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Fehringer M, Vogl T. Molecular mimicry in the pathogenesis of autoimmune rheumatic diseases. J Transl Autoimmun 2025; 10:100269. [PMID: 39877080 PMCID: PMC11773492 DOI: 10.1016/j.jtauto.2025.100269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 01/06/2025] [Accepted: 01/06/2025] [Indexed: 01/31/2025] Open
Abstract
Autoimmune rheumatic diseases (ARDs) are a heterogeneous group of conditions characterized by excessive and misdirected immune responses against the body's own musculoskeletal tissues. Their exact aetiology remains unclear, with genetic, demographic, behavioural and environmental factors implicated in disease onset. One prominent hypothesis for the initial breach of immune tolerance (leading to autoimmunity) is molecular mimicry, which describes structural or sequence similarities between human and microbial proteins (mimotopes). This similarity can lead to cross-reactive antibodies and T-cell receptors, resulting in an immune response against autoantigens. Both commensal microbes in the human microbiome and pathogens can trigger molecular mimicry, thereby potentially contributing to the onset of ARDs. In this review, we focus on the role of molecular mimicry in the onset of rheumatoid arthritis and systemic lupus erythematosus. Moreover, implications of molecular mimicry are also briefly discussed for ankylosing spondylitis, systemic sclerosis and myositis.
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Affiliation(s)
| | - Thomas Vogl
- Medical University of Vienna, Borschkegasse 8a, 1090, Vienna, Austria
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2
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O'Garra A. From Cytokines to Tuberculosis and Back: My Journey to Understanding the Immune Response to Infection. Annu Rev Immunol 2025; 43:1-28. [PMID: 40279305 DOI: 10.1146/annurev-immunol-010824-041601] [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] [Indexed: 04/27/2025]
Abstract
I felt honored by the invitation to write this autobiography, although it was an arduous task to describe my journey through science: first bacterial adhesion, then cytokine function, and then immune responses in tuberculosis. Since only seven women had been authors of autobiographies for the Annual Review of Immunology, I felt I couldn't refuse to contribute to Volume 43 of the journal. Moreover, this was a good occasion to record my appreciation to all the lab members and collaborators for their contributions over the last 40 years, to remember the exciting times, and to reflect on the obstacles we faced. I often reflect on this line that is commonly attributed to Winston Churchill: Success is not final; failure is not fatal: It is the courage to continue that counts. What kept me going was a burning desire to know how things work and find enjoyment in the discovery. This passion to understand immune responses to infection remains with me to this day. I thank all those I have interacted with for the support and friendship they provided.
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Affiliation(s)
- Anne O'Garra
- Laboratory of Immunoregulation and Infection, The Francis Crick Institute, London, United Kingdom;
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3
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Wang J, Wang R, Wang M, Ge J, Wang Y, Li Y, Chen C, He J, Zheng B, Xu M, Jiang X, Liu Y, Chen M, Long J. Cutting-Edge Therapy and Immune Escape Mechanisms in EBV-Associated Tumors. Med Res Rev 2025. [PMID: 40077924 DOI: 10.1002/med.22104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 12/19/2024] [Accepted: 02/21/2025] [Indexed: 03/14/2025]
Abstract
Epstein-Barr virus (EBV), the first identified human tumor virus, significantly influences the immune microenvironment of associated cancers. EBV-induced expression of viral antigens by tumor cells triggers immune recognition and elicits a pro-inflammatory response. While mild inflammation may help eliminate malignant cells, intense inflammation can accelerate tumor progression. Moreover, EBV can establish lifelong latency in human hosts, characterized by low immunogenicity of its proteins and noncoding RNAs. This enables tumor cells to evade immune detection and impair immune cell function, disrupting immune homeostasis. Consequently, EBV-associated malignancies pose a considerable public health challenge globally, often complicating the prognosis of cancer patients under conventional treatment. With deeper research into the oncogenic expressions and mechanisms of EBV, novel targeted therapies against EBV are gaining prominence. This review discusses recent advancements in understanding how EBV helps tumor cells evade immune surveillance and induce immune dysfunction. It also examines the clinical potential of targeting EBV-associated tumors, providing fresh perspectives on the mechanisms and therapeutic strategies for these cancers.
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Affiliation(s)
- Jie Wang
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences & Diagnostic Pathology Center, Fujian Medical University, Fuzhou, China
| | - Rong Wang
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences & Diagnostic Pathology Center, Fujian Medical University, Fuzhou, China
- Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Meifeng Wang
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences & Diagnostic Pathology Center, Fujian Medical University, Fuzhou, China
| | - Junshang Ge
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medicine Sciences, Central South University, Changsha, China
| | - Yian Wang
- The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, School of Medicine, Hunan Normal University; The Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Changsha, China
| | - Yanhan Li
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences & Diagnostic Pathology Center, Fujian Medical University, Fuzhou, China
| | - Changan Chen
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences & Diagnostic Pathology Center, Fujian Medical University, Fuzhou, China
| | - Jiale He
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences & Diagnostic Pathology Center, Fujian Medical University, Fuzhou, China
| | - Boshu Zheng
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences & Diagnostic Pathology Center, Fujian Medical University, Fuzhou, China
| | - Meifang Xu
- Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences & Diagnostic Pathology Center, Fujian Medical University, Fuzhou, China
| | - Xianjie Jiang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Yuhang Liu
- Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, China
| | - Mingfen Chen
- Department of Radiation Oncology, The Second Affiliated Hospital of Fujian Medical University, Fujian Medical University, Quanzhou, China
| | - Jun Long
- Shenzhen Geim Graphene Center, Tsinghua-Berkeley Shenzhen Institute & Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
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4
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DiDonato M, Simpson CT, Vo T, Knuth M, Geierstanger B, Jamontt J, Jones DH, Fathman JW, DeLarosa D, Junt T, Picard D, Sommer U, Bagger M, Peters E, Meeusen S, Spraggon G. A novel interleukin-10 antibody graft to treat inflammatory bowel disease. Structure 2025; 33:475-488.e7. [PMID: 39798572 DOI: 10.1016/j.str.2024.12.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 11/19/2024] [Accepted: 12/12/2024] [Indexed: 01/15/2025]
Abstract
Inflammatory bowel disease (IBD) consists of chronic conditions that severely impact a patient's health and quality of life. Interleukin-10 (IL-10), a potent anti-inflammatory cytokine has strong genetic links to IBD susceptibility and has shown strong efficacy in IBD rodent models, suggesting it has great therapeutic potential. However, when tested in clinical trials for IBD, recombinant human IL-10 (rhIL-10) showed weak and inconsistent efficacy due to its short half-life and pro-inflammatory properties that counteract the anti-inflammatory efficacy. Here we present an engineered, IL-10, antibody-graft therapeutic (GFT-IL10M) designed to rectify these issues. GFT-IL10M combines the half-life extension properties of a monoclonal IgG antibody with altered IL-10 cell-type selective signaling, retaining desirable signaling on monocytes while reducing unwanted signaling on T, natural killer (NK), and B cells. Our structural and biochemical results indicate that the altered IL-10 topology in GFT-IL10M leads to a predominantly anti-inflammatory profile, potentially altering cell-type specific signaling patterns and extending half-life.
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Affiliation(s)
- Michael DiDonato
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | - Carolina Turk Simpson
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | - Todd Vo
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | - Mark Knuth
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | - Bernhard Geierstanger
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | | | - David H Jones
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | - John W Fathman
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | - Donnie DeLarosa
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | - Tobias Junt
- Novartis Biomedical Research, Novartis Campus, Basel, Switzerland
| | - Damien Picard
- Novartis Biomedical Research, Novartis Campus, Basel, Switzerland
| | - Ulrike Sommer
- Novartis Biomedical Research, Novartis Campus, Basel, Switzerland
| | - Morten Bagger
- Novartis Biomedical Research, Novartis Campus, Basel, Switzerland
| | - Eric Peters
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | - Shelly Meeusen
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA
| | - Glen Spraggon
- Novartis Biomedical Research, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
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Qiu Q, Yang X, Li X, Ren Y, Huang N. Viral IL-10 can promote the proliferation, migration and invasion of nasopharyngeal carcinoma cells and inhibit their apoptosis. Discov Oncol 2025; 16:199. [PMID: 39964638 PMCID: PMC11836248 DOI: 10.1007/s12672-025-01937-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 02/05/2025] [Indexed: 02/21/2025] Open
Abstract
PURPOSE Nasopharyngeal carcinoma is a common clinical malignant tumour in the nasopharynx. The secretion of vIL-10 by EB virus can promote the development of nasopharyngeal carcinoma. The purpose of this study was to provide a theoretical basis for potential targets and mechanisms of vIL-10 in nasopharyngeal carcinoma. METHODS A total of 100 ng/mL vIL-10 was applied to the nasopharyngeal carcinoma CNE-2 cell line for 48 h, and then whole transcriptome sequencing analysis was performed to identify potential targets and signalling pathways of vIL-10 in nasopharyngeal carcinoma. The effects of vIL-10 on the proliferation, migration, invasion and apoptosis of human nasopharyngeal carcinoma cells were determined by ELISA, Ki67 immunofluorescence, colony formation, transwell migration/invasion, Hoechst 33,258 staining, flow cytometry and other experiments, and the potential effects of vIL-10 on nasopharyngeal carcinoma cells were verified at the cellular level. Western blotting was performed to measure the changes in key factors of the JAK1-STAT3 signalling pathway in nasopharyngeal carcinoma cells after vIL-10 treatment. RESULTS The whole transcriptome gene sequencing results showed that vIL-10 could effectively activate the JAK-STAT signalling pathway and upregulate the expression of JAK1 and STAT3. Moreover, vIL-10 inhibited the apoptosis of nasopharyngeal carcinoma cells, enhanced their migration and invasion capabilities, and further promoted the proliferation of nasopharyngeal carcinoma cells. CONCLUSION vIL-10 regulates the JAK1-STAT3 signalling pathway, promotes the proliferation of NPC cells, enhances their migration and invasion capabilities, inhibits tumour cell apoptosis, and participates in the progression of nasopharyngeal carcinoma.
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Affiliation(s)
- Qin Qiu
- Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Xingyu Yang
- Kunming Medical University, Kunming, Yunnan, People's Republic of China
| | - Xiaojiang Li
- Department of Head and Neck Surgery, Third Affiliated Hospital of Kunming Medical University, No.519 Kunzhou Street, Xishan District, Kunming, 650118, People's Republic of China.
| | - Yanxin Ren
- Department of Head and Neck Surgery, Third Affiliated Hospital of Kunming Medical University, No.519 Kunzhou Street, Xishan District, Kunming, 650118, People's Republic of China.
| | - Ning Huang
- Department of Pharmacology, Kunming Medical University, Kunming, Yunnan, People's Republic of China.
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Chakkalakkal GJ, Gopakumar ST, Sharma SRK, Raveendranathan DN, Jagannivasan A, Nair AV, Ramachandran V, Achamveetil G. Molecular features and expression kinetics of interleukin-10 gene from the marine teleost, Snubnose pompano (Trachinotus blochii). Mol Biol Rep 2024; 52:79. [PMID: 39718665 DOI: 10.1007/s11033-024-10180-w] [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: 09/19/2024] [Accepted: 12/13/2024] [Indexed: 12/25/2024]
Abstract
BACKGROUND Interleukin 10 (IL-10) is uniquely positioned in the immune regulation of teleosts. Modifying the IL-10 pathway changes the teleost's disease susceptibility; however, there is no data on its post-transcriptional regulation. Trachinotus blochii is a high-value mariculture species. METHODS The full-length tbil-10 gene was generated through the Rapid Amplification of cDNA Ends-PCR. After the detailed sequence analysis, the identified features were compared with other IL-10 sequences. The gene expressions in healthy and challenged (Vibrio harveyi) fish were studied. RESULTS The sequence analysis showed an open reading frame of 564 bp and a 3' UTR (untranslated region) of 217 bp. The phylogram revealed an evolutionary distinction between marine and freshwater teleost IL-10. The shorter 3' UTR, additional conserved cysteines capable of forming stable disulphide bonds, and lesser mRNA instability moieties suggest the better structural stability of teleost IL-10 than tetrapods. Results identified 60 miRNA-mRNA duplexes that can regulate IL-10 3' UTR. Nine identified miRNAs are involved in immune response and seven are expressed in macrophages. The gills showed the highest gene expression in healthy fish. The study discovered two IL-10 mRNA transcripts that differed in 5' UTR lengths and thermodynamic ensemble's free energy. There was an increased expression of both tbil-10-mRNA transcripts from 2 to 48 h post-challenge which peaked at 24 h after the challenge, with higher expression of short mRNA transcript. CONCLUSIONS The results gave insights into the structural, functional, post-transcriptional regulatory mechanisms, and expression characteristics of the IL-10 gene in T. blochii.
