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Costaguta A, Costaguta G, Álvarez F. Autoimmune hepatitis: Towards a personalized treatment. World J Hepatol 2024; 16:1225-1242. [PMID: 39606175 PMCID: PMC11586748 DOI: 10.4254/wjh.v16.i11.1225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 09/02/2024] [Accepted: 10/11/2024] [Indexed: 11/06/2024] Open
Abstract
Autoimmune hepatitis is an uncommon condition that affects both adults and children and is characterized by chronic and recurrent inflammatory activity in the liver. This inflammation is accompanied by elevated IgG and autoantibody levels. Historically, treatment consists of steroids with the addition of azathioprine, which results in remission in approximately 80% of patients. Despite significant advancements in our understanding of the immune system over the past two decades, few modifications have been made to treatment algorithms, which have remained largely unchanged since they were first proposed more than 40 years ago. This review summarized the various treatment options currently available as well as our experiences using them. Although steroids are the standard treatment for induction therapy, other medications may be considered. Cyclosporin A, a calcineurin inhibitor that decreases T cell activation, has proven effective for induction of remission, but its long-term side effects limit its appeal for maintenance. Tacrolimus, a drug belonging to the same family, has been used in patients with refractory diseases with fewer side effects. Sirolimus and everolimus have interesting effects on regulatory T cell populations and may become viable options in the future. Mycophenolate mofetil is not effective for induction but is a valid alternative for patients who are intolerant to azathioprine. B cell-depleting drugs, such as rituximab and belimumab, have been successfully used in refractory cases and are useful in both the short and long term. Other promising treatments include anti-tumor necrosis factors, Janus kinases inhibitors, and chimeric antigen receptor T cell therapy. This growing armamentarium allows us to imagine a more tailored approach to the treatment of autoimmune hepatitis in the near future.
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Affiliation(s)
- Alejandro Costaguta
- Department of Hepatology and Liver Transplant Unit, Sanatorio de Niños de Rosario, Rosario 2000, Santa Fe, Argentina.
| | - Guillermo Costaguta
- Department of Gastroenterology, Hepatology, and Nutrition, CHU Sainte-Justine, Montreal H3T 1C5, Quebec, Canada
| | - Fernando Álvarez
- Department of Pediatrics, CHU Sainte-Justine, Montreal H3T 1C5, Quebec, Canada
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Kuwano A, Nagasawa S, Koga Y, Tanaka K, Yada M, Masumoto A, Motomura K. Diagnostic features of autoimmune hepatitis in SARS‑CoV‑2‑vaccinated vs. unvaccinated individuals. Exp Ther Med 2024; 28:337. [PMID: 39006455 PMCID: PMC11240278 DOI: 10.3892/etm.2024.12626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 06/06/2024] [Indexed: 07/16/2024] Open
Abstract
The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected millions of lives, leading to significant morbidity and mortality. With >772 million cases and nearly seven million deaths reported worldwide to date, the development of vaccines has been a critical step in mitigating the impact of COVID-19. However, concerns have arisen regarding the potential for SARS-CoV-2 mRNA vaccination to trigger autoimmune diseases, including autoimmune hepatitis (AIH). The present single-center, retrospective study aimed to compare the clinical and pathological features of AIH in patients with or without a history of SARS-CoV-2 mRNA vaccination. A total of 72 patients with AIH were examined. Among them, 10 had received the SARS-CoV-2 mRNA vaccination prior to AIH onset. These patients exhibited more pronounced CD4+ T cell infiltration into the liver tissue compared with those who were unvaccinated. No significant differences in the levels of other liver enzymes, autoimmune antibodies, or CD8+ T cell infiltration were observed between the groups. Moreover, the AIH patients with a history of SARS-CoV-2 mRNA vaccination had more extensive CD4+ T cell infiltration in their liver tissues than the unvaccinated patients. These findings suggested that the immune response to SARS-CoV-2 mRNA vaccination may influence the pathogenesis of AIH, highlighting the need for further research into the relationship between SARS-CoV-2 mRNA vaccination and autoimmune liver diseases. Such studies will also help clarify the distinction between vaccine-induced liver injury and traditional AIH.
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Affiliation(s)
- Akifumi Kuwano
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka 820-8505, Japan
| | - Shigehiro Nagasawa
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka 820-8505, Japan
| | - Yuta Koga
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka 820-8505, Japan
| | - Kosuke Tanaka
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka 820-8505, Japan
| | - Masayoshi Yada
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka 820-8505, Japan
| | - Akihide Masumoto
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka 820-8505, Japan
| | - Kenta Motomura
- Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka 820-8505, Japan
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Sumida TS, Cheru NT, Hafler DA. The regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases. Nat Rev Immunol 2024; 24:503-517. [PMID: 38374298 PMCID: PMC11216899 DOI: 10.1038/s41577-024-00994-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/15/2024] [Indexed: 02/21/2024]
Abstract
The discovery of FOXP3+ regulatory T (Treg) cells as a distinct cell lineage with a central role in regulating immune responses provided a deeper understanding of self-tolerance. The transcription factor FOXP3 serves a key role in Treg cell lineage determination and maintenance, but is not sufficient to enable the full potential of Treg cell suppression, indicating that other factors orchestrate the fine-tuning of Treg cell function. Moreover, FOXP3-independent mechanisms have recently been shown to contribute to Treg cell dysfunction. FOXP3 mutations in humans cause lethal fulminant systemic autoinflammation (IPEX syndrome). However, it remains unclear to what degree Treg cell dysfunction is contributing to the pathophysiology of common autoimmune diseases. In this Review, we discuss the origins of Treg cells in the periphery and the multilayered mechanisms by which Treg cells are induced, as well as the FOXP3-dependent and FOXP3-independent cellular programmes that maintain the suppressive function of Treg cells in humans and mice. Further, we examine evidence for Treg cell dysfunction in the context of common autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus and rheumatoid arthritis.
