was analyzed by immunohistochemistry. RESULTS LyE was identified in 30% (17/57) of patients with achalasia and 6% (3/52) of patients with GERD, indicating a strong association with achalasia (odds ratio, 6.94; 95% confidence interval, 1.90-25.38). LyE was focal in 59% (10/17) of the cases and diffuse in 41% (7/17). CD4 T-cell predominance over CD8 T cells was observed in 88% of patients with achalasia and LyE. T helper 1 (Th1) cells, but not T helper 2 cells, were expanded in CD4 T cells; in the absence of evident infection, this was compatible with the role of Th1 cells in organ-specific autoimmunity. CONCLUSIONS Achalasia should be considered in the differential diagnosis of clinical entities associated with CD4-predominant LyE. Additional studies to explore the significance of Th1 cells in achalasia-associated LyE are warranted.
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Affiliation(s)
- Kristen Muller
- Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
| | - Jenny Xiao
- Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Juan Putra
- Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
| | - Richard Rothstein
- Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
| | - Collin McCourt
- Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
| | - Liza Konnikova
- Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mikhail Lisovsky
- Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
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Kalani M, Choopanizadeh M, Pourabbas B, Pouladfar G, Asaee S, Ghanbary Ghalati E, Moravej A. Dynamic alterations and durability of T helper 22 and its corresponding cytokines following treatment in pediatric visceral leishmaniasis. Cytokine 2021; 144:155579. [PMID: 34058570 DOI: 10.1016/j.cyto.2021.155579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 05/02/2021] [Accepted: 05/11/2021] [Indexed: 11/18/2022]
Abstract
Considering the collaboration between immune responses and medications for the improvement of visceral leishmaniasis (VL), this study investigated the levels of T helper (Th) 22 and the corresponding cytokines in the acute phase of VL and their alterations following treatment. The study was conducted on 18 patients with confirmed VL and 20 healthy sex and age matched children as the controls. The levels of Th22 cells and the cytokines driving their differentiations and functions in the blood and peripheral blood mononuclear cells (PBMC) cultured supernatants, were assessed using flow cytometry method. The results revealed significantly higher levels of Th22, IL-21 and IL-6 in the patients' blood than those in the controls. Additionally, higher levels of IL-21 and IL-22 were observed in the cultured supernatants of VL patients' PBMCs, compared to the controls. Upon treatment, Th22 and IL-6 were down-regulated and conversely, IL-21, IL-22, IL-23 and IL-33 were significantly up-regulated in the patients' blood at different time points. Receiver operating characteristic (ROC) curve analysis indicated that for the differential diagnosis of VL, plasma IL-21 is more sensitive and specific than Th22 and the above mentioned cytokines. The higher proportions of Th22 and IL-21 in the VL patients and their alterations post treatment confer their roles in the immunopathogenesis of VL. So, Th22 and IL-21 in the patients' blood can be considered as biomarkers to be used for the differential diagnosis of VL. Nevertheless, further studies are warranted to clarify their particular mechanisms in this process.
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Affiliation(s)
- Mehdi Kalani
- Professor Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maral Choopanizadeh
- Professor Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Bahman Pourabbas
- Professor Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Gholamreza Pouladfar
- Professor Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sadaf Asaee
- Professor Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Ali Moravej
- Department of Immunology, Fasa University of Medical Sciences, Fasa, Iran.
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Khan MA, Ashoor GA, Shamma T, Alanazi F, Altuhami A, Kazmi S, Ahmed HA, Mohammed Assiri A, Clemens Broering D. IL-10 Mediated Immunomodulation Limits Subepithelial Fibrosis and Repairs Airway Epithelium in Rejecting Airway Allografts. Cells 2021; 10:1248. [PMID: 34069395 PMCID: PMC8158696 DOI: 10.3390/cells10051248] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/01/2021] [Accepted: 04/20/2021] [Indexed: 12/11/2022] Open
Abstract
Interleukin-10 plays a vital role in maintaining peripheral immunotolerance and favors a regulatory immune milieu through the suppression of T effector cells. Inflammation-induced microvascular loss has been associated with airway epithelial injury, which is a key pathological source of graft malfunctioning and subepithelial fibrosis in rejecting allografts. The regulatory immune phase maneuvers alloimmune inflammation through various regulatory modulators, and thereby promotes graft microvascular repair and suppresses the progression of fibrosis after transplantation. The present study was designed to investigate the therapeutic impact of IL-10 on immunotolerance, in particular, the reparative microenvironment, which negates airway epithelial injury, and fibrosis in a mouse model of airway graft rejection. Here, we depleted and reconstituted IL-10, and serially monitored the phase of immunotolerance, graft microvasculature, inflammatory cytokines, airway epithelium, and subepithelial collagen in rejecting airway transplants. We demonstrated that the IL-10 depletion suppresses FOXP3+ Tregs, tumor necrosis factor-inducible gene 6 protein (TSG-6), graft microvasculature, and establishes a pro-inflammatory phase, which augments airway epithelial injury and subepithelial collagen deposition while the IL-10 reconstitution facilitates FOXP3+ Tregs, TSG-6 deposition, graft microvasculature, and thereby favors airway epithelial repair and subepithelial collagen suppression. These findings establish a potential reparative modulation of IL-10-associated immunotolerance on microvascular, epithelial, and fibrotic remodeling, which could provide a vital therapeutic option to rescue rejecting transplants in clinical settings.