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Affiliation(s)
- George Joseph Chakkalakkal
- Marine Biotechnology, Fish Health, and Nutrition Division, ICAR-Central Marine Fisheries Research Institute, Post Box No. 1603, Ernakulam North P.O, Kochi, 682 018, India
| | - Sumithra Thangalazhy Gopakumar
- Marine Biotechnology, Fish Health, and Nutrition Division, ICAR-Central Marine Fisheries Research Institute, Post Box No. 1603, Ernakulam North P.O, Kochi, 682 018, India
| | - S R Krupesha Sharma
- Marine Biotechnology, Fish Health, and Nutrition Division, ICAR-Central Marine Fisheries Research Institute, Post Box No. 1603, Ernakulam North P.O, Kochi, 682 018, India.
| | - Dhanutha Nikathil Raveendranathan
- Marine Biotechnology, Fish Health, and Nutrition Division, ICAR-Central Marine Fisheries Research Institute, Post Box No. 1603, Ernakulam North P.O, Kochi, 682 018, India
| | - Amritha Jagannivasan
- Marine Biotechnology, Fish Health, and Nutrition Division, ICAR-Central Marine Fisheries Research Institute, Post Box No. 1603, Ernakulam North P.O, Kochi, 682 018, India
- Cochin University of Science and Technology, Kochi, Kerala, 682022, India
| | - Anusree Velappan Nair
- Marine Biotechnology, Fish Health, and Nutrition Division, ICAR-Central Marine Fisheries Research Institute, Post Box No. 1603, Ernakulam North P.O, Kochi, 682 018, India
| | - Vishnu Ramachandran
- Marine Biotechnology, Fish Health, and Nutrition Division, ICAR-Central Marine Fisheries Research Institute, Post Box No. 1603, Ernakulam North P.O, Kochi, 682 018, India
- Cochin University of Science and Technology, Kochi, Kerala, 682022, India
| | - Gopalakrishnan Achamveetil
- Marine Biotechnology, Fish Health, and Nutrition Division, ICAR-Central Marine Fisheries Research Institute, Post Box No. 1603, Ernakulam North P.O, Kochi, 682 018, India
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7
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Weng S, Tian E, Gao M, Zhang S, Yang G, Zhou B. Eimeria: Navigating complex intestinal ecosystems. PLoS Pathog 2024; 20:e1012689. [PMID: 39576763 PMCID: PMC11584145 DOI: 10.1371/journal.ppat.1012689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2024] Open
Abstract
Eimeria is an intracellular obligate apicomplexan parasite that parasitizes the intestinal epithelial cells of livestock and poultry, exhibiting strong host and tissue tropism. Parasite-host interactions involve complex networks and vary as the parasites develop in the host. However, understanding the underlying mechanisms remains a challenge. Acknowledging the lack of studies on Eimeria invasion mechanism, we described the possible invasion process through comparative analysis with other apicomplexan parasites and explored the fact that parasite-host interactions serve as a prerequisite for successful recognition, penetration of the intestinal mechanical barrier, and completion of the invasion. Although it is recognized that microbiota can enhance the host immune capacity to resist Eimeria invasion, changes in the microenvironment can, in turn, contribute to Eimeria invasion and may be associated with reduced immune capacity. We also discuss the immune evasion strategies of Eimeria, emphasizing that the host employs sophisticated immune regulatory mechanisms to suppress immune evasion by parasites, thereby sustaining a balanced immune response. This review aims to deepen our understanding of Eimeria-host interactions, providing a theoretical basis for the study of the pathogenicity of Eimeria and the development of novel anticoccidial drugs.
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Affiliation(s)
- Shengjie Weng
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People’s Republic of China
| | - Erjie Tian
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People’s Republic of China
| | - Meng Gao
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People’s Republic of China
| | - Siyu Zhang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People’s Republic of China
| | - Guodong Yang
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People’s Republic of China
| | - Bianhua Zhou
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, Henan, People’s Republic of China
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Drosu N, Anderson M, Bilodeau PA, Nishiyama S, Mikami T, Bobrowski-Khoury N, Cabot J, Housman D, Levy M. CD4 T cells restricted to DRB1*15:01 recognize two Epstein-Barr virus glycoproteins capable of intracellular antigen presentation. Proc Natl Acad Sci U S A 2024; 121:e2416097121. [PMID: 39432795 PMCID: PMC11536159 DOI: 10.1073/pnas.2416097121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 09/06/2024] [Indexed: 10/23/2024] Open
Abstract
Both genetic and environmental factors contribute to multiple sclerosis (MS) risk. Infection with the Epstein-Barr virus (EBV) is the strongest environmental risk factor, and HLA-DR15 is the strongest genetic risk factor for MS. We employed computational methods and in vitro assays for CD4 T cell activation to investigate the DR15-restricted response to EBV. Using a machine learning-based HLA ligand predictor, the EBV glycoprotein B (gB) was predicted to be enriched in epitopes restricted to presentation by DRB1*15:01. In DR15-positive individuals, two epitopes comprised the major CD4 T cell response to gB. Surprisingly, the expression of recombinant gB in a DR15-homozygous B cell line or primary autologous B cells elicited a CD4 T cell response, indicating that intracellular gB was loaded onto HLA class II molecules. By deleting the signal sequence of gB, we determined that this pathway for direct activation of CD4 T cells was dependent on trafficking to the endoplasmic reticulum (ER) within the B cell. We screened seven recombinant EBV antigens from the ER compartment for immune responses in DR15-negative vs. DR15-homozygous individuals. In addition to gB, gH was a key CD4 T cell target in individuals homozygous for DR15. Compared to non-DR15 controls, DR15-homozygotes had significantly higher T cell responses to both gB and gH but not to EBV latent or lytic antigens overall. Responses to gB and gH were slightly elevated in DR15 homozygotes with MS. Our results link MS environmental and genetic risk factors by demonstrating that HLA-DR15 dictates CD4 T cell immunity to EBV antigens.
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Affiliation(s)
- Natalia Drosu
- Department of Neurology, Division of Neuroimmunology & Neuroinfectious Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA02114
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA02139
| | - Monique Anderson
- Department of Neurology, Division of Neuroimmunology & Neuroinfectious Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA02114
| | - Philippe A. Bilodeau
- Department of Neurology, Division of Neuroimmunology & Neuroinfectious Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA02114
| | - Shuhei Nishiyama
- Department of Neurology, Division of Neuroimmunology & Neuroinfectious Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA02114
| | - Takahisa Mikami
- Department of Neurology, Division of Neuroimmunology & Neuroinfectious Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA02114
| | - Natasha Bobrowski-Khoury
- Department of Neurology, Division of Neuroimmunology & Neuroinfectious Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA02114
| | - Jackson Cabot
- Department of Neurology, Division of Neuroimmunology & Neuroinfectious Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA02114
| | - David Housman
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA02139
| | - Michael Levy
- Department of Neurology, Division of Neuroimmunology & Neuroinfectious Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA02114
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Ding BN, Wu YL, Zhang YY, Li YG. Association between Epstein-Barr virus infection and serum positivity rate of anti-nuclear antibodies in Chongqing, China: A cross-sectional observational study. Medicine (Baltimore) 2024; 103:e39233. [PMID: 39121295 PMCID: PMC11315546 DOI: 10.1097/md.0000000000039233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 07/18/2024] [Indexed: 08/11/2024] Open
Abstract
Epstein-Barr virus (EBV) infects over 95% of the global population and is strongly associated with various autoimmune diseases. Anti-nuclear antibodies (ANA) serve as valuable laboratory biomarkers for screening and supporting the diagnosis of various autoimmune diseases. The aim of this study was to assess the prevalence of EBV infection and its association with ANA. This retrospective study employed standard indirect immunofluorescence assay to determine ANA levels, EBV-specific immunofluorescence assay, or plasma EBV-DNA testing. Demographic data including gender and age were collected to observe variations in EBV infection status and ANA positivity rates among different populations. Incorporating 6492 hospitalized patients who underwent ANA antibody spectrum testing, it was observed that serum positivity rates gradually increased with age. The overall serum positivity rate of ANA in females (25.14%) was significantly higher than that in males (13.76%). Among hospitalized patients undergoing EBV-DNA testing, adults aged 21 to 40 years were least affected by EBV, with a positivity rate of 11.96%; however, as age increased, the positivity rate gradually increased. Among the 5225 patients undergoing EBV antibody spectrum testing, ANA-positive patients exhibited significantly higher serum positivity rates for Epstein-Barr nuclear antigen 1 immunoglobulin G, Epstein-Barr virus early antigen immunoglobulin G, Epstein-Barr virus early antigen immunoglobulin A, and Epstein-Barr virus viral capsid antigen immunoglobulin A antibodies compared to ANA-negative patients (P < .001; P < .001; P = .013; P < .001). The EBV-DNA positivity rate in ANA-positive patients was also significantly higher than in ANA-negative patients, yielding the same conclusion (P = .012). The positivity rates of ANA antibodies in patients with past EBV infection and reactivation were significantly higher than those in uninfected patients (P < .001; P = .006). The positivity rate of ANA antibodies in reactivated patients was significantly higher than that in primary infected patients and those with past infections (P < .001; P < .001). Among ANA-positive patients, the positivity rates of EBV antibody spectrum and EBV-DNA were higher compared to ANA-negative patients. The positivity rates of ANA in patients with past EBV infection and reactivation were higher than those in uninfected patients.
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Affiliation(s)
- Bei-Ning Ding
- Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Yi-Lin Wu
- Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - You-Yu Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Yong-Guo Li
- Department of Infectious Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
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10
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Kitaya K, Yasuo T, Yamaguchi T. Bridging the Diagnostic Gap between Histopathologic and Hysteroscopic Chronic Endometritis with Deep Learning Models. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:972. [PMID: 38929589 PMCID: PMC11205857 DOI: 10.3390/medicina60060972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/17/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024]
Abstract
Chronic endometritis (CE) is an inflammatory pathologic condition of the uterine mucosa characterized by unusual infiltration of CD138(+) endometrial stromal plasmacytes (ESPCs). CE is often identified in infertile women with unexplained etiology, tubal factors, endometriosis, repeated implantation failure, and recurrent pregnancy loss. Diagnosis of CE has traditionally relied on endometrial biopsy and histopathologic/immunohistochemistrical detection of ESPCs. Endometrial biopsy, however, is a somewhat painful procedure for the subjects and does not allow us to grasp the whole picture of this mucosal tissue. Meanwhile, fluid hysteroscopy has been recently adopted as a less-invasive diagnostic modality for CE. We launched the ARCHIPELAGO (ARChival Hysteroscopic Image-based Prediction for histopathologic chronic Endometritis in infertile women using deep LeArninG mOdel) study to construct the hysteroscopic CE finding-based prediction tools for histopathologic CE. The development of these deep learning-based novel models and computer-aided detection/diagnosis systems potentially benefits infertile women suffering from this elusive disease.
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Affiliation(s)
- Kotaro Kitaya
- Infertility Center, Iryouhoujin Kouseikai Mihara Hospital, 6-8 Kamikatsura Miyanogo-cho, Nishikyo-ku, Kyoto 615-8227, Japan
- Iryouhoujin Kouseikai Katsura-ekimae Mihara Clinic, 103 Katsura OS Plaza Building, 133 Katsura Minamitatsumi-cho, Nishikyo-ku, Kyoto 615-8074, Japan
| | - Tadahiro Yasuo
- Department of Obstetrics and Gynecology, Otsu City Hospital, 2-9-9 Motomiya, Otsu 520-0804, Japan
| | - Takeshi Yamaguchi
- Infertility Center, Daigo Watanabe Clinic, 30-15 Daigo Takahata-cho, Fushimi-ku, Kyoto 601-1375, Japan
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11
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Jo HS, Kim HJ. Stabilin-2 mediated apoptotic cell phagocytosis induces interleukin-10 expression by p38 and Pbx1 signaling. Cell Biochem Biophys 2024; 82:919-925. [PMID: 38480573 PMCID: PMC11344723 DOI: 10.1007/s12013-024-01243-7] [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] [Accepted: 02/24/2024] [Indexed: 08/25/2024]
Abstract
Apoptotic cell death occurs under normal physiological conditions, such as development, tissue remodeling, and inflammation. Appropriate removal of apoptotic cells by phagocytes and the secretion of anti-inflammatory cytokines such as IL-10 are important mechanisms for maintaining tissue homeostasis. Apoptotic cell phagocytosis is mediated by several phosphatidylserine recognition receptors on non-professional or professional phagocytes, such as neighboring epithelial cells or macrophages. Stabilin-2 is reported as a phosphatidylserine recognition receptor for apoptotic cell phagocytosis, and its downstream signaling pathway for cytoskeletal rearrangement for phagocytosis is well known. However, the mechanisms for stabilin-2-mediated IL-10 production has not yet been reported. In this study, we aimed to investigate stabilin-2 receptor-mediated IL-10 transcription regulation signaling pathway.
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Affiliation(s)
- Han-Seul Jo
- Department of Physiology, Cell and Matrix Research Institute, Kyungpook National University, School of Medicine, Daegu, South Korea.
| | - Ha-Jeong Kim
- Department of Physiology, Cell and Matrix Research Institute, Kyungpook National University, School of Medicine, Daegu, South Korea.