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Affiliation(s)
- Tomokazu S Sumida
- Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
| | - Nardos T Cheru
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
| | - David A Hafler
- Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
- Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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Hardtke-Wolenski M, Landwehr-Kenzel S. Tipping the balance in autoimmunity: are regulatory t cells the cause, the cure, or both? Mol Cell Pediatr 2024; 11:3. [PMID: 38507159 PMCID: PMC10954601 DOI: 10.1186/s40348-024-00176-8] [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: 10/22/2023] [Accepted: 03/07/2024] [Indexed: 03/22/2024] Open
Abstract
Regulatory T cells (Tregs) are a specialized subgroup of T-cell lymphocytes that is crucial for maintaining immune homeostasis and preventing excessive immune responses. Depending on their differentiation route, Tregs can be subdivided into thymically derived Tregs (tTregs) and peripherally induced Tregs (pTregs), which originate from conventional T cells after extrathymic differentiation at peripheral sites. Although the regulatory attributes of tTregs and pTregs partially overlap, their modes of action, protein expression profiles, and functional stability exhibit specific characteristics unique to each subset. Over the last few years, our knowledge of Treg differentiation, maturation, plasticity, and correlations between their phenotypes and functions has increased. Genetic and functional studies in patients with numeric and functional Treg deficiencies have contributed to our mechanistic understanding of immune dysregulation and autoimmune pathologies. This review provides an overview of our current knowledge of Treg biology, discusses monogenetic Treg pathologies and explores the role of Tregs in various other autoimmune disorders. Additionally, we discuss novel approaches that explore Tregs as targets or agents of innovative treatment options.
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Affiliation(s)
- Matthias Hardtke-Wolenski
- Hannover Medical School, Department of Gastroenterology Hepatology, Infectious Diseases and Endocrinology, Carl-Neuberg-Str. 1, Hannover, 30625, Germany
- University Hospital Essen, Institute of Medical Microbiology, University Duisburg-Essen, Hufelandstraße 55, Essen, 45122, Germany
| | - Sybille Landwehr-Kenzel
- Hannover Medical School, Department of Pediatric Pneumology, Allergology and Neonatology, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.
- Hannover Medical School, Institute of Transfusion Medicine and Transplant Engineering, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.
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Yuming Z, Ruqi T, Gershwin ME, Xiong M. Autoimmune Hepatitis: Pathophysiology. Clin Liver Dis 2024; 28:15-35. [PMID: 37945156 DOI: 10.1016/j.cld.2023.06.003] [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: 11/12/2023]
Abstract
Genome-wide association analyses suggest that HLA genes including HLA-DRB*0301, HLA-DRB*0401, and HLA-B*3501 as well as non-HLA genes including CD28/CTLA4/ICOS and SYNPR increased AIH susceptibility. The destruction of hepatocytes is the result of the imbalance between proinflammatory cells and immunosuppressive cells, especially the imbalance between Tregs and Th17 cells. The microbiome in patients with AIH is decreased in diversity with a specific decline in Bifidobacterium and enrichment in Veillonella and Faecalibacterium. Recent evidence has demonstrated the pathogenic role of E. gallinarum and L.reuteri in inducing autoimmunity in the liver.
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Affiliation(s)
- Zhou Yuming
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Tang Ruqi
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China
| | - Merrill Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, USA.
| | - Ma Xiong
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, China; Institute of Aging & Tissue Regeneration, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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Xiang Y, Zhang M, Jiang D, Su Q, Shi J. The role of inflammation in autoimmune disease: a therapeutic target. Front Immunol 2023; 14:1267091. [PMID: 37859999 PMCID: PMC10584158 DOI: 10.3389/fimmu.2023.1267091] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 09/20/2023] [Indexed: 10/21/2023] Open
Abstract
Autoimmune diseases (AIDs) are immune disorders whose incidence and prevalence are increasing year by year. AIDs are produced by the immune system's misidentification of self-antigens, seemingly caused by excessive immune function, but in fact they are the result of reduced accuracy due to the decline in immune system function, which cannot clearly identify foreign invaders and self-antigens, thus issuing false attacks, and eventually leading to disease. The occurrence of AIDs is often accompanied by the emergence of inflammation, and inflammatory mediators (inflammatory factors, inflammasomes) play an important role in the pathogenesis of AIDs, which mediate the immune process by affecting innate cells (such as macrophages) and adaptive cells (such as T and B cells), and ultimately promote the occurrence of autoimmune responses, so targeting inflammatory mediators/pathways is one of emerging the treatment strategies of AIDs. This review will briefly describe the role of inflammation in the pathogenesis of different AIDs, and give a rough introduction to inhibitors targeting inflammatory factors, hoping to have reference significance for subsequent treatment options for AIDs.