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Affiliation(s)
- Mohammad Afzal Khan
- Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (T.S.); (F.A.); (A.A.); (S.K.); (D.C.B.)
| | | | - Talal Shamma
- Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (T.S.); (F.A.); (A.A.); (S.K.); (D.C.B.)
| | - Fatimah Alanazi
- Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (T.S.); (F.A.); (A.A.); (S.K.); (D.C.B.)
| | - Abdullah Altuhami
- Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (T.S.); (F.A.); (A.A.); (S.K.); (D.C.B.)
| | - Shadab Kazmi
- Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (T.S.); (F.A.); (A.A.); (S.K.); (D.C.B.)
| | - Hala Abdalrahman Ahmed
- Comparative Medicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (H.A.A.); (A.M.A.)
| | - Abdullah Mohammed Assiri
- Comparative Medicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (H.A.A.); (A.M.A.)
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Dieter Clemens Broering
- Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; (T.S.); (F.A.); (A.A.); (S.K.); (D.C.B.)
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Ali M, Yang F, Plachokova AS, Jansen JA, Walboomers XF. Application of specialized pro-resolving mediators in periodontitis and peri-implantitis: a review. Eur J Oral Sci 2021; 129:e12759. [PMID: 33565133 PMCID: PMC7986752 DOI: 10.1111/eos.12759] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 11/18/2020] [Accepted: 11/20/2020] [Indexed: 02/06/2023]
Abstract
Scaling and root planning is a key element in the mechanical therapy used for the eradication of biofilm, which is the major etiological factor for periodontitis and peri‐implantitis. However, periodontitis is also a host mediated disease, therefore, removal of the biofilm without adjunctive therapy may not achieve the desired clinical outcome due to persistent activation of the innate and adaptive immune cells. Most recently, even the resident cells of the periodontium, including periodontal ligament fibroblasts, have been shown to produce several inflammatory factors in response to bacterial challenge. With increased understanding of the pathophysiology of periodontitis, more research is focusing on opposing excessive inflammation with specialized pro‐resolving mediators (SPMs). This review article covers the major limitations of current standards of care for periodontitis and peri‐implantitis, and it highlights recent advances and prospects of SPMs in the context of tissue reconstruction and regeneration. Here, we focus primarily on the role of SPMs in restoring tissue homeostasis after periodontal infection.
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Affiliation(s)
- Muhanad Ali
- Department of Dentistry, Regenerative Biomaterials, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Fang Yang
- Department of Dentistry, Regenerative Biomaterials, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Adelina S Plachokova
- Department of Dentistry, Implantology and Periodontology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - John A Jansen
- Department of Dentistry, Regenerative Biomaterials, Radboud University Medical Center, Nijmegen, The Netherlands
| | - X Frank Walboomers
- Department of Dentistry, Regenerative Biomaterials, Radboud University Medical Center, Nijmegen, The Netherlands
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Wang Y, Lei Y, Gu Y, Kong X, Bian Z, Ji F. Effect of dexmedetomidine on CD4+ T cells and programmed cell death protein-1 in postoperative analgesia: a prospective, randomized, controlled study. Minerva Anestesiol 2021; 87:423-431. [PMID: 33432790 DOI: 10.23736/s0375-9393.20.14581-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Surgical trauma inhibits cellular immunity. Dexmedetomidine produces opioid-sparing effect and an impact on immune response. METHODS Eighty-six surgical patients were enrolled and received postoperative patient-controlled intravenous analgesia (PCIA) with either fentanyl alone (fentanyl group) or combined with dexmedetomidine (dexmedetomidine group). The percentages of T helper cells (Th1, Th2, and Th17) and regulatory T (Treg) cells, expression levels of programmed cell death protein-1 (PD-1) and its ligand (PD-L1) on the CD4+ T cells, and plasma levels of the cytokines were tested. Postoperative pain was measured by numerical rating scale (NRS), including NRS at rest (NRSR) and movement (NRSM). RESULTS In dexmedetomidine group, Th1 cells were increased significantly at 24 and 48 h following surgery (P=0.011 and P=0.013, respectively) and Treg cells were significantly higher at 48 h postoperatively (P=0.013). PD-1 was significantly lower in dexmedetomidine group at 24 h postoperatively (P=0.046) and interleukin 4 (IL-4) and IL-6 were significantly decreased at 48 h postoperatively (P=0.024 and P=0.035, respectively). Compared with fentanyl group, NRSR scores were lower in dexmedetomidine group at 24 h following surgery (P=0.018) and NRSR and NRSM scores were lower at 48 h postoperatively (P=0.007 and P=0.011, respectively). NRSR exhibited negative correlations with Th1 cells in fentanyl group and dexmedetomidine group (P=0.003 and P=0.005, respectively). CONCLUSIONS Dexmedetomidine increases the differentiation of Th1 and Treg cells and reduces the expression of PD-1 on CD4+ T cells. Dexmedetomidine may assist to ameliorate postoperative pain and attenuate proinflammatory response. There might be a negative correlation between pain and Th1 cells.