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12
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Lyu MH, Bian C, Dou YP, Gao K, Xu JJ, Ma P. Effects of interleukin-10 treated macrophages on bone marrow mesenchymal stem cells via signal transducer and activator of transcription 3 pathway. World J Stem Cells 2024; 16:560-574. [PMID: 38817327 PMCID: PMC11135252 DOI: 10.4252/wjsc.v16.i5.560] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/26/2024] [Accepted: 04/12/2024] [Indexed: 05/24/2024] Open
Abstract
BACKGROUND Alveolar bone defects caused by inflammation are an urgent issue in oral implant surgery that must be solved. Regulating the various phenotypes of macrophages to enhance the inflammatory environment can significantly affect the progression of diseases and tissue engineering repair process. AIM To assess the influence of interleukin-10 (IL-10) on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) following their interaction with macrophages in an inflammatory environment. METHODS IL-10 modulates the differentiation of peritoneal macrophages in Wistar rats in an inflammatory environment. In this study, we investigated its impact on the proliferation, migration, and osteogenesis of BMSCs. The expression levels of signal transducer and activator of transcription 3 (STAT3) and its activated form, phosphorylated-STAT3, were examined in IL-10-stimulated macrophages. Subsequently, a specific STAT3 signaling inhibitor was used to impede STAT3 signal activation to further investigate the role of STAT3 signaling. RESULTS IL-10-stimulated macrophages underwent polarization to the M2 type through substitution, and these M2 macrophages actively facilitated the osteogenic differentiation of BMSCs. Mechanistically, STAT3 signaling plays a crucial role in the process by which IL-10 influences macrophages. Specifically, IL-10 stimulated the activation of the STAT3 signaling pathway and reduced the macrophage inflammatory response, as evidenced by its diminished impact on the osteogenic differentiation of BMSCs. CONCLUSION Stimulating macrophages with IL-10 proved effective in improving the inflammatory environment and promoting the osteogenic differentiation of BMSCs. The IL-10/STAT3 signaling pathway has emerged as a key regulator in the macrophage-mediated control of BMSCs' osteogenic differentiation.
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Affiliation(s)
- Meng-Hao Lyu
- Department of Periodontics, School of Stomatology, Capital Medical University, Beijing 100050, China
| | - Ce Bian
- Department of Orthodontics, School of Stomatology, Capital Medical University, Beijing 100050, China
| | - Yi-Ping Dou
- Department of Dental Implantology, School of Stomatology, Capital Medical University, Beijing 100050, China
| | - Kang Gao
- Department of Dental Implantology, School of Stomatology, Capital Medical University, Beijing 100050, China
| | - Jun-Ji Xu
- Department of Periodontics, School of Stomatology, Capital Medical University, Beijing 100050, China
- Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing 100050, China
- Beijing Laboratory of Oral Health, Capital Medical University, Beijing 100050, China
| | - Pan Ma
- Department of Dental Implantology, School of Stomatology, Capital Medical University, Beijing 100050, China.
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13
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Elemam NM, Mekky RY, Rashid G, Braoudaki M, Youness RA. Pharmacogenomic and epigenomic approaches to untangle the enigma of IL-10 blockade in oncology. Expert Rev Mol Med 2024; 26:e1. [PMID: 38186186 PMCID: PMC10941350 DOI: 10.1017/erm.2023.26] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/29/2023] [Accepted: 11/10/2023] [Indexed: 01/09/2024]
Abstract
The host immune system status remains an unresolved mystery among several malignancies. An immune-compromised state or smart immune-surveillance tactics orchestrated by cancer cells are the primary cause of cancer invasion and metastasis. Taking a closer look at the tumour-immune microenvironment, a complex network and crosstalk between infiltrating immune cells and cancer cells mediated by cytokines, chemokines, exosomal mediators and shed ligands are present. Cytokines such as interleukins can influence all components of the tumour microenvironment (TME), consequently promoting or suppressing tumour invasion based on their secreting source. Interleukin-10 (IL-10) is an interlocked cytokine that has been associated with several types of malignancies and proved to have paradoxical effects. IL-10 has multiple functions on cellular and non-cellular components within the TME. In this review, the authors shed the light on the regulatory role of IL-10 in the TME of several malignant contexts. Moreover, detailed epigenomic and pharmacogenomic approaches for the regulation of IL-10 were presented and discussed.
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Affiliation(s)
- Noha M. Elemam
- Research Instiute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Radwa Y. Mekky
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA University), Cairo 12622, Egypt
| | - Gowhar Rashid
- Amity Medical School, Amity University, Gurugram (Manesar) 122413, Haryana, India
| | - Maria Braoudaki
- Department of Clinical, Pharmaceutical and Biological Sciences, School of Life and Medical Sciences, University of Hertfordshire, Hatfield AL10 9AB, UK
| | - Rana A. Youness
- Biology and Biochemistry Department, Faculty of Biotechnology, German International University, Cairo 11835, Egypt
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14
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Emami Fard N, Xiao M, Sehmi R. Regulatory ILC2-Role of IL-10 Producing ILC2 in Asthma. Cells 2023; 12:2556. [PMID: 37947634 PMCID: PMC10650705 DOI: 10.3390/cells12212556] [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: 09/13/2023] [Revised: 10/27/2023] [Accepted: 10/29/2023] [Indexed: 11/12/2023] Open
Abstract
Over the past two decades, a growing body of evidence observations have shown group two innate lymphoid cells (ILC2) to be critical drivers of Type 2 (T2) inflammatory responses associated with allergic inflammatory conditions such as asthma. ILC2 releases copious amounts of pro-inflammatory T2 cytokines-interleukin (IL)-4, IL-5, IL-9, and IL-13. This review provides a comprehensive overview of the newly discovered regulatory subtype of ILC2 described in murine and human mucosal tissue and blood. These KLRG1+ILC2 have the capacity to produce the anti-inflammatory cytokine IL-10. Papers compiled in this review were based on queries of PubMed and Google Scholar for articles published from 2000 to 2023 using keywords "IL-10" and "ILC2". Studies with topical relevance to IL-10 production by ILC2 were included. ILC2 responds to microenvironmental cues, including retinoic acid (RA), IL-2, IL-4, IL-10, and IL-33, as well as neuropeptide mediators such as neuromedin-U (NMU), prompting a shift towards IL-10 and away from T2 cytokine production. In contrast, TGF-β attenuates IL-10 production by ILC2. Immune regulation provided by IL-10+ILC2s holds potential significance for the management of T2 inflammatory conditions. The observation of context-specific cues that alter the phenotype of ILC warrants examining characteristics of ILC subsets to determine the extent of plasticity or whether the current classification of ILCs requires refinement.
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Affiliation(s)
| | | | - Roma Sehmi
- Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada; (N.E.F.)
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15
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Fan YX, Chen LR, Gan RX, Yin SJ, Wang P, Meng R, Huang YH, Jiang FF, He GH. A meta-analysis of associations of IL-10 gene polymorphisms with acute leukemia susceptibility. Cytokine 2023; 170:156312. [PMID: 37542945 DOI: 10.1016/j.cyto.2023.156312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 07/26/2023] [Accepted: 07/28/2023] [Indexed: 08/07/2023]
Abstract
BACKGROUND Recently, increasing evidence has demonstrated that IL-10 single nucleotide polymorphisms (SNPs) are associated with the risk of acute leukemia (AL), but the findings of different articles remain controversial. Thus, we performed a meta-analysis to further investigate the exact roles of IL-10 SNPs in AL susceptibility. METHODS Six common Chinese and English databases were utilized to retrieve eligible studies. The strength of the association was assessed by calculating odds ratios and 95 % confidence intervals. All analyses were carried out using Review Manager (version 5.3) and STATA (version 15.1). The registered number of this research is CRD42022373362. RESULTS A total of 6391 participants were enrolled in this research. The results showed that the AG genotype of rs1800896 increased AL risk in the heterozygous codominant model (AG vs. AA, OR = 1.41, 95 % CI = 1.04-1.92, P = 0.03) and overdominant model (AG vs. AA + GG, OR = 1.32, 95 % CI = 1.04-1.70, P = 0.03). In the subgroup analysis, associations between the G allele, GG genotype, AG genotype, AG + GG genotype of rs1800896 and increased AL risk were also observed in the mixed population based on allelic, homozygote codominant, heterozygous codominant, dominant, and overdominant models. Furthermore, an association between the AC genotype of rs1800872 and increased AL risk was observed in the Caucasian population in the overdominant model. However, the rs1800871, rs3024489 and rs3024493 polymorphisms did not affect AL risk. CONCLUSION IL-10 rs1800896 and rs1800872 affected the susceptibility of AL and therefore may be biomarkers for early screening and risk prediction of AL.
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Affiliation(s)
- Yu-Xin Fan
- Research Center of Clinical Pharmacology, The First Affiliated Hospital of Yunnan University of Chinese Medicine, Kunming, China
| | - Li-Rong Chen
- Department of Clinical Pharmacy, 920th Hospital of Joint Logistics Support Force of People's Liberation Army, Kunming, China
| | - Run-Xin Gan
- Reproductive Medicine Center, Xiangya Hospital, Central South University, Changsha, China
| | - Sun-Jun Yin
- Department of Clinical Pharmacy, 920th Hospital of Joint Logistics Support Force of People's Liberation Army, Kunming, China
| | - Ping Wang
- Department of Clinical Pharmacy, 920th Hospital of Joint Logistics Support Force of People's Liberation Army, Kunming, China
| | - Rui Meng
- Department of Clinical Pharmacy, 920th Hospital of Joint Logistics Support Force of People's Liberation Army, Kunming, China
| | - Yan-Hua Huang
- Department of Clinical Pharmacy, 920th Hospital of Joint Logistics Support Force of People's Liberation Army, Kunming, China
| | - Fang-Fang Jiang
- Department of Clinical Pharmacy, 920th Hospital of Joint Logistics Support Force of People's Liberation Army, Kunming, China
| | - Gong-Hao He
- Department of Clinical Pharmacy, 920th Hospital of Joint Logistics Support Force of People's Liberation Army, Kunming, China.
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Moniruzzaman M, Erazo Garcia MP, Farzad R, Ha AD, Jivaji A, Karki S, Sheyn U, Stanton J, Minch B, Stephens D, Hancks DC, Rodrigues RAL, Abrahao JS, Vardi A, Aylward FO. Virologs, viral mimicry, and virocell metabolism: the expanding scale of cellular functions encoded in the complex genomes of giant viruses. FEMS Microbiol Rev 2023; 47:fuad053. [PMID: 37740576 PMCID: PMC10583209 DOI: 10.1093/femsre/fuad053] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 08/29/2023] [Accepted: 09/21/2023] [Indexed: 09/24/2023] Open
Abstract
The phylum Nucleocytoviricota includes the largest and most complex viruses known. These "giant viruses" have a long evolutionary history that dates back to the early diversification of eukaryotes, and over time they have evolved elaborate strategies for manipulating the physiology of their hosts during infection. One of the most captivating of these mechanisms involves the use of genes acquired from the host-referred to here as viral homologs or "virologs"-as a means of promoting viral propagation. The best-known examples of these are involved in mimicry, in which viral machinery "imitates" immunomodulatory elements in the vertebrate defense system. But recent findings have highlighted a vast and rapidly expanding array of other virologs that include many genes not typically found in viruses, such as those involved in translation, central carbon metabolism, cytoskeletal structure, nutrient transport, vesicular trafficking, and light harvesting. Unraveling the roles of virologs during infection as well as the evolutionary pathways through which complex functional repertoires are acquired by viruses are important frontiers at the forefront of giant virus research.
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Affiliation(s)
- Mohammad Moniruzzaman
- Rosenstiel School of Marine Atmospheric, and Earth Science, University of Miami, Coral Gables, FL 33149, United States
| | - Maria Paula Erazo Garcia
- Department of Biological Sciences, Virginia Tech, 926 West Campus Drive, Blacksburg, VA 24061, United States
| | - Roxanna Farzad
- Department of Biological Sciences, Virginia Tech, 926 West Campus Drive, Blacksburg, VA 24061, United States
| | - Anh D Ha
- Department of Biological Sciences, Virginia Tech, 926 West Campus Drive, Blacksburg, VA 24061, United States
| | - Abdeali Jivaji
- Department of Biological Sciences, Virginia Tech, 926 West Campus Drive, Blacksburg, VA 24061, United States
| | - Sangita Karki
- Department of Biological Sciences, Virginia Tech, 926 West Campus Drive, Blacksburg, VA 24061, United States
| | - Uri Sheyn
- Department of Biological Sciences, Virginia Tech, 926 West Campus Drive, Blacksburg, VA 24061, United States
| | - Joshua Stanton
- Department of Biological Sciences, Virginia Tech, 926 West Campus Drive, Blacksburg, VA 24061, United States
| | - Benjamin Minch
- Rosenstiel School of Marine Atmospheric, and Earth Science, University of Miami, Coral Gables, FL 33149, United States
| | - Danae Stephens
- Rosenstiel School of Marine Atmospheric, and Earth Science, University of Miami, Coral Gables, FL 33149, United States
| | - Dustin C Hancks
- Department of Immunology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX, United States
| | - Rodrigo A L Rodrigues
- Laboratório de Vírus, Departamento de Microbiologia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil
| | - Jonatas S Abrahao
- Laboratório de Vírus, Departamento de Microbiologia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil
| | - Assaf Vardi
- Department of Plant and Environmental Sciences, Weizmann Institute of Science, 7610001 Rehovot, Israel
| | - Frank O Aylward
- Department of Biological Sciences, Virginia Tech, 926 West Campus Drive, Blacksburg, VA 24061, United States
- Center for Emerging, Zoonotic, and Arthropod-Borne Infectious Disease, Virginia Tech, Blacksburg, VA 24061, United States
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17
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Zhu X, Liu Y, Xu N, Ai X, Yang Y. Molecular Characterization and Expression Analysis of IL-10 and IL-6 in Channel Catfish ( Ictalurus punctatus). Pathogens 2023; 12:886. [PMID: 37513733 PMCID: PMC10384647 DOI: 10.3390/pathogens12070886] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 06/25/2023] [Accepted: 06/27/2023] [Indexed: 07/30/2023] Open
Abstract
IL-10 and IL-6 play important roles in protecting against inflammation and clearing pathogens from the body. In this study, homologous compounds of IL-10 and IL-6 were identified in channel catfish, and their immune responses were analyzed. The CDS sequences of IL-10 and IL-6 were 549 bp and 642 bp, respectively, and showed the highest homology with Ameiurus melas. In addition, the expression of the IL-10 and IL-6 genes was ubiquitous in 10 tissues examined. IL-10 is highly expressed in the liver and slightly expressed in the gill. The high expression of the IL-6 gene was observed in the spleen, heart, and gonad, with the lowest levels in the liver. LPS, Poly(I:C), PHA, and PMA showed a highly significant increase in IL-10 and IL-6 expression 48 h after CCK stimulation (p < 0.01). Otherwise, Yersinia ruckeri, Streptococcus iniae, channel catfish virus, and deltamethrin induced IL-10 and IL-6 expression, varying in intensity between different organs. Our results suggest that IL-10 and IL-6 are involved in the immune response of the host against the pathogen.