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Affiliation(s)
- Yu Xiang
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan, Sichuan Academy of Medical Science & Sichuan Provincial People’s Hospital, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Mingxue Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Die Jiang
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China
| | - Qian Su
- Department of Health Management & Institute of Health Management, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Jianyou Shi
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan, Sichuan Academy of Medical Science & Sichuan Provincial People’s Hospital, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
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Yilmaz K, Haeberle S, Kim YO, Fritzler MJ, Weng SY, Goeppert B, Raker VK, Steinbrink K, Schuppan D, Enk A, Hadaschik EN. Regulatory T-cell deficiency leads to features of autoimmune liver disease overlap syndrome in scurfy mice. Front Immunol 2023; 14:1253649. [PMID: 37818371 PMCID: PMC10561387 DOI: 10.3389/fimmu.2023.1253649] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 09/08/2023] [Indexed: 10/12/2023] Open
Abstract
Introduction Scurfy mice have a complete deficiency of functional regulatory T cells (Treg) due to a frameshift mutation in the Foxp3 gene. The impaired immune homeostasis results in a lethal lymphoproliferative disorder affecting multiple organs, including the liver. The autoimmune pathology in scurfy mice is in part accompanied by autoantibodies such as antinuclear antibodies (ANA). ANA are serological hallmarks of several autoimmune disorders including autoimmune liver diseases (AILD). However, the underlying pathogenesis and the role of Treg in AILD remain to be elucidated. The present study therefore aimed to characterize the liver disease in scurfy mice. Methods Sera from scurfy mice were screened for ANA by indirect immunofluorescence assay (IFA) and tested for a wide range of AILD-associated autoantibodies by enzyme-linked immunosorbent assay, line immunoassay, and addressable laser bead immunoassay. CD4+ T cells of scurfy mice were transferred into T cell-deficient B6/nude mice. Monoclonal autoantibodies from scurfy mice and recipient B6/nude mice were tested for ANA by IFA. Liver tissue of scurfy mice was analyzed by conventional histology. Collagen deposition in scurfy liver was quantified via hepatic hydroxyproline content. Real-time quantitative PCR was used to determine fibrosis-related hepatic gene expression. Hepatic immune cells were differentiated by flow cytometry. Results All scurfy mice produced ANA. AILD-associated autoantibodies, predominantly antimitochondrial antibodies, were detected at significantly higher levels in scurfy sera. CD4+ T cells from scurfy mice were sufficient to induce anti-dsDNA autoantibodies and ANA with an AILD-related nuclear envelope staining pattern. Liver histology revealed portal inflammation with bile duct damage and proliferation, as in primary biliary cholangitis (PBC), and interface hepatitis with portal-parenchymal necroinflammation, as found in autoimmune hepatitis (AIH). In scurfy liver, TNFα and fibrosis-related transcripts including Col1a1, Timp1, Acta2, Mmp2, and Mmp9 were upregulated. The level of proinflammatory monocytic macrophages (Ly-6Chi) was increased, while M2-type macrophages (CD206+) were downregulated compared to wildtype controls. Despite severe hepatic inflammation, fibrosis did not develop within 25 days, which is close to the lifespan of scurfy mice. Discussion Our findings suggest that Treg-deficient scurfy mice spontaneously develop clinical, serological, and immunopathological characteristics of AILD with overlapping features of PBC and AIH.