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Affiliation(s)
- Yulan Wang
- Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yishan Lei
- Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yanzheng Gu
- Clinical Immunology Institute of Jiangsu Province, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiaoqi Kong
- Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhen Bian
- Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Fuhai Ji
- Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, China -
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Bozkurt SB, Tuncer Gokdag I, Hakki SS. Porphyromonas gingivalis-Lipopolysaccharide induces cytokines and enzymes of the mouse cementoblasts. Cytokine 2020; 138:155380. [PMID: 33264747 DOI: 10.1016/j.cyto.2020.155380] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 11/10/2020] [Accepted: 11/21/2020] [Indexed: 12/22/2022]
Abstract
Lipopolysaccharide is a potent virulence factor of Porphyromonas gingivalis and has been implicated predominant pathogen in the development and progression of periodontal diseases. The aim of this study was to determine the effect of Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) on cementoblasts. Cementoblast (OCCM-30) were evaluated proliferation using real-time cell analyzer. In addition, total RNA was isolated at 8, 16, 24 and 72 h from 1000 ng/mL Pg-LPS treated OCCM-30 cells and mRNA expressions of pro/anti-inflammatory cytokine mediators, extracellular matrix enzymes and their tissue inhibitors and of oxidative stress enzymes were studied by real-time polymerase chain reaction. Proliferation analysis indicated that Pg-LPS slightly decreased proliferation of OCCM-30. Pg-LPS had a time-dependent impact on the expression of cytokines and enzymes. There was statistically significant up-regulation of IL-1β and IL-10 in response to Pg-LPS at 8, 16, 24, 72 h but IL-6 expression was reduced compared to control at 8 h. While IL-8 and IL-17 expressions were determined higher than control group at 16 and 24 h, their expressions were decreased compared to control groups at 72 h (p < 0.01). While MMP-1, MMP-2, MMP-3, TIMP-1, TIMP-2 expressions increased, MMP-9 expression reduced at time-points. Also, a time-dependent up-regulation in mRNA levels for oxidative stress enzymes was detected. These results indicated that up-regulation in the transcripts of inflammation-associated cytokines and degradation enzymes were noted in the cementoblasts exposed to Pg-LPS. Cementoblasts infected with the virulence factors of periodontopathogens might also involve to the induction of inflammation and degradation of the periodontal tissues.
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Affiliation(s)
- S B Bozkurt
- Department of Research Center, Faculty of Dentistry, Hacettepe University, Ankara, Turkey.
| | - I Tuncer Gokdag
- Republic of Turkey Ministry of Health, Oral and Dental Health Center, Ankara, Turkey
| | - Sema Sezgin Hakki
- Department of Periodontology, Faculty of Dentistry, Selcuk University, Konya, Turkey
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Rai G, Das S, Ansari MA, Singh PK, Dar SA, Haque S, Gupta N, Sharma S, Ramachandran VG, Sharma S, Jain C, Sharma S. TLR-2 expression and dysregulated human Treg/Th17 phenotype in Aspergillus flavus infected patients of chronic rhinosinusitis with nasal polyposis. Microb Cell Fact 2020; 19:215. [PMID: 33238997 PMCID: PMC7689976 DOI: 10.1186/s12934-020-01481-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 11/20/2020] [Indexed: 12/17/2022] Open
Abstract
Background T helper (Th)17 and regulatory T (Treg) cells with toll-like receptor (TLR)-2 have been acknowledged to play a critical role in chronic rhinosinusitis with nasal polyposis (CRSwNP). However, its pathogenesis has been perplexed by conflicting reports on the role of Th17/Treg cells in patients of distinct ethnicities. We attempted to understand the role of Th responses induced during host defense against Aspergillus flavus. Results The percentages of Th17 (CD4+CD161+IL23R+) and Treg (CD4+CD25+FoxP3+) cell populations and various cytokine profiles in peripheral blood mononuclear cells (PBMCs) challenged by A. flavus antigens were characterized from 50 CRSwNP cases, before and after treatment, and in 50 healthy controls. TLR-2 expression was analyzed in tissues of cases and controls for disease co-relation. The major pathogen identified in our study was A. flavus by mycological investigations. A marked immune imbalance was noted with elevated Th17 and decreased Tregs in PBMCs of CRSwNP patients after A. flavus stimulation. Comparatively, interleukin (IL)-17 and IL-10 levels were increased, with low transforming growth factor (TGF)-β levels in A. flavus stimulated PBMC supernatants of patients. The mRNA expression of TLR-2 in polyps of CRSwNP patients indicated significant (p = 0.001) upregulation in comparison to the controls. Conclusions Our data highlights the excessive expression of TLR-2 in nasal polyps contributing to the imbalance in Th17/Tregs population in patients. After therapy, recovery of Tregs cells indicates restoration and tissue homeostasis, though high circulating CD4+CD161+ Th17 cells may continue to be a threat to patients predisposed to future recurrences. The constant exposure and tendency of A. flavus to colonize nasal cavities can lead to a Th17 driven airway inflammation. Dysregulated Th17 with TLR-2 promote resistance to treatment and progression to the chronicity of the disease.