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Affiliation(s)
- Xia Zhu
- Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan 430223, China
| | - Yongtao Liu
- Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan 430223, China
| | - Ning Xu
- Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan 430223, China
| | - Xiaohui Ai
- Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan 430223, China
| | - Yibin Yang
- Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan 430223, China
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18
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Dorothea M, Xie J, Yiu SPT, Chiang AKS. Contribution of Epstein–Barr Virus Lytic Proteins to Cancer Hallmarks and Implications from Other Oncoviruses. Cancers (Basel) 2023; 15:cancers15072120. [PMID: 37046781 PMCID: PMC10093119 DOI: 10.3390/cancers15072120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 03/27/2023] [Accepted: 03/31/2023] [Indexed: 04/05/2023] Open
Abstract
Epstein–Barr virus (EBV) is a prevalent human gamma-herpesvirus that infects the majority of the adult population worldwide and is associated with several lymphoid and epithelial malignancies. EBV displays a biphasic life cycle, namely, latent and lytic replication cycles, expressing a diversity of viral proteins. Among the EBV proteins being expressed during both latent and lytic cycles, the oncogenic roles of EBV lytic proteins are largely uncharacterized. In this review, the established contributions of EBV lytic proteins in tumorigenesis are summarized according to the cancer hallmarks displayed. We further postulate the oncogenic properties of several EBV lytic proteins by comparing the evolutionary conserved oncogenic mechanisms in other herpesviruses and oncoviruses.
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Affiliation(s)
- Mike Dorothea
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
| | - Jia Xie
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
| | - Stephanie Pei Tung Yiu
- Division of Infectious Diseases, Department of Medicine, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA 02115, USA
- Harvard Graduate Program in Virology, Boston, MA 02115, USA
| | - Alan Kwok Shing Chiang
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China
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19
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Functional Implications of Epstein-Barr Virus Lytic Genes in Carcinogenesis. Cancers (Basel) 2022; 14:cancers14235780. [PMID: 36497262 PMCID: PMC9740547 DOI: 10.3390/cancers14235780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/19/2022] [Accepted: 11/21/2022] [Indexed: 11/27/2022] Open
Abstract
Epstein-Barr virus (EBV) is associated with a diverse range of tumors of both lymphoid and epithelial origin. Similar to other herpesviruses, EBV displays a bipartite life cycle consisting of latent and lytic phases. Current dogma indicates that the latent genes are key drivers in the pathogenesis of EBV-associated cancers, while the lytic genes are primarily responsible for viral transmission. In recent years, evidence has emerged to show that the EBV lytic phase also plays an important role in EBV tumorigenesis, and the expression of EBV lytic genes is frequently detected in tumor tissues and cell lines. The advent of next generation sequencing has allowed the comprehensive profiling of EBV gene expression, and this has revealed the consistent expression of several lytic genes across various types of EBV-associated cancers. In this review, we provide an overview of the functional implications of EBV lytic gene expression to the oncogenic process and discuss possible avenues for future investigations.
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20
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Cao JF, Yang X, Xiong L, Wu M, Chen S, Xiong C, He P, Zong Y, Zhang L, Fu H, Qi Y, Ying X, Liu D, Hu X, Zhang X. Mechanism of N-0385 blocking SARS-CoV-2 to treat COVID-19 based on molecular docking and molecular dynamics. Front Microbiol 2022; 13:1013911. [PMID: 36329841 PMCID: PMC9622768 DOI: 10.3389/fmicb.2022.1013911] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/26/2022] [Indexed: 11/21/2023] Open
Abstract
PURPOSE 2019 Coronavirus disease (COVID-19) has caused millions of confirmed cases and deaths worldwide. TMPRSS2-mediated hydrolysis and maturation of spike protein is essential for SARS-CoV-2 infection in vivo. The latest research found that a TMPRSS2 inhibitor called N-0385 could effectively prevent the infection of the SARS-CoV-2 and its variants. However, it is not clear about the mechanism of N-0385 treatment COVID-19. Therefore, this study used computer simulations to investigate the mechanism of N-0385 treatment COVID-19 by impeding SARS-CoV-2 infection. METHODS The GeneCards database was used to search disease gene targets, core targets were analyzed by PPI, GO and KEGG. Molecular docking and molecular dynamics were used to validate and analyze the binding stability of small molecule N-0385 to target proteins. The supercomputer platform was used to simulate and analyze the number of hydrogen bonds, binding free energy, stability of protein targets at the residue level, radius of gyration and solvent accessible surface area. RESULTS There were 4,600 COVID-19 gene targets from GeneCards database. PPI, GO and KEGG analysis indicated that signaling pathways of immune response and inflammation played crucial roles in COVID-19. Molecular docking showed that N-0385 could block SARS-CoV-2 infection and treat COVID-19 by acting on ACE2, TMPRSS2 and NLRP3. Molecular dynamics was used to demonstrate that the small molecule N-0385 could form very stable bindings with TMPRSS2 and TLR7. CONCLUSION The mechanism of N-0385 treatment COVID-19 was investigated by molecular docking and molecular dynamics simulation. We speculated that N-0385 may not only inhibit SARS-CoV-2 invasion directly by acting on TMPRSS2, ACE2 and DPP4, but also inhibit the immune recognition process and inflammatory response by regulating TLR7, NLRP3 and IL-10 to prevent SARS-CoV-2 invasion. Therefore, these results suggested that N-0385 may act through multiple targets to reduce SARS-CoV-2 infection and damage caused by inflammatory responses.
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Affiliation(s)
- Jun-Feng Cao
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Xingyu Yang
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Li Xiong
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Mei Wu
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Shengyan Chen
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Chenyang Xiong
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Peiyong He
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | | | - Lixin Zhang
- Yunnan Academy of Forestry Sciences, Kunming, Yunnan, China
| | - Hongjiao Fu
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Yue Qi
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Xiran Ying
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Dengxin Liu
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Xiaosong Hu
- Chengdu Medical College of Basic Medical Sciences, Chengdu, China
| | - Xiao Zhang
- Chengdu Medical College of Basic Medical Sciences, Chengdu, China
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Shao C, Wang H, Sang F, Xu L. Study on the Mechanism of Improving HIV/AIDS Immune Function with Jian Aikang Concentrated Pill Based on Network Pharmacology Combined with Experimental Validation. Drug Des Devel Ther 2022; 16:2731-2753. [PMID: 36003311 PMCID: PMC9394786 DOI: 10.2147/dddt.s369832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 08/05/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose This study was the first to screen the active compounds of Jian Aikang Concentrated Pill (JAKCP) with network pharmacology, predict its potential targets, screen the signaling pathways, and combine with cellular experimental validation to explore the potential mechanism of JAKCP for the treatment of acquired immunodeficiency syndrome (AIDS). Methods The main compounds and targets of Chinese herbs in JAKCP were identified by TCMSP; the targets of AIDS were collected from Genecards, Online Mendelian Inheritance in Man (OMIM), Disgenet, Therapeutic Target Database (TTD) and Drugbank; the network of "Chinese herbs-active compounds-targets" for JAKCP was constructed by Cytoscape, and protein-protein interaction (PPI) network was constructed using STRING to generate the intersection targets, Metascape was conducted to analyze the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), and the network of "main active compounds-core targets-pathways" was constructed by Cytoscape. Finally, the effect of JAKCP on the survival rate of HIV pseudovirus-infected MT-4 cells was investigated by CCK-8 assay, and the predicted targets were verified by ELISA, qPCR and Western blot. Results A total of 147 active compounds of JAKCP were screened covering 351 targets and 416 AIDS disease targets were obtained, besides 140 intersection targets and 321 KEGG pathways were collected. Ultimately, quercetin, kaempferol, stigmasterol, beta-sitosterol, epigallocatechin gallate were identified as the important compounds, the core targets are HSP90AA1, IL-10, IL-6, TNF, IL-1β, TP53, and IL-1ɑ, and the biological pathways and processes mainly include T cell activation, regulation of DNA-binding transcription factor activity and apoptotic signaling pathway. Experiments on the targets of "T cell activation" demonstrated that JAKCP promotes the survival of HIV pseudovirus-infected MT-4 cells. Also, JAKCP down-regulated mRNA and protein levels of IL-1ɑ, IL-1β, and IL-6 while up-regulated mRNA and protein levels of IL-2, IL-6ST, and IL-10 in vitro. Conclusion JAKCP exerted regulatory immune functions through multi-component, multi-target and multi-pathway, thereby providing novel ideas and clues for the treatment of AIDS.
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Affiliation(s)
- Cancan Shao
- Department of First Clinical School of Medicine of Henan University of Chinese Medicine, Zhengzhou, Henan, 450000, People’s Republic of China
| | - Haojie Wang
- Department of Tuberculosis of Henan Provincial Chest Hospital, Zhengzhou, Henan, 450000, People’s Republic of China
| | - Feng Sang
- Key Laboratory of Viral Diseases Prevention and Treatment with TCM of Henan Province, Zhengzhou, Henan, 450000, People’s Republic of China
- Department of Acquired Immune Deficiency Syndrome Treatment and Research Center, The First Affiliated Hospital of Henan University of CM, Zhengzhou, Henan, 450000, People’s Republic of China
| | - Liran Xu
- Department of First Clinical School of Medicine of Henan University of Chinese Medicine, Zhengzhou, Henan, 450000, People’s Republic of China
- Key Laboratory of Viral Diseases Prevention and Treatment with TCM of Henan Province, Zhengzhou, Henan, 450000, People’s Republic of China
- Department of Acquired Immune Deficiency Syndrome Treatment and Research Center, The First Affiliated Hospital of Henan University of CM, Zhengzhou, Henan, 450000, People’s Republic of China
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22
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Maquet C, Baiwir J, Loos P, Rodriguez-Rodriguez L, Javaux J, Sandor R, Perin F, Fallon PG, Mack M, Cataldo D, Gillet L, Machiels B. Ly6C
hi
monocytes balance regulatory and cytotoxic CD4 T cell responses to control virus-induced immunopathology. Sci Immunol 2022; 7:eabn3240. [DOI: 10.1126/sciimmunol.abn3240] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Gammaherpesviruses (γHVs) have coevolved with their host, leading to a remarkably high infection prevalence and establishment of latency. The lifelong persistence of γHVs in hosts appears to broadly shape host immunity, and we show here that pulmonary infection with Murid herpesvirus 4 (MuHV-4), a mouse γHV, drives the recruitment of Ly6C
hi
monocytes (MOs) into the airway, thereby modulating the host immune response. The absence of Ly6C
hi
MOs is associated with severe virus-induced immunopathology and the systemic release of inflammatory mediators. Mechanistically, MuHV-4–imprinted MOs recruit CD4 T cells to the airways and trigger immunosuppressive signaling pathways through the PD-L1/PD-1 axis, thereby dampening the deleterious activation of cytotoxic CD4 T cells. These results uncover a role for Ly6C
hi
MOs in modulating CD4 T cell functions and reveal pathways that could be targeted therapeutically to reduce detrimental immunopathological responses associated with respiratory viral infections.