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Affiliation(s)
- Kaan Yilmaz
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany
- Department of Dermatology, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Stefanie Haeberle
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany
| | - Yong Ook Kim
- Institute of Translational Immunology, University Medical Center of Johannes Gutenberg University Mainz, Mainz, Germany
| | - Marvin J. Fritzler
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Shih-Yen Weng
- Institute of Translational Immunology, University Medical Center of Johannes Gutenberg University Mainz, Mainz, Germany
- Smart Healthcare Interdisciplinary College, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan
| | - Benjamin Goeppert
- Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
- Institute of Pathology and Neuropathology, RKH Klinikum Ludwigsburg, Ludwigsburg, Germany
| | - Verena K. Raker
- Department of Dermatology, University Hospital Muenster, Muenster, Germany
| | - Kerstin Steinbrink
- Department of Dermatology, University Hospital Muenster, Muenster, Germany
| | - Detlef Schuppan
- Institute of Translational Immunology, University Medical Center of Johannes Gutenberg University Mainz, Mainz, Germany
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Alexander Enk
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany
| | - Eva N. Hadaschik
- Department of Dermatology, University of Heidelberg, Heidelberg, Germany
- Department of Dermatology, University Hospital of Essen, Essen, Germany
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8
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Huang Z, Nie S, Wang H, Yan W, Tian D, Liu M. The proportion of regulatory T cells in peripheral blood of patients with autoimmune hepatitis: A systematic review and meta-analysis. Int Immunopharmacol 2023; 122:110576. [PMID: 37390643 DOI: 10.1016/j.intimp.2023.110576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 06/22/2023] [Accepted: 06/23/2023] [Indexed: 07/02/2023]
Abstract
BACKGROUND Many researches have reported the impairment of regulatory T cells (Tregs) in autoimmune hepatitis (AIH), whilst the change of Tregs in peripheral blood remains controversial. We performed this systematic review and meta-analysis to clarify the numerical change of circulating Tregs in AIH patients compared with healthy individuals. METHODS Relevant studies were identified from Medline, PubMed, Embase, Web of Science, the Cochrane Library, China National Knowledge Infrastructure, and WanFang Data. Twenty-nine studies involving 968 AIH patients and 583 healthy controls were included. Subgroup analysis stratified by Treg definition or ethnicity was performed, and analysis of active-phase AIH was conducted. RESULTS The proportions of Tregs among CD4 T cells and PBMCs were generally decreased in AIH patients compared with healthy controls. Subgroup analysis showed that circulating Tregs identified by CD4+CD25+/high, CD4+CD25+Foxp3+, CD4+CD25+/highCD127-/low, and Tregs in Asian population were decreased among CD4 T cells in AIH patients. No significant change of CD4+CD25+/highFoxp3+CD127-/low Tregs and Tregs in Caucasian population among CD4 T cells were found in AIH patients, whereas the number of studies was limited in these subgroups. Moreover, analysis of the active-phase AIH patients showed that Treg proportions were decreased generally, whereas no significant differences in Tregs/CD4 T cells were observed when markers CD4+CD25+Foxp3+, CD4+CD25+/highFoxp3+CD127-/low were used or in Caucasian population. CONCLUSIONS The proportions of Tregs among CD4 T cells and PBMCs were decreased in AIH patients compared with healthy controls generally, whereas Treg definition markers, ethnicity, and disease activity had influence on the results. Further large-scale and rigorous study is warranted.
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Affiliation(s)
- Zheng Huang
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Shangshu Nie
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Han Wang
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Wei Yan
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Dean Tian
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - Mei Liu
- Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China.
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Zheng H, Zhang T, Xu Y, Lu X, Sang X. Autoimmune hepatitis after COVID-19 vaccination. Front Immunol 2022; 13:1035073. [PMID: 36505482 PMCID: PMC9732229 DOI: 10.3389/fimmu.2022.1035073] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/04/2022] [Indexed: 11/27/2022] Open
Abstract
Vaccination is one of the most vigorous ways to intervene in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Cases of autoimmune hepatitis (AIH) after coronavirus disease (COVID-19) vaccination have been increasingly reported. Twenty-seven cases of AIH are summarized in this study, providing emerging evidence of autoimmune reactions in response to various COVID-19 vaccines, including in patients with special disease backgrounds such as primary sclerosing cholangitis (PSC), liver transplantation, and previous hepatitis C virus (HCV) treatment. Molecular mimicry, adjuvants, epitope spreading, bystander activation, X chromosome, and sceptical hepatotropism of SARS-CoV-2 may account for, to some extent, such autoimmune phenomena. Immunosuppressive corticosteroids perform well with or without azathioprine in such post-COVID-19-vaccination AIH. However, determination of the exact mechanism and establishment of causality require further confirmation.
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Sirbe C, Simu G, Szabo I, Grama A, Pop TL. Pathogenesis of Autoimmune Hepatitis-Cellular and Molecular Mechanisms. Int J Mol Sci 2021; 22:13578. [PMID: 34948375 PMCID: PMC8703580 DOI: 10.3390/ijms222413578] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 12/09/2021] [Accepted: 12/14/2021] [Indexed: 02/05/2023] Open
Abstract
Pediatric autoimmune liver disorders include autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC), and de novo AIH after liver transplantation. AIH is an idiopathic disease characterized by immune-mediated hepatocyte injury associated with the destruction of liver cells, causing inflammation, liver failure, and fibrosis, typically associated with autoantibodies. The etiology of AIH is not entirely unraveled, but evidence supports an intricate interaction among genetic variants, environmental factors, and epigenetic modifications. The pathogenesis of AIH comprises the interaction between specific genetic traits and molecular mimicry for disease development, impaired immunoregulatory mechanisms, including CD4+ T cell population and Treg cells, alongside other contributory roles played by CD8+ cytotoxicity and autoantibody production by B cells. These findings delineate an intricate pathway that includes gene to gene and gene to environment interactions with various drugs, viral infections, and the complex microbiome. Epigenetics emphasizes gene expression through hereditary and reversible modifications of the chromatin architecture without interfering with the DNA sequence. These alterations comprise DNA methylation, histone transformations, and non-coding small (miRNA) and long (lncRNA) RNA transcriptions. The current first-line therapy comprises prednisolone plus azathioprine to induce clinical and biochemical remission. Further understanding of the cellular and molecular mechanisms encountered in AIH may depict their impact on clinical aspects, detect biomarkers, and guide toward novel, effective, and better-targeted therapies with fewer side effects.