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Affiliation(s)
- Gargi Rai
- Department of Microbiology, University College of Medical Sciences (University of Delhi) and Guru Teg Bahadur Hospital, Delhi, India
| | - Shukla Das
- Department of Microbiology, University College of Medical Sciences (University of Delhi) and Guru Teg Bahadur Hospital, Delhi, India.
| | - Mohammad Ahmad Ansari
- Department of Microbiology, University College of Medical Sciences (University of Delhi) and Guru Teg Bahadur Hospital, Delhi, India
| | - Praveen Kumar Singh
- Department of Microbiology, University College of Medical Sciences (University of Delhi) and Guru Teg Bahadur Hospital, Delhi, India
| | - Sajad Ahmad Dar
- Department of Microbiology, University College of Medical Sciences (University of Delhi) and Guru Teg Bahadur Hospital, Delhi, India.,Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
| | - Neelima Gupta
- Department of Otorhinolaryngology, University College of Medical Sciences (University of Delhi) and Guru Teg Bahadur Hospital, Delhi, India
| | - Sonal Sharma
- Department of Pathology, University College of Medical Sciences (University of Delhi) and Guru Teg Bahadur Hospital, Delhi, India
| | | | | | - Charu Jain
- Department of Microbiology, ESIC Medical College, Faridabad, Haryana, India
| | - Shipra Sharma
- S R Institute of Management and Technology, Lucknow, UP, India
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Romano F, Del Buono W, Bianco L, Arena M, Mariani GM, Di Scipio F, Berta GN, Aimetti M. Gingival Crevicular Fluid Cytokines in Moderate and Deep Sites of Stage III Periodontitis Patients in Different Rates of Clinical Progression. Biomedicines 2020; 8:biomedicines8110515. [PMID: 33218047 PMCID: PMC7698864 DOI: 10.3390/biomedicines8110515] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/11/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023] Open
Abstract
Clinical criteria are inappropriate to measure the degree of susceptibility to progression of periodontal damage. Thus, the aim of this study was to assess whether gingival crevicular fluid (GCF) levels of cytokines could discriminate patients suffering from stage III periodontitis with moderate (Grade B) and rapid rates of progression (Grade C) prior to and 6 months after non-surgical periodontal treatment. GCF samples were obtained from moderate and deep sites of 20 patients diagnosed as Grade B and 20 patients as grade C stage III periodontitis and analyzed for interleukin (IL)-1β, IL-9, tumor necrosis factor (TNF)-α, and vascular endothelial growth factor (VEGF) using a high-sensitivity Bio-Plex Suspension Array System. At baseline, higher IL-1β but lower IL-9 GCF levels were observed in moderate sites of the grade C compared to the grade B group. In spite of comparable clinical improvement, this difference maintained after treatment, suggesting a residual pro-inflammatory state. In deep sites, no differences were observed between periodontitis groups except for VEGF levels that decreased more in Grade B periodontitis at 6 months post-therapy. A mathematical model was constructed to identify Grade C periodontitis patients based on the subjects’ GCF levels of IL-1β and IL-9, which achieved an area under the receiver-operating characteristic (ROC) curve of 0.94. This study can contribute to the early assessment of risk of future breakdown in periodontitis patients.
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Affiliation(s)
- Federica Romano
- Department of Surgical Sciences, C.I.R. Dental School, Section of Periodontology, University of Turin, 10126 Turin, Italy; (F.R.); (W.D.B.); (L.B.); (M.A.); (G.M.M.)
| | - Wilma Del Buono
- Department of Surgical Sciences, C.I.R. Dental School, Section of Periodontology, University of Turin, 10126 Turin, Italy; (F.R.); (W.D.B.); (L.B.); (M.A.); (G.M.M.)
| | - Laura Bianco
- Department of Surgical Sciences, C.I.R. Dental School, Section of Periodontology, University of Turin, 10126 Turin, Italy; (F.R.); (W.D.B.); (L.B.); (M.A.); (G.M.M.)