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Affiliation(s)
- Céline Maquet
- Laboratory of Immunology and Vaccinology, Faculty of Veterinary Medicine, FARAH, ULiège, Liège 4000, Belgium
| | - Jérôme Baiwir
- Laboratory of Immunology and Vaccinology, Faculty of Veterinary Medicine, FARAH, ULiège, Liège 4000, Belgium
| | - Pauline Loos
- Laboratory of Immunology and Vaccinology, Faculty of Veterinary Medicine, FARAH, ULiège, Liège 4000, Belgium
| | - Lucia Rodriguez-Rodriguez
- Laboratory of Immunology and Vaccinology, Faculty of Veterinary Medicine, FARAH, ULiège, Liège 4000, Belgium
| | - Justine Javaux
- Laboratory of Immunology and Vaccinology, Faculty of Veterinary Medicine, FARAH, ULiège, Liège 4000, Belgium
| | - Rémy Sandor
- Laboratory of Immunology and Vaccinology, Faculty of Veterinary Medicine, FARAH, ULiège, Liège 4000, Belgium
| | - Fabienne Perin
- Laboratory of Biology of Tumor and Development, GIGA-Cancer ULiège and “Centre Hospitalier Universitaire de Liège (CHU)”, Liège 4000, Belgium
| | - Padraic G. Fallon
- School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Matthias Mack
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Didier Cataldo
- Laboratory of Biology of Tumor and Development, GIGA-Cancer ULiège and “Centre Hospitalier Universitaire de Liège (CHU)”, Liège 4000, Belgium
| | - Laurent Gillet
- Laboratory of Immunology and Vaccinology, Faculty of Veterinary Medicine, FARAH, ULiège, Liège 4000, Belgium
| | - Bénédicte Machiels
- Laboratory of Immunology and Vaccinology, Faculty of Veterinary Medicine, FARAH, ULiège, Liège 4000, Belgium
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23
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Marques CR, Fiuza BSD, da Silva TM, Carneiro TCB, Costa RS, de Assis Silva MF, Viana WLL, Carneiro VL, Alcantara-Neves NM, Barreto ML, Figueiredo CA. Impact of FOXP3 gene polymorphisms and gene-environment interactions in asthma and atopy in a Brazilian population. Gene 2022; 838:146706. [PMID: 35772656 DOI: 10.1016/j.gene.2022.146706] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/21/2022] [Accepted: 06/24/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUND Polymorphisms in genes related to the activation and development of regulatory T cells (Tregs), such as FOXP3, may be associated with asthma and atopy development. Additionally, environmental factors such as exposure to infections can modify the effect of these associations. This study evaluated the impact of polymorphisms in the FOXP3 on the risk of asthma and atopy as also gene-environment interactions in these outcomes. METHODS This study included 1,246 children from the SCAALA program, between 4 and 11 years of age. DNA was extracted from peripheral blood and eight SNPs (rs2280883, rs11465476, rs11465472, rs2232368, rs3761549, rs3761548, rs2232365 and rs2294021) were genotyped using the 2.5 HumanOmni Beadchip from Illumina (San Diego, California, USA) or TaqMan qRT-PCR. RESULTS The rs2232368 (Allele T) was positively associated with asthma symptoms (OR=1.95, CI=1.04 to 3.66, p = 0.040) and skin prick test (SPT) reactivity to aeroallergens (OR=2.31, CI=1.16 to 4.59, p = 0.017). The rs3761549 (Allele T) was positively associated with SPT reactivity (OR=1.44, CI=1.03 to 2.02, p = 0.034). The rs2280883 (Allele C) was negatively associated with specific IgE to aeroallergens (OR=0.83, CI=0.70 to 0.99, p = 0.040). Furthermore, the rs2280883 played a protective role in the development of atopy only in individuals seropositive to Epstein-Barr virus (EBV) infection (OR=0.74, CI=0.60 to 0.92, p = 0.003 and OR=0.74; 95% CI=0.61-0.91, p = 0.007 for SPT and slgE respectively), but not in individuals without EBV infection. CONCLUSION Polymorphisms in the FOXP3 gene were associated with the risk of atopy and asthma development in our population. In addition, EBV infection had an effect modifier of the observed association for rs2280883 variant.
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Affiliation(s)
| | | | | | | | - Ryan Santos Costa
- Institute of Health Sciences, Federal University of Bahia, Salvador, Brazil
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24
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Recent Progress on the Roles of Regulatory T Cells in IgG4-Related Disease. IMMUNO 2022. [DOI: 10.3390/immuno2020026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
IgG4-related disease (RD) is a proposed concept of systemic inflammatory condition from Japanese researchers. Patients with IgG4-RD manifest several immunological and histological characterizations in the organs involved, including elevated levels of serum IgG4 and lympho-plasmacytic infiltration, storiform fibrosis, IgG4-positive plasma cells infiltration, and obstructive phlebitis. Nevertheless, the pathogenesis of IgG4-RD still remains unclear. It has been made clear that several immune cells with regulatory function play a vital part in several diseases. In particular, abnormalities in the function and proportion of regulatory T cells (Tregs) are implicated in several diseases, and their part in IgG4-RD has been investigated. This review offers an overview of the research in IgG4-RD related to Tregs. Herein, the basic information of Tregs, knowledge gained from animal models involving Tregs, and the role of IgG4-RD has been provided. We also included the immunological mechanisms of IgG4-RD based on the data accumulated so far in our hypothesis.
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25
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Stijlemans B, Schoovaerts M, De Baetselier P, Magez S, De Trez C. The Role of MIF and IL-10 as Molecular Yin-Yang in the Modulation of the Host Immune Microenvironment During Infections: African Trypanosome Infections as a Paradigm. Front Immunol 2022; 13:865395. [PMID: 35464430 PMCID: PMC9022210 DOI: 10.3389/fimmu.2022.865395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
African trypanosomes are extracellular flagellated unicellular protozoan parasites transmitted by tsetse flies and causing Sleeping Sickness disease in humans and Nagana disease in cattle and other livestock. These diseases are usually characterized by the development of a fatal chronic inflammatory disease if left untreated. During African trypanosome infection and many other infectious diseases, the immune response is mediating a see-saw balance between effective/protective immunity and excessive infection-induced inflammation that can cause collateral tissue damage. African trypanosomes are known to trigger a strong type I pro-inflammatory response, which contributes to peak parasitaemia control, but this can culminate into the development of immunopathologies, such as anaemia and liver injury, if not tightly controlled. In this context, the macrophage migration inhibitory factor (MIF) and the interleukin-10 (IL-10) cytokines may operate as a molecular “Yin-Yang” in the modulation of the host immune microenvironment during African trypanosome infection, and possibly other infectious diseases. MIF is a pleiotropic pro-inflammatory cytokine and critical upstream mediator of immune and inflammatory responses, associated with exaggerated inflammation and immunopathology. For example, it plays a crucial role in the pro-inflammatory response against African trypanosomes and other pathogens, thereby promoting the development of immunopathologies. On the other hand, IL-10 is an anti-inflammatory cytokine, acting as a master regulator of inflammation during both African trypanosomiasis and other diseases. IL-10 is crucial to counteract the strong MIF-induced pro-inflammatory response, leading to pathology control. Hence, novel strategies capable of blocking MIF and/or promoting IL-10 receptor signaling pathways, could potentially be used as therapy to counteract immunopathology development during African trypanosome infection, as well as during other infectious conditions. Together, this review aims at summarizing the current knowledge on the opposite immunopathological molecular “Yin-Yang” switch roles of MIF and IL-10 in the modulation of the host immune microenvironment during infection, and more particularly during African trypanosomiasis as a paradigm.
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Affiliation(s)
- Benoit Stijlemans
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.,Myeloid Cell Immunology Laboratory, Vlaams Instituut voor Biotechnologie (VIB) Centre for Inflammation Research, Brussels, Belgium
| | - Maxime Schoovaerts
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Patrick De Baetselier
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.,Myeloid Cell Immunology Laboratory, Vlaams Instituut voor Biotechnologie (VIB) Centre for Inflammation Research, Brussels, Belgium
| | - Stefan Magez
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.,Laboratory of Biomedical Research, Ghent University Global Campus, Incheon, South Korea
| | - Carl De Trez
- Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium
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26
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Wen Y, Xu H, Han J, Jin R, Chen H. How Does Epstein–Barr Virus Interact With Other Microbiomes in EBV-Driven Cancers? Front Cell Infect Microbiol 2022; 12:852066. [PMID: 35281433 PMCID: PMC8904896 DOI: 10.3389/fcimb.2022.852066] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 01/28/2022] [Indexed: 12/12/2022] Open
Abstract
The commensal microbiome refers to a large spectrum of microorganisms which mainly consists of viruses and bacteria, as well as some other components such as protozoa and fungi. Epstein–Barr virus (EBV) is considered as a common component of the human commensal microbiome due to its spread worldwide in about 95% of the adult population. As the first oncogenic virus recognized in human, numerous studies have reported the involvement of other components of the commensal microbiome in the increasing incidence of EBV-driven cancers. Additionally, recent advances have also defined the involvement of host–microbiota interactions in the regulation of the host immune system in EBV-driven cancers as well as other circumstances. The regulation of the host immune system by the commensal microbiome coinfects with EBV could be the implications for how we understand the persistence and reactivation of EBV, as well as the progression of EBV-associated cancers, since majority of the EBV persist as asymptomatic carrier. In this review, we attempt to summarize the possible mechanisms for EBV latency, reactivation, and EBV-driven tumorigenesis, as well as casting light on the role of other components of the microbiome in EBV infection and reactivation. Besides, whether novel microbiome targeting strategies could be applied for curing of EBV-driven cancer is discussed as well.
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Affiliation(s)
| | | | | | - Runming Jin
- *Correspondence: Hongbo Chen, ; Runming Jin,
| | - Hongbo Chen
- *Correspondence: Hongbo Chen, ; Runming Jin,
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27
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Ghoneum M, El-Gerbed MSA. Human placental extract ameliorates methotrexate-induced hepatotoxicity in rats via regulating antioxidative and anti-inflammatory responses. Cancer Chemother Pharmacol 2021; 88:961-971. [PMID: 34505929 PMCID: PMC8536621 DOI: 10.1007/s00280-021-04349-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 08/27/2021] [Indexed: 01/24/2023]
Abstract
PURPOSE Methotrexate (MTX) induces hepatotoxicity, limiting its clinical efficacy as a widely known chemotherapy drug. In the current study, we examined the protective effect of human placenta extract (HPE) against MTX-induced liver damage in rats, as well as its ability to regulate antioxidative and anti-inflammatory liver responses. METHODS Male rats were orally administered MTX at a daily dose of 5 mg/kg-body-weight in the presence or absence of HPE (10.08 mg/kg) for 2 weeks. We measured the biological effects of MTX and HPE on the levels of liver enzymes, lipid profile, lipid peroxidation, oxidative stress biomarkers, and cytokines [tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10)]. In addition, histological examination and histopathological scoring of liver tissues were performed. RESULTS MTX-treated rats showed significantly increased (p < 0.001) liver enzyme levels for aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, total cholesterol, and triglyceride levels. However, HPE supplementation in MTX-treated rats significantly decreased (p < 0.001) these elevated levels. HPE supplementation also significantly reduced the oxidative stress biomarker malondialdehyde (MDA), reversed the reduction in glutathione (GSH), and markedly increased the antioxidant enzyme activities of catalase (CAT) and superoxide dismutase (SOD) in the livers of MTX-treated rats. Furthermore, HPE supplementation significantly decreased the MTX-elevated levels of the pro-inflammatory cytokines TNF-α, IL-6, and IL-10. Histopathological examinations showed that MTX produced severe cellular damage and inflammatory lesions in liver tissues, while treatment with HPE improved hepatic histologic architecture. CONCLUSION HPE has the ability to ameliorate methotrexate-induced liver injury in rats by mechanisms that include boosting antioxidative responses and down-regulating MDA and pro-inflammatory cytokine production.
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Affiliation(s)
- Mamdooh Ghoneum
- Department of Surgery, Charles R. Drew University of Medicine and Science, 1621 E. 120th Street, Los Angeles, CA, 90059, USA.
- Department of Surgery, University of California Los Angeles, Los Angeles, CA, 90095, USA.
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28
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Rasquinha MT, Sur M, Lasrado N, Reddy J. IL-10 as a Th2 Cytokine: Differences Between Mice and Humans. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2021; 207:2205-2215. [PMID: 34663593 PMCID: PMC8544817 DOI: 10.4049/jimmunol.2100565] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023]
Abstract
The discovery of IL-10 more than 30 years ago marked the beginning of our understanding of how cytokines regulate immune responses, based on cross-regulation between Th1 and Th2 cytokines. Although multiple cell types were shown to produce IL-10, its identity as a Th2 cytokine remained strong because it was rigidly associated with Th2 clones in mice, whereas both Th1 and Th2 clones could secrete IL-10 in humans. However, as new Th1/Th2 cell functionalities emerged, anti-inflammatory action of IL-10 gained more attention than its inhibitory effect on Th1 cells, which may occur as an indirect consequence of suppression of APCs. This notion is also supported by the discovery of regulatory T cells, whose suppressor functions involve the mediation of IL-10, among other molecules. From this perspective, we discuss the functionalities of IL-10 by highlighting important differences between mice and humans with an emphasis on the Th1 and Th2 paradigm.