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Affiliation(s)
- Claudia Sirbe
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (C.S.); (T.L.P.)
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
| | - Gelu Simu
- Cardiology Department, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
- Cardiology Department, Rehabilitation Hospital, 400066 Cluj-Napoca, Romania
| | - Iulia Szabo
- Department of Rheumatology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania;
| | - Alina Grama
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (C.S.); (T.L.P.)
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
| | - Tudor Lucian Pop
- 2nd Pediatric Discipline, Department of Mother and Child, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (C.S.); (T.L.P.)
- 2nd Pediatric Clinic, Emergency Clinical Hospital for Children, 400177 Cluj-Napoca, Romania
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Franceschini T, Vasuri F, Muratori P, Muratori L, Guido M, Lenzi M, D'Errico A. A practical histological approach to the diagnosis of autoimmune hepatitis: experience of an Italian tertiary referral center. Virchows Arch 2021; 479:937-945. [PMID: 34189631 PMCID: PMC8241564 DOI: 10.1007/s00428-021-03122-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 05/04/2021] [Accepted: 05/11/2021] [Indexed: 12/17/2022]
Abstract
Liver biopsy is crucial for the diagnosis of autoimmune hepatitis (AIH), and new reproducible histological criteria would be highly desirable, especially in acute-on-chronic cases. The aims of the present study were (i) to evaluate the AIH histopathological criteria as a function of the time and modality of AIH onset, and (ii) to validate the count of apoptotic bodies in the portal tracts as a histopathological criterion for AIH diagnosis. Sixty-five patients were retrospectively enrolled: 20 underwent biopsy for the first diagnosis and 45 had a previous histological AIH diagnosis. Biopsies were revised, and all histological variables were collected, including the lymphocytic apoptotic bodies in the portal tracts. Clinical and serological data were revised as well. First-diagnosis patients showed a higher grade of inflammation (p = 0.001), but also worse portal fibrosis (p = 0.001). The apoptotic body count was higher in first-diagnosis patients than in follow-up patients (p = 0.002), and it was strongly correlated to inflammation. Using the apoptotic body count among the simplified AIH score variables, the first-biopsy patients in the "definite" category rose from 42 to 68%. Our results confirm the histopathological criteria proposed by the literature and introduce the count of portal apoptotic bodies for the diagnosis of active AIH, especially in first biopsies without other classic features, as well as in AIH diagnostic score, albeit future studies are required to find a definite cutoff.
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Affiliation(s)
- Tania Franceschini
- Pathology Unit, IRCCS, Azienda Ospedaliero-Universitaria Di Bologna, via Albertoni 15, 40138, Bologna, Italy
| | - Francesco Vasuri
- Pathology Unit, IRCCS, Azienda Ospedaliero-Universitaria Di Bologna, via Albertoni 15, 40138, Bologna, Italy.
| | - Paolo Muratori
- Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, IRCCS, Azienda Ospedaliero-Universitaria Di Bologna, via Albertoni 15, Bologna, Italy
| | - Luigi Muratori
- Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, IRCCS, Azienda Ospedaliero-Universitaria Di Bologna, via Albertoni 15, Bologna, Italy
| | - Maria Guido
- Department of Medicine-Dimed, University of Padova, Padova, Italy
- Pathology Department, Azienda ULSS 2, Veneto Region, Italy
| | - Marco Lenzi
- Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System, IRCCS, Azienda Ospedaliero-Universitaria Di Bologna, via Albertoni 15, Bologna, Italy
| | - Antonia D'Errico
- Pathology Unit, IRCCS, Azienda Ospedaliero-Universitaria Di Bologna, via Albertoni 15, 40138, Bologna, Italy
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12
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Muscate F, Woestemeier A, Gagliani N. Functional heterogeneity of CD4 + T cells in liver inflammation. Semin Immunopathol 2021; 43:549-561. [PMID: 34463867 PMCID: PMC8443520 DOI: 10.1007/s00281-021-00881-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 07/14/2021] [Indexed: 12/24/2022]
Abstract
CD4+ T cells play an essential role in orchestrating adequate immunity, but their overactivity has been associated with the development of immune-mediated inflammatory diseases, including liver inflammatory diseases. These cells can be subclassified according to their maturation stage, cytokine profile, and pro or anti-inflammatory functions, i.e., functional heterogeneity. In this review, we summarize what has been discovered so far regarding the role of the different CD4+ T cell polarization states in the progression of two prominent and still different liver inflammatory diseases: non-alcoholic steatohepatitis (NASH) and autoimmune hepatitis (AIH). Finally, the potential of CD4+ T cells as a therapeutic target in both NASH and AIH is discussed.