| | - Martina Arena
- Department of Surgical Sciences, C.I.R. Dental School, Section of Periodontology, University of Turin, 10126 Turin, Italy; (F.R.); (W.D.B.); (L.B.); (M.A.); (G.M.M.)
| | - Giulia Maria Mariani
- Department of Surgical Sciences, C.I.R. Dental School, Section of Periodontology, University of Turin, 10126 Turin, Italy; (F.R.); (W.D.B.); (L.B.); (M.A.); (G.M.M.)
| | - Federica Di Scipio
- Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy;
| | - Giovanni Nicolao Berta
- Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy;
- Correspondence: (G.N.B.); (M.A.)
| | - Mario Aimetti
- Department of Surgical Sciences, C.I.R. Dental School, Section of Periodontology, University of Turin, 10126 Turin, Italy; (F.R.); (W.D.B.); (L.B.); (M.A.); (G.M.M.)
- Correspondence: (G.N.B.); (M.A.)
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Cytokine saga in visceral leishmaniasis. Cytokine 2020; 147:155322. [PMID: 33127259 DOI: 10.1016/j.cyto.2020.155322] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 09/21/2020] [Accepted: 09/25/2020] [Indexed: 12/12/2022]
Abstract
In humans, infection with Leishmania manifests into a spectrum of diseases. The manifestation of the diseases depend on the resultant evasion of the parasite to immune responses namely by macrophages, which is an exclusive host of Leishmania. The B cells valiantly mount antibody responses, however, to no avail as the Leishmania parasites occupy the intracellular niches of the macrophages and subvert the immune response. Extensive studies have been documented on the role of cell-mediated immunity (CMI) in protection and counter survival strategies of the parasites leading to downregulation of CMI. The present review attempts to discuss the cytokines in progression or resolution of visceral form of leishmaniasis or kala-azar, predominantly affecting the Indian subcontinent. The components/cytokine(s) responsible for the regulation of the critical balance of T helper cells and their subsets have been discussed in the perspective. Therefore, any strategy involving the treatment of visceral leishmania (VL) needs to consider the balance and regulation of T cell function.
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Sag E, Kale G, Haliloglu G, Bilginer Y, Akcoren Z, Orhan D, Gucer S, Topaloglu H, Ozen S, Talim B. Inflammatory milieu of muscle biopsies in juvenile dermatomyositis. Rheumatol Int 2020; 41:77-85. [PMID: 33106894 DOI: 10.1007/s00296-020-04735-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 10/13/2020] [Indexed: 01/08/2023]
Abstract
Juvenile dermatomyositis (JDM) is an inflammatory myopathy which causes severe morbidity and high mortality if untreated. In this study, we aimed to define the T-helper cell profile in the muscle biopsies of JDM patients. Muscle biopsies of twenty-six patients (50% female) were included in the study. Immunohistochemical expression of CD3, CD20, CD138, CD68, IL-17, Foxp3, IFN-ɣ, IFN-alpha and IL-4 was studied and muscle biopsies were scored using the JDM muscle biopsy scoring tool. Inflammatory cells were in small clusters in perimysium and perivascular area or scattered throughout the endomysium in most biopsies; however in 2 biopsies, lymphoid follicle-like big clusters were observed, and in one, there was a very dense and diffuse inflammatory infiltration nearly destroying all the muscle architecture. Seventy-three per cent of the biopsies had T cells, 88% had B cells, 57% had plasma cells, and all had macrophages. As for T-helper cell subtypes, 80% of the biopsies were Th1 positive, 92% Th17 positive and 30% Treg positive. No IL-4 positive inflammatory cell was detected, and only 2 biopsies showed IFN-alpha positivity. The mean JDM biopsy score was 17.6, meaning moderate to severe muscular involvement. Visual analogue score of the pathologist was strongly correlated with histopathological features. B cells, macrophages, plasma cells and T cells constitute the inflammatory milieu of the JDM muscle biopsies. As for T cells, JDM is a disease mainly related with Th1 and Th17 T-helper cell subtypes and to some extend Treg. Th2 cells are not involved in the pathogenesis.
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Affiliation(s)
- Erdal Sag
- Division of Pediatric Rheumatology, Department of Pediatrics, Hacettepe University, Ankara, Turkey.