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Affiliation(s)
- Mahima T Rasquinha
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE
| | - Meghna Sur
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE
| | - Ninaad Lasrado
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE
| | - Jay Reddy
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE
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29
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Interleukin-10 induces interferon-γ-dependent emergency myelopoiesis. Cell Rep 2021; 37:109887. [PMID: 34706233 DOI: 10.1016/j.celrep.2021.109887] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 05/17/2021] [Accepted: 10/05/2021] [Indexed: 12/13/2022] Open
Abstract
In emergency myelopoiesis (EM), expansion of the myeloid progenitor compartment and increased myeloid cell production are observed and often mediated by the pro-inflammatory cytokine interferon gamma (IFN-γ). Interleukin-10 (IL-10) inhibits IFN-γ secretion, but paradoxically, its therapeutic administration to humans causes hematologic changes similar to those observed in EM. In this work, we use different in vivo systems, including a humanized immune system mouse model, to show that IL-10 triggers EM, with a significant expansion of the myeloid progenitor compartment and production of myeloid cells. Hematopoietic progenitors display a prominent IFN-γ transcriptional signature, and we show that IFN-γ mediates IL-10-driven EM. We also find that IL-10, unexpectedly, reprograms CD4 and CD8 T cells toward an activation state that includes IFN-γ production by these T cell subsets in vivo. Therefore, in addition to its established anti-inflammatory properties, IL-10 can induce IFN-γ production and EM, opening additional perspectives for the design of IL-10-based immunotherapies.
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30
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Marongiu L, Allgayer H. Viruses in colorectal cancer. Mol Oncol 2021; 16:1423-1450. [PMID: 34514694 PMCID: PMC8978519 DOI: 10.1002/1878-0261.13100] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/15/2021] [Accepted: 09/10/2021] [Indexed: 12/23/2022] Open
Abstract
Increasing evidence suggests that microorganisms might represent at least highly interesting cofactors in colorectal cancer (CRC) oncogenesis and progression. Still, associated mechanisms, specifically in colonocytes and their microenvironmental interactions, are still poorly understood. Although, currently, at least seven viruses are being recognized as human carcinogens, only three of these – Epstein–Barr virus (EBV), human papillomavirus (HPV) and John Cunningham virus (JCV) – have been described, with varying levels of evidence, in CRC. In addition, cytomegalovirus (CMV) has been associated with CRC in some publications, albeit not being a fully acknowledged oncovirus. Moreover, recent microbiome studies set increasing grounds for new hypotheses on bacteriophages as interesting additional modulators in CRC carcinogenesis and progression. The present Review summarizes how particular groups of viruses, including bacteriophages, affect cells and the cellular and microbial microenvironment, thereby putatively contributing to foster CRC. This could be achieved, for example, by promoting several processes – such as DNA damage, chromosomal instability, or molecular aspects of cell proliferation, CRC progression and metastasis – not necessarily by direct infection of epithelial cells only, but also by interaction with the microenvironment of infected cells. In this context, there are striking common features of EBV, CMV, HPV and JCV that are able to promote oncogenesis, in terms of establishing latent infections and affecting p53‐/pRb‐driven, epithelial–mesenchymal transition (EMT)‐/EGFR‐associated and especially Wnt/β‐catenin‐driven pathways. We speculate that, at least in part, such viral impacts on particular pathways might be reflected in lasting (e.g. mutational or further genomic) fingerprints of viruses in cells. Also, the complex interplay between several species within the intestinal microbiome, involving a direct or indirect impact on colorectal and microenvironmental cells but also between, for example, phages and bacterial and viral pathogens, and further novel species certainly might, in part, explain ongoing difficulties to establish unequivocal monocausal links between specific viral infections and CRC.
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Affiliation(s)
- Luigi Marongiu
- Department of Experimental Surgery - Cancer Metastasis, Medical Faculty Mannheim, Ruprecht-Karls-University of Heidelberg, Mannheim, Germany
| | - Heike Allgayer
- Department of Experimental Surgery - Cancer Metastasis, Medical Faculty Mannheim, Ruprecht-Karls-University of Heidelberg, Mannheim, Germany
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31
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Yamashita M, Niisato M, Kawasaki Y, Karaman S, Robciuc MR, Shibata Y, Ishida Y, Nishio R, Masuda T, Sugai T, Ono M, Tuder RM, Alitalo K, Yamauchi K. VEGF-C/VEGFR-3 signaling in macrophages ameliorates acute lung injury. Eur Respir J 2021; 59:13993003.00880-2021. [PMID: 34446463 DOI: 10.1183/13993003.00880-2021] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 08/14/2021] [Indexed: 11/05/2022]
Abstract
RATIONALE Successful recovery from acute lung injury requires inhibition of neutrophil influx and clearance of apoptotic neutrophils. However, the mechanisms underlying recovery remain unclear. OBJECTIVES We investigated the ameliorative effects of vascular endothelial growth factor receptor-3 (VEGFR-3)/VEGF-C signaling in macrophages in lipopolysaccharide-induced lung injury. METHODS Lipopolysaccharides were intranasally injected into wild-type and transgenic mice. Gain- and loss- of VEGF-C/VEGFR-3 signaling function experiments employed adenovirus-mediated intranasal delivery of VEGF-C (Ad-VEGF-C vector) and soluble VEGFR-3, or, anti-VEGFR-3 blocking antibodies and mice with a deletion of VEGFR-3 in myeloid cells. MEASUREMENTS AND MAIN RESULTS The early phase of lung injury was significantly alleviated by the overexpression of VEGF-C with increased levels of bronchoalveolar lavage fluid (BALF) interleukin (IL)-10, but worsened in the later phase by VEGFR-3 inhibition upon administration of Ad-sVEGFR-3 vector. Injection of anti-VEGFR-3 antibodies to the mice in the resolution phase inhibited recovery from lung injury. The VEGFR-3 deleted mice had a shorter survival time than littermates and more severe lung injury in the resolution phase. Alveolar macrophages in the resolution phase digested most of extrinsic apoptotic neutrophils, and VEGF-C/VEGFR-3 signaling increased efferocytosis via upregulation of integrin alpha v in the macrophages. We also found that incubation with BALF from acute respiratory distress syndrome (ARDS) patients, but not from controls, decreases VEGFR-3 expression and the efficiency of IL-10 expression and efferocytosis in human monocyte-derived macrophages. CONCLUSIONS VEGFR-3/VEGF-C signaling in macrophages ameliorates experimental lung injury. This mechanism may provide an explanation also for ARDS resolution.
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Affiliation(s)
- Masahiro Yamashita
- Department of Pulmonary Medicine, Allergy and Immunological Diseases, Iwate Medical University School of Medicine, Morioka, Japan
| | - Miyuki Niisato
- Department of Pulmonary Medicine, Allergy and Immunological Diseases, Iwate Medical University School of Medicine, Morioka, Japan
| | - Yasushi Kawasaki
- Department of Health Chemistry, Iwate Medical University School of Pharmacology, Shiwa, Japan
| | - Sinem Karaman
- Wihuri Research Institute and Translational Cancer Medicine Program, University of Helsinki, Finland
| | - Marius R Robciuc
- Wihuri Research Institute and Translational Cancer Medicine Program, University of Helsinki, Finland
| | - Yuji Shibata
- Department of Pathology, Iwate Medical University School of Medicine, Japan
| | - Yoji Ishida
- Department of Hematology, Iwate Medical University School of Medicine, Japan
| | | | - Tomoyuki Masuda
- Department of Pathology, Iwate Medical University School of Medicine, Japan
| | - Tamotsu Sugai
- Department of Pathology, Iwate Medical University School of Medicine, Japan
| | - Masao Ono
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Rubin M Tuder
- Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, CO, USA
| | - Kari Alitalo
- Wihuri Research Institute and Translational Cancer Medicine Program, University of Helsinki, Finland
| | - Kohei Yamauchi
- Department of Pulmonary Medicine, Allergy and Immunological Diseases, Iwate Medical University School of Medicine, Morioka, Japan
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Gonzalez Acera M, Patankar JV, Diemand L, Siegmund B, Neurath MF, Wirtz S, Becker C. Comparative Transcriptomics of IBD Patients Indicates Induction of Type 2 Immunity Irrespective of the Disease Ideotype. Front Med (Lausanne) 2021; 8:664045. [PMID: 34136502 PMCID: PMC8200538 DOI: 10.3389/fmed.2021.664045] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 05/04/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory cytokines initiate and sustain the perpetuation of processes leading to chronic inflammatory conditions such as inflammatory bowel diseases (IBD). The nature of the trigger causing an inflammatory reaction decides whether type 1, type 17, or type 2 immune responses, typically characterized by the respective T- helper cell subsets, come into effect. In the intestine, Type 2 responses have been linked with mucosal healing and resolution upon an immune challenge involving parasitic infections. However, type 2 cytokines are frequently elevated in certain types of IBD in particular ulcerative colitis (UC) leading to the assumption that Th2 cells might critically support the pathogenesis of UC raising the question of whether such elevated type 2 responses in IBD are beneficial or detrimental. In line with this, previous studies showed that suppression of IL-13 and other type 2 related molecules in murine models could improve the outcomes of intestinal inflammation. However, therapeutic attempts of neutralizing IL-13 in ulcerative colitis patients have yielded no benefits. Thus, a better understanding of the role of type 2 cytokines in regulating intestinal inflammation is required. Here, we took a comparative transcriptomic approach to address how Th2 responses evolve in different mouse models of colitis and human IBD datasets. Our data show that type 2 immune-related transcripts are induced in the inflamed gut of IBD patients in both Crohn's disease and UC and across widely used mouse models of IBD. Collectively our data implicate that the presence of a type 2 signature rather defines a distinct state of intestinal inflammation than a disease-specific pathomechanism.
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Affiliation(s)
- Miguel Gonzalez Acera
- Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Jay V Patankar
- Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Leonard Diemand
- Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Britta Siegmund
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Berlin, Germany
| | - Markus F Neurath
- Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Stefan Wirtz
- Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Christoph Becker
- Department of Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
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IL-10 in Mast Cell-Mediated Immune Responses: Anti-Inflammatory and Proinflammatory Roles. Int J Mol Sci 2021; 22:ijms22094972. [PMID: 34067047 PMCID: PMC8124430 DOI: 10.3390/ijms22094972] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/30/2021] [Accepted: 05/05/2021] [Indexed: 12/31/2022] Open
Abstract
Mast cells (MCs) play critical roles in Th2 immune responses, including the defense against parasitic infections and the initiation of type I allergic reactions. In addition, MCs are involved in several immune-related responses, including those in bacterial infections, autoimmune diseases, inflammatory bowel diseases, cancers, allograft rejections, and lifestyle diseases. Whereas antigen-specific IgE is a well-known activator of MCs, which express FcεRI on the cell surface, other receptors for cytokines, growth factors, pathogen-associated molecular patterns, and damage-associated molecular patterns also function as triggers of MC stimulation, resulting in the release of chemical mediators, eicosanoids, and various cytokines. In this review, we focus on the role of interleukin (IL)-10, an anti-inflammatory cytokine, in MC-mediated immune responses, in which MCs play roles not only as initiators of the immune response but also as suppressors of excessive inflammation. IL-10 exhibits diverse effects on the proliferation, differentiation, survival, and activation of MCs in vivo and in vitro. Furthermore, IL-10 derived from MCs exerts beneficial and detrimental effects on the maintenance of tissue homeostasis and in several immune-related diseases including contact hypersensitivity, auto-immune diseases, and infections. This review introduces the effects of IL-10 on various events in MCs, and the roles of MCs in IL-10-related immune responses and as a source of IL-10.
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Ram PK, Singh SK, Srivastava A, Kumar G, Jaiswal AK, Yadav B, Garg SK. Effects of Injectable Trace Minerals (ITMs) on Th1/Th2 Cytokine Balance of Newborn Calves with Tropical Theileriosis. Biol Trace Elem Res 2021; 199:1397-1404. [PMID: 32572800 DOI: 10.1007/s12011-020-02263-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 06/17/2020] [Indexed: 11/30/2022]
Abstract
Injectable trace minerals (ITMs) could provide a potential alternative way of trace mineral delivery for sick animals. Therefore, evaluation of ameliorative potentials of ITMs (copper, manganese, selenium, and zinc) on the circulating Th1/Th2 cytokine misbalance in Theileria annulata-infected calves was aimed. Forty-three T. annulata-infected newborn calves were randomly allocated into four groups: buparvaquone alone-treated group (BUPA), buparvaquone + oxytetracycline (BUPA + OXY)-treated group, buparvaquone + injectable trace minerals (BUPA + ITMs)-treated group, and BUPA + OXY + ITM-treated group. Blood samples were collected from each of the calves before the start of therapy (day 0) and on day 14 post-therapy. Serum contents of pro- and anti-inflammatory cytokines were estimated by bovine specific ELISA kits. On day 14 post-therapy, significant amelioration in the circulating levels of the studied cytokines was not observed in the calves treated with BUPA, while the calves treated with BUPA + OXY revealed significant (P ≤ 0.04) amelioration in the circulating tumour necrosis factor-α (TNF-α) level. The calves treated with BUPA + ITMs revealed significant (P ≤ 0.041) elevation in the circulating interferon-γ (IFN-γ) and significant (P ≤ 0.011) reduction in the interleukin-10 (IL-10) levels. Moreover, the calves treated with BUPA + OXY + ITMs revealed significant reduction in TNF-α (P ≤ 0.0001) and IL-10 (P ≤ 0.012) contents, and significant elevation in IFN-γ (P ≤ 0.0002) content on day 14 post-therapy. None of the treated calve group revealed significant alteration in the circulating level of transforming growth factor-β (TGF-β) on day 14 post-therapy. In conclusion, administration of ITMs to the therapeutic regimen of newborn calves with tropical theileriosis could be a promising therapeutic strategy. ITMs can be recommended for the amelioration of immunological misbalance due to tropical theileriosis in newborn calves.