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Affiliation(s)
- Franziska Muscate
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anna Woestemeier
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Nicola Gagliani
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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13
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Lundberg AK, Chung RWS, Zeijlon L, Fernström G, Jonasson L. Oxidative stress response in regulatory and conventional T cells: a comparison between patients with chronic coronary syndrome and healthy subjects. J Transl Med 2021; 19:241. [PMID: 34082767 PMCID: PMC8173731 DOI: 10.1186/s12967-021-02906-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 05/24/2021] [Indexed: 11/10/2022] Open
Abstract
Background Inflammation and oxidative stress form a vicious circle in atherosclerosis. Oxidative stress can have detrimental effects on T cells. A unique subset of CD4+ T cells, known as regulatory T (Treg) cells, has been associated with atheroprotective effects. Reduced numbers of Treg cells is a consistent finding in patients with chronic coronary syndrome (CCS). However, it is unclear to what extent these cells are sensitive to oxidative stress. In this pilot study, we tested the hypothesis that oxidative stress might be a potential contributor to the Treg cell deficit in CCS patients. Methods Thirty patients with CCS and 24 healthy controls were included. Treg (CD4+CD25+CD127−) and conventional T (CD4+CD25−, Tconv) cells were isolated and treated with increasing doses of H2O2. Intracellular ROS levels and cell death were measured after 2 and 18 h, respectively. The expression of antioxidant genes was measured in freshly isolated Treg and Tconv cells. Also, total antioxidant capacity (TAC) was measured in fresh peripheral blood mononuclear cells, and oxidized (ox) LDL/LDL ratios were determined in plasma. Results At all doses of H2O2, Treg cells accumulated more ROS and exhibited higher rates of death than their Tconv counterparts, p < 0.0001. Treg cells also expressed higher levels of antioxidant genes, including thioredoxin and thioredoxin reductase-1 (p < 0.0001), though without any differences between CCS patients and controls. Tconv cells from CCS patients were, on the other hand, more sensitive to oxidative stress ex vivo and expressed more thioredoxin reductase-1 than Tconv cells from controls, p < 0.05. Also, TAC levels were lower in patients, 0.97 vs 1.53 UAE/100 µg, p = 0.001, while oxLDL/LDL ratios were higher, 29 vs 22, p = 0.006. Conclusion Treg cells isolated from either CCS patients or healthy controls were all highly sensitive to oxidative stress ex vivo. There were signs of oxidant-antioxidant imbalance in CCS patients and we thus assume that oxidative stress may play a role in the reduction of Treg cells in vivo. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-021-02906-2.
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Affiliation(s)
- Anna K Lundberg
- Department of Health, Medicine and Caring Sciences, Unit of Cardiovascular Medicine, Linköping University, Linköping, Sweden
| | - Rosanna W S Chung
- Department of Health, Medicine and Caring Sciences, Unit of Cardiovascular Medicine, Linköping University, Linköping, Sweden
| | - Louise Zeijlon
- Department of Health, Medicine and Caring Sciences, Unit of Cardiovascular Medicine, Linköping University, Linköping, Sweden
| | - Gustav Fernström
- Department of Health, Medicine and Caring Sciences, Unit of Cardiovascular Medicine, Linköping University, Linköping, Sweden
| | - Lena Jonasson
- Department of Cardiology in Linköping, and Department of Health, Medicine and Caring Sciences, Unit of Cardiovascular Medicine, Linköping University, Linköping, Sweden. .,Department of Cardiology, Linköping University Hospital, 581 85, Linköping, Sweden.
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14
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Aghabi YO, Yasin A, Kennedy JI, Davies SP, Butler AE, Stamataki Z. Targeting Enclysis in Liver Autoimmunity, Transplantation, Viral Infection and Cancer. Front Immunol 2021; 12:662134. [PMID: 33953725 PMCID: PMC8089374 DOI: 10.3389/fimmu.2021.662134] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 03/22/2021] [Indexed: 12/14/2022] Open
Abstract
Persistent liver inflammation can lead to cirrhosis, which associates with significant morbidity and mortality worldwide. There are no curative treatments beyond transplantation, followed by long-term immunosuppression. The global burden of end stage liver disease has been increasing and there is a shortage of donor organs, therefore new therapies are desperately needed. Harnessing the power of the immune system has shown promise in certain autoimmunity and cancer settings. In the context of the liver, regulatory T cell (Treg) therapies are in development. The hypothesis is that these specialized lymphocytes that dampen inflammation may reduce liver injury in patients with chronic, progressive diseases, and promote transplant tolerance. Various strategies including intrinsic and extracorporeal expansion of Treg cells, aim to increase their abundance to suppress immune responses. We recently discovered that hepatocytes engulf and delete Treg cells by enclysis. Herein, we propose that inhibition of enclysis may potentiate existing regulatory T cell therapeutic approaches in patients with autoimmune liver diseases and in patients receiving a transplant. Moreover, in settings where the abundance of Treg cells could hinder beneficial immunity, such us in chronic viral infection or liver cancer, enhancement of enclysis could result in transient, localized reduction of Treg cell numbers and tip the balance towards antiviral and anti-tumor immunity. We describe enclysis as is a natural process of liver immune regulation that lends itself to therapeutic targeting, particularly in combination with current Treg cell approaches.