| | - Gulsev Kale
- Pediatric Pathology Unit, Department of Pediatrics, Hacettepe University, Ankara, Turkey
| | - Goknur Haliloglu
- Division of Pediatric Neurology, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Yelda Bilginer
- Division of Pediatric Rheumatology, Department of Pediatrics, Hacettepe University, Ankara, Turkey
| | - Zuhal Akcoren
- Pediatric Pathology Unit, Department of Pediatrics, Hacettepe University, Ankara, Turkey
| | - Diclehan Orhan
- Pediatric Pathology Unit, Department of Pediatrics, Hacettepe University, Ankara, Turkey
| | - Safak Gucer
- Pediatric Pathology Unit, Department of Pediatrics, Hacettepe University, Ankara, Turkey
| | - Haluk Topaloglu
- Division of Pediatric Neurology, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Seza Ozen
- Division of Pediatric Rheumatology, Department of Pediatrics, Hacettepe University, Ankara, Turkey
| | - Beril Talim
- Pediatric Pathology Unit, Department of Pediatrics, Hacettepe University, Ankara, Turkey
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45
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Magni G, Ceruti S. Adenosine Signaling in Autoimmune Disorders. Pharmaceuticals (Basel) 2020; 13:ph13090260. [PMID: 32971792 PMCID: PMC7558305 DOI: 10.3390/ph13090260] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 09/15/2020] [Accepted: 09/18/2020] [Indexed: 12/14/2022] Open
Abstract
The molecular components of the purinergic system (i.e., receptors, metabolizing enzymes and membrane transporters) are widely expressed in the cells of the immune system. Additionally, high concentrations of adenosine are generated from the hydrolysis of ATP in any "danger" condition, when oxygen and energy availability dramatically drops. Therefore, adenosine acts as a retaliatory metabolite to counteract the nucleotide-mediated boost of the immune reaction. Based on this observation, it can be foreseen that the recruitment with selective agonists of the receptors involved in the immunomodulatory effect of adenosine might represent an innovative anti-inflammatory approach with potential exploitation in autoimmune disorders. Quite surprisingly, pro-inflammatory activity exerted by some adenosine receptors has been also identified, thus paving the way for the hypothesis that at least some autoimmune disorders may be caused by a derailment of adenosine signaling. In this review article, we provide a general overview of the roles played by adenosine on immune cells with a specific focus on the development of adenosine-based therapies for autoimmune disorders, as demonstrated by the exciting data from concluded and ongoing clinical trials.
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Talotta R, Robertson E. Autoimmunity as the comet tail of COVID-19 pandemic. World J Clin Cases 2020; 8:3621-3644. [PMID: 32953841 PMCID: PMC7479552 DOI: 10.12998/wjcc.v8.i17.3621] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 07/29/2020] [Accepted: 08/26/2020] [Indexed: 02/05/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can give rise to different clinical manifestations that are directly related to viral tissue damage or indirectly induced by the antiviral immune response. Hyper-activation of the immune system in an attempt to eradicate the infection may trigger autoimmunity. Several immune-mediated disorders have been described in SARS-CoV-2-infected individuals. These include cutaneous rashes and vasculitis, autoimmune cytopenia, anti-phospholipid syndrome, central or peripheral neuropathy, myositis and myocarditis. On the other hand, rheumatic patients were reported to have similar coronavirus disease 2019 (COVID-19) incidence, morbidity and mortality rates compared to general population. This opinion review will summarize the crucial immunologic steps which occur during SARS-CoV-2-infection that may link autoimmunity to COVID-19 and provides an opportunity for further discussion regarding this association.
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Affiliation(s)
- Rossella Talotta
- Department of Clinical and Experimental Medicine, Rheumatology Unit, AOU “Gaetano Martino”, University of Messina, Messina 98100, Italy
| | - Erle Robertson
- Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19014, United States
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47
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Valero MA, Gironès N, Reguera-Gomez M, Pérez-Crespo I, López-García MP, Quesada C, Bargues MD, Fresno M, Mas-Coma S. Impact of fascioliasis reinfection on Fasciola hepatica egg shedding: relationship with the immune-regulatory response. Acta Trop 2020; 209:105518. [PMID: 32371223 DOI: 10.1016/j.actatropica.2020.105518] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 04/07/2020] [Accepted: 04/24/2020] [Indexed: 11/29/2022]
Abstract
Fascioliasis is a disease caused by liver flukes. In human fascioliasis hyperendemic areas, reinfection and chronicity are the norm. Control strategies in humans require the use of egg count techniques to calculate the appropriate treatment dose for colic risk prevention. The present study investigates how fascioliasis reinfection affects liver fluke egg shedding and its relationship with the immune-regulatory response. The experimental design reproduced the usual reinfection/chronicity conditions in human fascioliasis endemic areas and included Fasciola hepatica primo-infected Wistar rats (PI) and rats reinfected at 4 weeks (R4), 8 weeks (R8), 12 weeks (R12), and negative control rats. In a longitudinal study (0-20 weeks post-infection, p.i.), serical IgG1 levels and eggs per gram of faeces (epg) were analyzed. In a cross-sectional study, the expression of the genes associated with Th1 (Ifng, Il12a, Il12b, Nos2), Th2 (Il4, Arg1), Treg (Foxp3, Il10, Tgfb, Ebi3), and Th17 (Il17) in the spleen and thymus was analyzed. In R8 and R12, transiently higher averages of epg and epg/worm in reinfected groups vs PI group were detected at least in the weeks following reinfection. The kinetics of IgG1 levels shows that reinfected groups followed a pattern similar to the one in the PI group, but transiently higher averages of IgG1 levels in reinfected groups vs the PI group were detected in the weeks following reinfection. Epg correlated with IgG1 levels and also with systemic Il10 and thymic Ifng, and Il10 expression levels. These results suggest that epg depends on the Th1 and Treg phenotype and that the determination of the fluke burden by epg is likely to be an overestimation in cases of recent reinfection in low burden situations. A strategy to facilitate the implementation of epg count techniques and the subsequent decision on the appropriate treatment dose for each patient to prevent colic risk is required.