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Affiliation(s)
- Pradeep K Ram
- Department of Veterinary Medicine, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sansthan (DUVASU), Mathura, Uttar Pradesh, 281001, India
- Animal Production Research Institute, Dr Rajendra Prasad Central Agricultural University Pusa, Samastipur, Bihar, 848125, India
| | - Shanker K Singh
- Department of Veterinary Medicine, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sansthan (DUVASU), Mathura, Uttar Pradesh, 281001, India.
| | - Ashish Srivastava
- Department of Veterinary Medicine, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sansthan (DUVASU), Mathura, Uttar Pradesh, 281001, India
| | - Gulshan Kumar
- Department of Veterinary Surgery and Radiology, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sansthan (DUVASU), Mathura, Uttar Pradesh, 281001, India
| | - Amit K Jaiswal
- Department of Veterinary Parasitology, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sansthan (DUVASU), Mathura, Uttar Pradesh, 281001, India
| | - Brijesh Yadav
- Department of Animal Physiology, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sansthan (DUVASU), Mathura, Uttar Pradesh, 281001, India
| | - Satish K Garg
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sansthan (DUVASU), Mathura, Uttar Pradesh, 281001, India
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35
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Lidbury BA. Ross River Virus Immune Evasion Strategies and the Relevance to Post-viral Fatigue, and Myalgic Encephalomyelitis Onset. Front Med (Lausanne) 2021; 8:662513. [PMID: 33842517 PMCID: PMC8024622 DOI: 10.3389/fmed.2021.662513] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 02/24/2021] [Indexed: 01/06/2023] Open
Abstract
Ross River virus (RRV) is an endemic Australian arbovirus, and member of the Alphavirus family that also includes Chikungunya virus (CHIK). RRV is responsible for the highest prevalence of human disease cases associated with mosquito-borne transmission in Australia, and has long been a leading suspect in cases of post-viral fatigue syndromes, with extrapolation of this link to Myalgic Encephalomyelitis (ME). Research into RRV pathogenesis has revealed a number of immune evasion strategies, impressive for a virus with a genome size of 12 kb (plus strand RNA), which resonate with insights into viral pathogenesis broadly. Drawing from observations on RRV immune evasion, mechanisms of relevance to long term idiopathic fatigue are featured as a perspective on infection and eventual ME symptoms, which include considerations of; (1) selective pro-inflammatory gene suppression post antibody-dependent enhancement (ADE) of RRV infection, (2) Evidence from other virus families of immune disruption and evasion post-ADE, and (3) how virally-driven immune evasion may impact on mitochondrial function via target of rapamycin (TOR) complexes. In light of these RRV measures to counter the host immune - inflammatory responses, links to recent discoveries explaining cellular, immune and metabolomic markers of ME will be explored and discussed, with the implications for long-COVID post SARS-CoV-2 also considered. Compelling issues on the connections between virally-induced alterations in cytokine expression, for example, will be of particular interest in light of energy pathways, and how these perturbations manifest clinically.
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Affiliation(s)
- Brett A Lidbury
- National Centre for Epidemiology and Population Health, Research School of Population Health, The Australian National University, Canberra, ACT, Australia
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36
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Jog NR, James JA. Epstein Barr Virus and Autoimmune Responses in Systemic Lupus Erythematosus. Front Immunol 2021; 11:623944. [PMID: 33613559 PMCID: PMC7886683 DOI: 10.3389/fimmu.2020.623944] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 12/21/2020] [Indexed: 11/13/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease. Infections or infectious reactivation are potential triggers for initiation of autoimmunity and for SLE flares. Epstein-Barr virus (EBV) is gamma herpes virus that has been associated with several autoimmune diseases such as SLE, multiple sclerosis, Sjogren’s syndrome, and systemic sclerosis. In this review, we will discuss the recent advances regarding how EBV may contribute to immune dysregulation, and how these mechanisms may relate to SLE disease progression.
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Affiliation(s)
- Neelakshi R Jog
- Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
| | - Judith A James
- Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States.,Departments of Medicine, Pathology, Microbiology & Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
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37
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Houen G, Trier NH. Epstein-Barr Virus and Systemic Autoimmune Diseases. Front Immunol 2021; 11:587380. [PMID: 33488588 PMCID: PMC7817975 DOI: 10.3389/fimmu.2020.587380] [Citation(s) in RCA: 196] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 11/19/2020] [Indexed: 12/11/2022] Open
Abstract
Epstein-Barr Virus (EBV) is an extremely successful human herpes virus, which infects essentially all human beings at some time during their life span. EBV infection and the associated immune response results in production of antibodies (seroconversion), which occurs mainly during the first years of life, but may also happen during adolescence or later in life. Infection of adolescents can result in infectious mononucleosis, an acute serious condition characterized by massive lymphocytosis. Transmission of EBV mainly occurs through saliva but can rarely be spread through semen or blood, e.g. through organ transplantations and blood transfusions. EBV transmission through oral secretions results in infection of epithelial cells of the oropharynx. From the epithelial cells EBV can infect B cells, which are the major reservoir for the virus, but other cell types may also become infected. As a result, EBV can shuttle between different cell types, mainly B cells and epithelial cells. Moreover, since the virus can switch between a latent and a lytic life cycle, EBV has the ability to cause chronic relapsing/reactivating infections. Chronic or recurrent EBV infection of epithelial cells has been linked to systemic lupus erythematosus and Sjögren’s syndrome, whereas chronic/recurrent infection of B cells has been associated with rheumatoid arthritis, multiple sclerosis and other diseases. Accordingly, since EBV can shuttle between epithelial cells and B cells, the systemic autoimmune diseases often occur as overlapping syndromes with symptoms and characteristic autoantibodies (e.g. antinuclear antibodies and rheumatoid factors) reflecting epithelial and/or B cell infection.
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Affiliation(s)
- Gunnar Houen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.,Department of Neurology, Rigshospitalet, Glostrup, Denmark
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38
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Batchu RB, Gruzdyn OV, Kolli BK, Dachepalli R, Umar PS, Rai SK, Singh N, Tavva PS, Weaver DW, Gruber SA. IL-10 Signaling in the Tumor Microenvironment of Ovarian Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1290:51-65. [PMID: 33559854 DOI: 10.1007/978-3-030-55617-4_3] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Unlike other malignancies, ovarian cancer (OC) creates a complex tumor microenvironment with distinctive peritoneal ascites consisting of a mixture of several immunosuppressive cells which impair the ability of the patient's immune system to fight the disease. The poor survival rates observed in advanced stage OC patients and the lack of effective conventional therapeutic options have been attributed in large part to the immature dendritic cells (DCs), IL-10 secreting regulatory T cells, tumor-associated macrophages, myeloid-derived suppressor cells, and cancer stem cells that secrete inhibitory cytokines. This review highlights the critical role played by the intraperitoneal presence of IL-10 in the generation of an immunosuppressive tumor microenvironment. Further, the effect of antibody neutralization of IL-10 on the efficacy of DC and chimeric antigen receptor T-cell vaccines will be discussed. Moreover, we will review the influence of IL-10 in the promotion of cancer stemness in concert with the NF-κB signaling pathway with regard to OC progression. Finally, understanding the role of IL-10 and its crosstalk with various cells in the ascitic fluid may contribute to the development of novel immunotherapeutic approaches with the potential to kill drug-resistant OC cells while minimizing toxic side effects.
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Affiliation(s)
- Ramesh B Batchu
- Wayne State University School of Medicine, Detroit, MI, USA. .,John D. Dingell VA Medical Center, Detroit, MI, USA.
| | - Oksana V Gruzdyn
- Wayne State University School of Medicine, Detroit, MI, USA.,John D. Dingell VA Medical Center, Detroit, MI, USA
| | - Bala K Kolli
- Wayne State University School of Medicine, Detroit, MI, USA.,John D. Dingell VA Medical Center, Detroit, MI, USA.,Med Manor Organics Pvt. Ltd., Hyderabad, India
| | | | - Prem S Umar
- Med Manor Organics Pvt. Ltd., Hyderabad, India
| | | | | | | | | | - Scott A Gruber
- Wayne State University School of Medicine, Detroit, MI, USA.,John D. Dingell VA Medical Center, Detroit, MI, USA
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Uddin MN, Yao Y, Manley K, Lawrence DA. Development, phenotypes of immune cells in BTBR T +Itpr3 tf/J mice. Cell Immunol 2020; 358:104223. [PMID: 33137646 DOI: 10.1016/j.cellimm.2020.104223] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 09/18/2020] [Accepted: 09/20/2020] [Indexed: 01/01/2023]
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is characterized by a lack of social interaction, decreased verbal and non-verbal communication skills, and stereotyped repetitive behavior. There is strong evidence that a dysregulated immune response may influence neurodevelopment and thus may have a role in the development of ASD. This study focuses on the characterization of immune cell phenotypes in the BTBR T+Itpr3tf/J (BTBR) mouse strain, a widely used animal model for autism research. Our study demonstrated that BTBR mice have a different immune profile compared to C57BL/6J (B6) mice, which do not display ASD-like characteristics. Thymic cells of BTBR mice have more single positive (SP) CD4+ and CD8+ T cells and fewer double positive (DP) T cells than B6 mice. The development of T cells is increased in BTBR mice with regard to the double negative (DN4) population being much higher in BTBR mice. The spleens and blood of BTBR mice also have more T helper type 1 (Th1), T helper type 2 (Th2) and T regulatory (Treg) cells compared to B6 mice. Aire expression in the thymus and spleen of BTBR mice compared to B6 mice was equivalent and lower, respectively. The mature natural killer (NK) innate immune cell population in blood and spleen is lower in BTBR than B6 mice; NK cell development is blocked prior to the double positive (DN) CD11b+CD27+ stage in BTBR mice. Since BTBR mice have more CD4+ T cells and elevated numbers of Th1 (T-bet+) and Th2 (GATA3+) cells, their low defense against pathogen may be explained by the lower number of NK cells and the significantly lower Th1 to Th2 ratio. The elevated number of plasma cells and autoantibodies of BTBR mice may be due to less presence and function of splenic AIRE.
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Affiliation(s)
- Mohammad Nizam Uddin
- Wadsworth Center, New York State Department of Health, Albany, NY, United States
| | - Yunyi Yao
- Wadsworth Center, New York State Department of Health, Albany, NY, United States
| | - Kevin Manley
- Wadsworth Center, New York State Department of Health, Albany, NY, United States
| | - David A Lawrence
- Wadsworth Center, New York State Department of Health, Albany, NY, United States; University at Albany School of Public Health, Rensselaer, NY, United States.
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40
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Saraiva M, Vieira P, O'Garra A. Biology and therapeutic potential of interleukin-10. J Exp Med 2020; 217:jem.20190418. [PMID: 31611251 PMCID: PMC7037253 DOI: 10.1084/jem.20190418] [Citation(s) in RCA: 584] [Impact Index Per Article: 116.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 08/05/2019] [Accepted: 09/11/2019] [Indexed: 12/13/2022] Open
Abstract
The authors review the molecular mechanisms regulating IL-10 production and response and describe classic and novel functions of IL-10 in immune and non-immune cells. They further discuss the therapeutic potential of IL-10 in different diseases and the outstanding questions underlying an effective application of IL-10 in clinical settings. The cytokine IL-10 is a key anti-inflammatory mediator ensuring protection of a host from over-exuberant responses to pathogens and microbiota, while playing important roles in other settings as sterile wound healing, autoimmunity, cancer, and homeostasis. Here we discuss our current understanding of the regulation of IL-10 production and of the molecular pathways associated with IL-10 responses. In addition to IL-10’s classic inhibitory effects on myeloid cells, we also describe the nonclassic roles attributed to this pleiotropic cytokine, including how IL-10 regulates basic processes of neural and adipose cells and how it promotes CD8 T cell activation, as well as epithelial repair. We further discuss its therapeutic potential in the context of different diseases and the outstanding questions that may help develop an effective application of IL-10 in diverse clinical settings.
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Affiliation(s)
- Margarida Saraiva
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
| | - Paulo Vieira
- Department of Immunology, Unité Lymphopoièse, Institut Pasteur, Paris, France.,University Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, Paris, France.,Institut National de la Santé et de la Recherche Médicale U1223, Paris, France
| | - Anne O'Garra
- Laboratory of Immunoregulation and Infection, The Francis Crick Institute, London, UK.,National Heart and Lung Institute, Imperial College London, UK
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41
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Porro C, Cianciulli A, Panaro MA. The Regulatory Role of IL-10 in Neurodegenerative Diseases. Biomolecules 2020; 10:biom10071017. [PMID: 32659950 PMCID: PMC7407888 DOI: 10.3390/biom10071017] [Citation(s) in RCA: 130] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 07/01/2020] [Accepted: 07/07/2020] [Indexed: 02/06/2023] Open
Abstract
IL-10, an immunosuppressive cytokine, is considered an important anti-inflammatory modulator of glial activation, preventing inflammation-mediated neuronal degeneration under pathological conditions. In this narrative review, we summarize recent insights about the role of IL-10 in the neurodegeneration associated with neuroinflammation, in diseases such as Multiple Sclerosis, Traumatic Brain Injury, Amyotrophic lateral sclerosis, Alzheimer’s Disease, and Parkinson’s Disease, focusing on the contribution of this cytokine not only in terms of protective action, but also as possibly responsible for clinical worsening. The knowledge of this double face of the same coin, regarding the biological role of the IL-10, could aid the development of targeted therapies useful for limiting neurodegenerative processes.