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Affiliation(s)
| | | | | | | | | | - Zania Stamataki
- College of Medical and Dental Sciences, Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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15
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Panfili E, Mondanelli G, Orabona C, Belladonna ML, Gargaro M, Fallarino F, Orecchini E, Prontera P, Proietti E, Frontino G, Tirelli E, Iacono A, Vacca C, Puccetti P, Grohmann U, Esposito S, Pallotta MT. Novel mutations in the WFS1 gene are associated with Wolfram syndrome and systemic inflammation. Hum Mol Genet 2021; 30:265-276. [PMID: 33693650 PMCID: PMC8091036 DOI: 10.1093/hmg/ddab040] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 01/29/2021] [Accepted: 01/29/2021] [Indexed: 02/06/2023] Open
Abstract
Mutations in the WFS1 gene, encoding wolframin (WFS1), cause endoplasmic reticulum (ER) stress and are associated with a rare autosomal-recessive disorder known as Wolfram syndrome (WS). WS is clinically characterized by childhood-onset diabetes mellitus, optic atrophy, deafness, diabetes insipidus and neurological signs. We identified two novel WFS1 mutations in a patient with WS, namely, c.316-1G > A (in intron 3) and c.757A > T (in exon 7). Both mutations, located in the N-terminal region of the protein, were predicted to generate a truncated and inactive form of WFS1. We found that although the WFS1 protein was not expressed in peripheral blood mononuclear cells (PBMCs) of the proband, no constitutive ER stress activation could be detected in those cells. In contrast, WS proband’s PBMCs produced very high levels of proinflammatory cytokines (i.e. TNF-α, IL-1β, and IL-6) in the absence of any stimulus. WFS1 silencing in PBMCs from control subjects by means of small RNA interference also induced a pronounced proinflammatory cytokine profile. The same cytokines were also significantly higher in sera from the WS patient as compared to matched healthy controls. Moreover, the chronic inflammatory state was associated with a dominance of proinflammatory T helper 17 (Th17)-type cells over regulatory T (Treg) lymphocytes in the WS PBMCs. The identification of a state of systemic chronic inflammation associated with WFS1 deficiency may pave the way to innovative and personalized therapeutic interventions in WS.
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Affiliation(s)
- Eleonora Panfili
- Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy
| | - Giada Mondanelli
- Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy
| | - Ciriana Orabona
- Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy
| | - Maria L Belladonna
- Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy
| | - Marco Gargaro
- Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy
| | - Francesca Fallarino
- Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy
| | - Elena Orecchini
- Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy
| | - Paolo Prontera
- Medical Genetics Unit, University-Hospital "Santa Maria della Misericordia", Perugia, 06132, Italy
| | - Elisa Proietti
- Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy
| | - Giulio Frontino
- Department of Pediatrics, Diabetes Research Institute, IRCCS San Raffaele Hospital, Milan, 20132, Italy
| | - Eva Tirelli
- Department of Pediatrics, Diabetes Research Institute, IRCCS San Raffaele Hospital, Milan, 20132, Italy
| | - Alberta Iacono
- Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy
| | - Carmine Vacca
- Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy
| | - Paolo Puccetti
- Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy
| | - Ursula Grohmann
- Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy.,Visiting Professor, Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Susanna Esposito
- Pediatric Clinic Pietro Barilla Children's Hospital, Department of Medicine and Surgery, Università di Parma, Parma, 43126, Italy
| | - Maria T Pallotta
- Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy
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16
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Wang H, Feng X, Yan W, Tian D. Regulatory T Cells in Autoimmune Hepatitis: Unveiling Their Roles in Mouse Models and Patients. Front Immunol 2020; 11:575572. [PMID: 33117375 PMCID: PMC7575771 DOI: 10.3389/fimmu.2020.575572] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 09/07/2020] [Indexed: 12/11/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a severe and chronic liver disease, and its incidence has increased worldwide in recent years. Research into the pathogenesis of AIH remains limited largely owing to the lack of suitable mouse models. The concanavalin A (ConA) mouse model is a typical and well-established model used to investigate T cell-dependent liver injury. However, ConA-induced hepatitis is acute and usually disappears after 48 h; thus, it does not mimic the pathogenesis of AIH in the human body. Several studies have explored various AIH mouse models, but as yet there is no widely accepted and valid mouse model for AIH. Immunosuppression is the standard clinical therapy for AIH, but patient side effects and recurrence limit its use. Regulatory T cells (Tregs) play critical roles in the maintenance of immune homeostasis and in the prevention of autoimmune diseases, which may provide a potential therapeutic target for AIH therapy. However, the role of Tregs in AIH has not yet been clarified, partly because of difficulties in diagnosing AIH and in collecting patient samples. In this review, we discuss the studies related to Treg in various AIH mouse models and patients with AIH and provide some novel insights for this research area.