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Affiliation(s)
- M Adela Valero
- Departamento de Parasitología, Facultad de Farmacia, Universidad de Valencia, Av. Vicent Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain.
| | - Nuria Gironès
- Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Cantoblanco, 28049 Madrid, Spain.
| | - Marta Reguera-Gomez
- Departamento de Parasitología, Facultad de Farmacia, Universidad de Valencia, Av. Vicent Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain.
| | - Ignacio Pérez-Crespo
- Departamento de Parasitología, Facultad de Farmacia, Universidad de Valencia, Av. Vicent Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain
| | - M Pilar López-García
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Valencia, Av. Vicent Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain
| | - Carla Quesada
- Departamento de Parasitología, Facultad de Farmacia, Universidad de Valencia, Av. Vicent Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain
| | - M Dolores Bargues
- Departamento de Parasitología, Facultad de Farmacia, Universidad de Valencia, Av. Vicent Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain.
| | - Manuel Fresno
- Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Cantoblanco, 28049 Madrid, Spain
| | - Santiago Mas-Coma
- Departamento de Parasitología, Facultad de Farmacia, Universidad de Valencia, Av. Vicent Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain.
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Peter J, Sabu V, Aswathy IS, Krishnan S, Lal Preethi SS, Simon M, Helen A. Dietary amaranths modulate the immune response via balancing Th1/Th2 and Th17/Treg response in collagen-induced arthritis. Mol Cell Biochem 2020; 472:57-66. [PMID: 32529499 DOI: 10.1007/s11010-020-03783-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 06/04/2020] [Indexed: 11/25/2022]
Abstract
Imbalance between Th1/Th2 and Th17/Treg is crucial in RA progression. Various dietary factors can modulate the disease severity by restoring the balance in differentiation of CD4+ T cell subsets. Dietary amaranths hold an important part of diet as vegetables, where commonly consumed species includes Amaranthus cruentus (Ac), Amaranthus viridis (Av), and Amaranthus hybridus (Ah). The present study focuses on to evaluate whether these dietary amaranths can modulate the immune activation in collagen-induced arthritis. For in vivo study, Female Wistar rats were immunized with type II collagen and after immunization period, rats were separately supplemented with cooked Ac, Av, and Ah at 500 mg/100 g bwt concentration mixed with standard rat feed for 60 days. HPTLC fingerprint analysis identified peaks for compounds in these three amaranths. The results showed a protective role of immunomodulation in Th1/Th2 response of the three dietary amaranths, by significantly augmenting lymphocyte activation with increased IL-4 secretion, but decreased IFN-γ by cultured spleen lymphocytes subjected to collagen-induced inflammation. Moreover, Th17/Treg imbalance created by increase in IL-17 and decrease in IL-10 was significantly balanced by the three dietary supplemented groups. Furthermore, Th1/Th2 status reflected from Tbet/GATA3 ratio and Th17/Treg status reflected from RORγt/FOXP3 ratio was significantly decreased in the three dietary amaranth supplemented groups. Thus, dietary amaranths provide an immune-modulating role by keeping the balance between Th1/Th2 and Th17/Treg response in collagen-induced inflammation.
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Affiliation(s)
- Jasmine Peter
- Department of Biochemistry, University of Kerala, Kariavattom Campus, Thiruvananthapuram, Kerala, 695581, India
| | - Vidya Sabu
- Department of Biochemistry, University of Kerala, Kariavattom Campus, Thiruvananthapuram, Kerala, 695581, India
| | - I S Aswathy
- Department of Biochemistry, University of Kerala, Kariavattom Campus, Thiruvananthapuram, Kerala, 695581, India
| | - Santhi Krishnan
- Department of Biochemistry, University of Kerala, Kariavattom Campus, Thiruvananthapuram, Kerala, 695581, India
| | - S S Lal Preethi
- Department of Biochemistry, University of Kerala, Kariavattom Campus, Thiruvananthapuram, Kerala, 695581, India
| | - Monisha Simon
- Department of Biochemistry, University of Kerala, Kariavattom Campus, Thiruvananthapuram, Kerala, 695581, India
| | - A Helen
- Department of Biochemistry, University of Kerala, Kariavattom Campus, Thiruvananthapuram, Kerala, 695581, India.