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Affiliation(s)
- Chiara Porro
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy;
| | - Antonia Cianciulli
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy;
| | - Maria Antonietta Panaro
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy;
- Correspondence:
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42
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Wei HX, Wang B, Li B. IL-10 and IL-22 in Mucosal Immunity: Driving Protection and Pathology. Front Immunol 2020; 11:1315. [PMID: 32670290 PMCID: PMC7332769 DOI: 10.3389/fimmu.2020.01315] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 05/26/2020] [Indexed: 12/12/2022] Open
Abstract
The barrier surfaces of the gastrointestinal tract are in constant contact with various microorganisms. Cytokines orchestrate the mucosal adaptive and innate immune cells in the defense against pathogens. IL-10 and IL-22 are the best studied members of the IL-10 family and play essential roles in maintaining mucosal homeostasis. IL-10 serves as an important regulator in preventing pro-inflammatory responses while IL-22 plays a protective role in tissue damage and contributes to pathology in certain settings. In this review, we focus on these two cytokines in the development of gastrointestinal diseases, including inflammatory bowel diseases (IBD) and colitis-associated cancer (CAC). We summarize the recent studies and try to gain a better understanding on how they regulate immune responses to maintain equilibrium under inflammatory conditions.
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Affiliation(s)
- Hua-Xing Wei
- Division of Life Sciences and Medicine, Department of Laboratory Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Baolong Wang
- Division of Life Sciences and Medicine, Department of Laboratory Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Bofeng Li
- Division of Life Sciences and Medicine, Department of Medical Oncology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
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43
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Ram PK, Singh SK, Kumari P, Srivastava M, Sudan V, Pandey RP, Garg SK. Role of cytokines in the clinical manifestation of exophthalmia in newborn calves with tropical theileriosis. Parasite Immunol 2020; 42:e12761. [PMID: 32497247 DOI: 10.1111/pim.12761] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 05/25/2020] [Accepted: 05/26/2020] [Indexed: 12/30/2022]
Abstract
The present study aimed to evaluate the pathology of the exophthalmia and the host-immune response in naturally Theileria annulata-infected calves. The newborn calves detected positive for theileriosis were grouped into calves with theileriosis and absence of exophthalmia (n = 30), and calves with theileriosis and the presence of exophthalmia (n = 13). Sixteen healthy calves, free from any haemoprotozoal infection, were kept as healthy controls. A significantly (P ≤ .001) higher circulating levels of tumour necrosis factor-α (TNF-α) and interleukin-10 (IL-10) were estimated in diseased calves with and without exophthalmia as compared to healthy controls. Contrarily, significantly (P ≤ .01) lower interferon-γ (IFN-γ) level was estimated in diseased calves. The diseased calves with exophthalmia revealed significantly higher levels of TNF-α (P ≤ .001) and IL-10 (P ≤ .006) as compared to the diseased calves without exophthalmia. The diseased calves were not found to have an elevated intraocular pressure; rather they had significantly (P ≤ .001) lower intraocular pressure compared to the healthy controls. An elevated systemic TNF-α level might be attributed to the exophthalmia in calves with tropical theileriosis. The elevated circulatory IL-10 and reduced IFN-γ levels could be one of the strategies of Theileria annulata to escape the host immunity.
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Affiliation(s)
- Pradeep K Ram
- Department of Veterinary Medicine, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sansthan (DUVASU), Mathura, U.P., India
| | - Shanker K Singh
- Department of Veterinary Medicine, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sansthan (DUVASU), Mathura, U.P., India
| | - Priyambada Kumari
- College of Biotechnology, U.P. Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sansthan (DUVASU), Mathura, U.P., India
| | - Mukesh Srivastava
- Department of Veterinary Medicine, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sansthan (DUVASU), Mathura, U.P., India
| | - Vikrant Sudan
- Department of Veterinary Parasitology, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sansthan (DUVASU), Mathura, U.P., India
| | - Rudra P Pandey
- Department of Veterinary Surgery and Radiology, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sansthan (DUVASU), Mathura, U.P., India
| | - Satish K Garg
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Science and Animal Husbandry, U.P. Pandit Deen Dayal Upadhyaya Pashu-Chikitsa Vigyan Vishwavidyalaya Evam Go Anusandhan Sansthan (DUVASU), Mathura, U.P., India
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44
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SARS-CoV-2 infection: The role of cytokines in COVID-19 disease. Cytokine Growth Factor Rev 2020; 54:62-75. [PMID: 32513566 PMCID: PMC7265853 DOI: 10.1016/j.cytogfr.2020.06.001] [Citation(s) in RCA: 770] [Impact Index Per Article: 154.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 05/19/2020] [Accepted: 06/01/2020] [Indexed: 02/06/2023]
Abstract
A wide range of cytokines are involved in the development of COVID-19 disease. Some of these biomolecules are related to the progression and even to the prognosis of the infection. Findings on the role of cytokine storm associated with SARS-CoV-2 infection can be useful in order to manage this highly virulent disease. COVID-19 disease, caused by infection with SARS-CoV-2, is related to a series of physiopathological mechanisms that mobilize a wide variety of biomolecules, mainly immunological in nature. In the most severe cases, the prognosis can be markedly worsened by the hyperproduction of mainly proinflammatory cytokines, such as IL-1, IL-6, IL-12, IFN-γ, and TNF-α, preferentially targeting lung tissue. This study reviews published data on alterations in the expression of different cytokines in patients with COVID-19 who require admission to an intensive care unit. Data on the implication of cytokines in this disease and their effect on outcomes will support the design of more effective approaches to the management of COVID-19.
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45
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Zachova K, Kosztyu P, Zadrazil J, Matousovic K, Vondrak K, Hubacek P, Julian BA, Moldoveanu Z, Novak Z, Kostovcikova K, Raska M, Mestecky J. Role of Epstein-Barr Virus in Pathogenesis and Racial Distribution of IgA Nephropathy. Front Immunol 2020; 11:267. [PMID: 32184780 PMCID: PMC7058636 DOI: 10.3389/fimmu.2020.00267] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 02/03/2020] [Indexed: 02/04/2023] Open
Abstract
IgA nephropathy (IgAN) is the dominant type of primary glomerulonephritis worldwide. However, IgAN rarely affects African Blacks and is uncommon in African Americans. Polymeric IgA1 with galactose-deficient hinge-region glycans is recognized as auto-antigen by glycan-specific antibodies, leading to formation of circulating immune complexes with nephritogenic consequences. Because human B cells infected in vitro with Epstein-Barr virus (EBV) secrete galactose-deficient IgA1, we examined peripheral blood B cells from adult IgAN patients, and relevant controls, for the presence of EBV and their phenotypic markers. We found that IgAN patients had more lymphoblasts/plasmablasts that were surface-positive for IgA, infected with EBV, and displayed increased expression of homing receptors for targeting the upper respiratory tract. Upon polyclonal stimulation, these cells produced more galactose-deficient IgA1 than did cells from healthy controls. Unexpectedly, in healthy African Americans, EBV was detected preferentially in surface IgM- and IgD-positive cells. Importantly, most African Blacks and African Americans acquire EBV within 2 years of birth. At that time, the IgA system is naturally deficient, manifested as low serum IgA levels and few IgA-producing cells. Consequently, EBV infects cells secreting immunoglobulins other than IgA. Our novel data implicate Epstein-Barr virus infected IgA+ cells as the source of galactose-deficient IgA1 and basis for expression of relevant homing receptors. Moreover, the temporal sequence of racial-specific differences in Epstein-Barr virus infection as related to the naturally delayed maturation of the IgA system explains the racial disparity in the prevalence of IgAN.
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Affiliation(s)
- Katerina Zachova
- Department of Immunology, Faculty of Medicine and Dentistry, University Hospital Olomouc, Palacky University Olomouc, Olomouc, Czechia
| | - Petr Kosztyu
- Department of Immunology, Faculty of Medicine and Dentistry, University Hospital Olomouc, Palacky University Olomouc, Olomouc, Czechia
| | - Josef Zadrazil
- Department of Internal Medicine III Nephrology, Rheumatology and Endocrinology, University Hospital Olomouc, Palacky University Olomouc, Olomouc, Czechia
| | - Karel Matousovic
- Department of Medicine, Second Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czechia
| | - Karel Vondrak
- Department of Pediatrics, Second Faculty of Medicine, Charles University, Prague, Czechia
| | - Petr Hubacek
- Department of Medical Microbiology, Second Faculty of Medicine, University Hospital Motol, Charles University, Prague, Czechia
| | - Bruce A Julian
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Zina Moldoveanu
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Zdenek Novak
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Klara Kostovcikova
- Laboratory of Cellular and Molecular Immunology, Institute of Microbiology, Czech Academy of Sciences, Prague, Czechia
| | - Milan Raska
- Department of Immunology, Faculty of Medicine and Dentistry, University Hospital Olomouc, Palacky University Olomouc, Olomouc, Czechia.,Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Jiri Mestecky
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States.,Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States.,Laboratory of Cellular and Molecular Immunology, Institute of Microbiology, Czech Academy of Sciences, Prague, Czechia
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46
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Johnson KE, Tarakanova VL. Gammaherpesviruses and B Cells: A Relationship That Lasts a Lifetime. Viral Immunol 2020; 33:316-326. [PMID: 31913773 DOI: 10.1089/vim.2019.0126] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Gammaherpesviruses are highly prevalent pathogens that establish life-long infection and are associated with diverse malignancies, including lymphoproliferative diseases and B cell lymphomas. Unlike other viruses that either do not infect B cells or infect B cells transiently, gammaherpesviruses manipulate physiological B cell differentiation to establish life-long infection in memory B cells. Disruption of such viral manipulation by genetic or environmental causes is likely to seed viral lymphomagenesis. In this review, we discuss physiological and unique host and viral mechanisms usurped by gammaherpesviruses to fine tune host B cell biology for optimal infection establishment and maintenance.
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Affiliation(s)
- Kaitlin E Johnson
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Vera L Tarakanova
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.,Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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47
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48
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Abstract
Interleukin (IL)-10 is an essential anti-inflammatory cytokine and functions as a negative regulator of immune responses to microbial antigens. IL-10 is particularly important in maintaining the intestinal microbe-immune homeostasis. Loss of IL-10 promotes the development of inflammatory bowel disease (IBD) as a consequence of an excessive immune response to the gut microbiota. IL-10 also functions more generally to prevent excessive inflammation during the course of infection. Although IL-10 can be produced by virtually all cells of the innate and adaptive immune system, T cells constitute a non-redundant source for IL-10 in many cases. The various roles of T cell-derived IL-10 will be discussed in this review. Given that IL-10 is at the center of maintaining the delicate balance between effective immunity and tissue protection, it is not surprising that IL-10 expression is highly dynamic and tightly regulated. We summarize the environmental signals and molecular pathways that regulate IL-10 expression. While numerous studies have provided us with a deep understanding of IL-10 biology, the majority of findings have been made in murine models, prompting us to highlight gaps in our knowledge about T cell-derived IL-10 in the human system.
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49
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Tio SY, Nickless D, McCracken J, Nedumannil R, Stewart J, Aboltins C. A Man With Tonsillitis and Hepatitis. Clin Infect Dis 2019; 67:1303-1305. [PMID: 30265322 DOI: 10.1093/cid/ciy107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Shio Yen Tio
- Department of Infectious Diseases, University of Melbourne, Victoria, Australia
| | - David Nickless
- Department of Pathology, University of Melbourne, Victoria, Australia
| | - James McCracken
- Department of Oncology, The Northern Hospital, University of Melbourne, Victoria, Australia
| | - Rithin Nedumannil
- Department of Oncology, The Northern Hospital, University of Melbourne, Victoria, Australia
| | - Josephine Stewart
- Department of Oncology, The Northern Hospital, University of Melbourne, Victoria, Australia
| | - Craig Aboltins
- Department of Infectious Diseases, University of Melbourne, Victoria, Australia.,Northern Clinical School, University of Melbourne, Victoria, Australia
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50
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Abramson JS, Irwin KE, Frigault MJ, Dietrich J, McGree B, Jordan JT, Yee AJ, Chen YB, Raje NS, Barnes JA, Davis B. Successful anti-CD19 CAR T-cell therapy in HIV-infected patients with refractory high-grade B-cell lymphoma. Cancer 2019; 125:3692-3698. [PMID: 31503324 DOI: 10.1002/cncr.32411] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Affiliation(s)
- Jeremy S Abramson
- Division of Hematology-Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Kelly E Irwin
- Division of Psychiatric Oncology, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts
| | - Matthew J Frigault
- Division of Hematology-Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Jorg Dietrich
- Division of Neuro-Oncology, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts
| | - Brianne McGree
- Division of Hematology-Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Justin T Jordan
- Division of Neuro-Oncology, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts
| | - Andrew J Yee
- Division of Hematology-Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Yi-Bin Chen
- Division of Hematology-Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Noopur S Raje
- Division of Hematology-Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Jeffrey A Barnes
- Division of Hematology-Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Benjamin Davis
- Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
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