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49
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Chen P, Ming S, Lao J, Li C, Wang H, Xiong L, Zhang S, Liang Z, Niu X, Deng S, Geng L, Wu M, Wu Y, Gong S. CD103 Promotes the Pro-inflammatory Response of Gastric Resident CD4 + T Cell in Helicobacter pylori-Positive Gastritis. Front Cell Infect Microbiol 2020; 10:436. [PMID: 32974219 PMCID: PMC7472738 DOI: 10.3389/fcimb.2020.00436] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 07/16/2020] [Indexed: 12/12/2022] Open
Abstract
CD103 is considered as a surface marker for the resident immune cells. However, little is known about the intrinsic function of CD103 in infection and inflammation. In this study, we found that CD103 was highly expressed in CD4+T cells of the gastric mucosa from patients with H. pylori-positive gastritis. Mucosal resident CD103+CD4+T cells exhibited an increase in the CD45RO+CCR7− effector memory phenotype and high expression of the chemokine receptors CXCR3 and CCR9 compared with those in CD103−CD4+T cells. An In vitro coculture study demonstrated that H. pylori-specific antigen CagA/VacA-primed dendritic cells (DCs) induced proliferation and IFN-γ, TNF as well as IL-17 production by CD103+CD4+T cells from patients with H. pylori-positive gastritis, while blocking CD103 with a neutralizing antibody reduced proliferation and IFN-γ, TNF, and IL-17 production by CD103+CD4+T cells cocultured with DCs. Moreover, immunoprecipitation revealed that CD103 interacted with TCR α/β and CD3ζ, and activation of CD103 enhanced the phosphorylation of ZAP70 induced by the TCR signal. Finally, increased T-bet and Blimp1 levels were also observed in CD103+CD4+T cells, and activating CD103 increased T-bet and Blimp1 expression in CD4+T cells. Our results explored the intrinsic function of CD103 in gastric T cells from patients with H. pylori-positive gastritis, which may provide a therapeutic target for the treatment of gastritis.
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Affiliation(s)
- Peiyu Chen
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, China
| | - Siqi Ming
- Center for Infection and Immunity, Zhongshan School of Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Juanfeng Lao
- Center for Infection and Immunity, Zhongshan School of Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chunna Li
- Center for Infection and Immunity, Zhongshan School of Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hongli Wang
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, China
| | - Liya Xiong
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, China
| | - Shunxian Zhang
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, China
| | - Zibin Liang
- Center for Infection and Immunity, Zhongshan School of Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoli Niu
- Center for Infection and Immunity, Zhongshan School of Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Simei Deng
- Center for Infection and Immunity, Zhongshan School of Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Lanlan Geng
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, China
| | - Minhao Wu
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, China.,Center for Infection and Immunity, Zhongshan School of Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yongjian Wu
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, China.,Center for Infection and Immunity, Zhongshan School of Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Sitang Gong
- Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou Institute of Pediatrics, Guangzhou Medical University, Guangzhou, China
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50
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Cannas D, Loi E, Serra M, Firinu D, Valera P, Zavattari P. Relevance of Essential Trace Elements in Nutrition and Drinking Water for Human Health and Autoimmune Disease Risk. Nutrients 2020; 12:E2074. [PMID: 32668647 PMCID: PMC7400883 DOI: 10.3390/nu12072074] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 02/07/2023] Open
Abstract
Trace elements produce double-edged effects on the lives of animals and particularly of humans. On one hand, these elements represent potentially toxic agents; on the other hand, they are essentially needed to support growth and development and confer protection against disease. Certain trace elements and metals are particularly involved in humoral and cellular immune responses, playing the roles of cofactors for essential enzymes and antioxidant molecules. The amount taken up and the accumulation in human tissues decisively control whether the exerted effects are toxic or beneficial. For these reasons, there is an urgent need to re-consider, harmonize and update current legislative regulations regarding the concentrations of trace elements in food and in drinking water. This review aims to provide information on the interrelation of certain trace elements with risk of autoimmune disease, with a particular focus on type 1 diabetes and multiple sclerosis. In addition, an overview of the current regulations and regulatory gaps is provided in order to highlight the importance of this issue for everyday nutrition and human health.
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Affiliation(s)
- Daniela Cannas
- Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, 09042 Cagliari, Italy; (D.C.); (E.L.)
| | - Eleonora Loi
- Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, 09042 Cagliari, Italy; (D.C.); (E.L.)
| | - Matteo Serra
- Department of Civil, Environmental Engineering and Architecture, University of Cagliari, 09123 Cagliari, Italy;
| | - Davide Firinu
- Department of Medical Sciences and Public Health, Monserrato Campus, University of Cagliari, 09042 Cagliari, Italy;
| | - Paolo Valera
- Department of Civil, Environmental Engineering and Architecture, University of Cagliari, 09123 Cagliari, Italy;
| | - Patrizia Zavattari
- Department of Biomedical Sciences, Unit of Biology and Genetics, University of Cagliari, 09042 Cagliari, Italy; (D.C.); (E.L.)
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