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Affiliation(s)
- Han Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinxia Feng
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Yan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dean Tian
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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17
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Tandon A, Anupam K, Kaushal J, Gautam P, Sharma A, Bhatnagar A. Altered oxidative stress markers in relation to T cells, NK cells & killer immunoglobulin receptors that are associated with disease activity in SLE patients. Lupus 2020; 29:1831-1844. [PMID: 32998620 DOI: 10.1177/0961203320959441] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Systemic Lupus Erythematosus is an autoimmune disease with symptoms pervasive to all organ systems. It affects more females as compared to males (in the ratio 9:1). Oxidative stress plays a major role in the pathogenesis of SLE and other autoimmune diseases. In order to understand the relationship between cell specific oxidative stress and the severity of SLE, this research study involving the estimation of intracellular ROS accumulation in T and NK cell was conducted on SLE patients of North Indian Population. At the same time, to estimate anti-oxidant defense, Keap1 and Nrf2 levels were estimated in these cell types. The relationship between the expression of Killer immunoglobulin receptors i.e., KIR2DL4 & KIR3DL1 and oxidative stress was also evaluated as these receptors are imperative for the function and self-tolerance of NK cells.Oxidative stress was raised along with Keap1 and Nrf2 in T and NK cell subsets in SLE patients. The expression of KIR2DL4 was raised and that of KIR3DL1 was reduced in the NK cells of patients. The intensity of change in expression and its significance varied among the subsets. Nrf2 expression was raised in these species against oxidative stress as the antioxidant defense mechanism pertaining to Keap1-Nrf2 pathway, but the adequacy of response needs to be understood in further studies. The expression of KIR2DL4 and KIR3DL1 varied among the patient and healthy controls and the expression of the latter was found to have a significant positive relationship with plasma Glutathione(reduced) concentration.
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Affiliation(s)
- Ankit Tandon
- Department of Biochemistry, Panjab University, Chandigarh, India
| | - Kumari Anupam
- Department of Biochemistry, Panjab University, Chandigarh, India
| | - Jyotsana Kaushal
- Department of Biochemistry, Panjab University, Chandigarh, India
| | - Preeti Gautam
- Department of Biochemistry, Panjab University, Chandigarh, India
| | - Aman Sharma
- Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
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18
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An J. Expression and Significance of Th17 Cells and Related Factors in Patients with Autoimmune Hepatitis. Comb Chem High Throughput Screen 2020; 22:232-237. [PMID: 30947662 DOI: 10.2174/1386207322666190402160455] [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: 09/26/2018] [Revised: 11/02/2018] [Accepted: 12/11/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVE This study aims to investigate the expression and clinical significance of Th17 cells and related factors in peripheral blood of patients with Autoimmune Hepatitis (AIH). METHODS A retrospective selection of 100 patients with AIH were included as a study group, and 100 healthy volunteers in the outpatient clinic were selected as the control group. The levels of IL- 17, IL-6, IL-21 and TNF-α in peripheral blood of all subjects were detected by enzyme-linked immunosorbent assay and the frequency of Th17 cells and Treg cells was detected by flow cytometry. RESULTS Results showed that the study group had higher levels of serum total bilirubin (TBil), alkaline phosphatase (ALP), γ -glutamyltranspeptidase (γ-GT), immunoglobulin G (IgG), immunoglobulin M (IgM), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) than the control group, as well as higher levels of IL-17, IL-6, IL-21 and TNF-α in serum. The frequency of Th17 cells in peripheral blood was higher in the study group, while the frequency of Treg cells was lower. Also, serum IL-17, TNF-α levels and Th17 cells frequency were positively correlated with ALT and AST, whereas Treg cells frequency were negatively correlated with ALT and AST levels. CONCLUSION Our finding demonstrates that Th17 cell frequency and their related factors IL-17 and TNF-α, are associated with liver damage, which might be used to monitor AIH disease severity.
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Affiliation(s)
- Jihong An
- Department of Infectious Diseases, Inner Mongolia People's Hospital, Inner Mongolia 010017, China
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19
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Feng M, Guo H, Zhang C, Wang Y, Liang Z, Zhao X, Qin Y, Wu Y, Liu G, Gao C, Luo J. Absolute reduction of regulatory T cells and regulatory effect of short-term and low-dose IL-2 in polymyositis or dermatomyositis. Int Immunopharmacol 2019; 77:105912. [DOI: 10.1016/j.intimp.2019.105912] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 09/09/2019] [Accepted: 09/12/2019] [Indexed: 11/26/2022]
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20
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Chen J, Liu W, Zhu W. Foxp3⁺ Treg Cells Are Associated with Pathological Process of Autoimmune Hepatitis by Activating Methylation Modification in Autoimmune Hepatitis Patients. Med Sci Monit 2019; 25:6204-6212. [PMID: 31422415 PMCID: PMC6711260 DOI: 10.12659/msm.915408] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background Autoimmune hepatitis (AIH) is a chronic hepatic disorder. This study investigated role of Foxp3+ regulatory T cells (Treg) and methylation-regulated Tregs in AIH pathological processes. Material/Methods Forty consecutive patients diagnosed with hepatitis were enrolled and divided into a virus hepatitis (n=20) group and an AIH group (n=20). Twenty healthy individuals were assigned to the healthy control group (HC, n=20), Liver function biomarkers were detected on an automatic biochemical analyzer. Serum auto-antibodies were evaluated using immunofluorescence method. Histopathological evaluation was conducted with liver tissues. Treg cells were counted using FACS flow cytometry. Peripheral lymphocytes surface/intracellular biomarkers, CD4+CD25+, CD127, and Foxp3, were examined. Serum cytokines were evaluated using cytometric bead array. Methylation-specific PCR (MS-PCR) was conducted to identify the status of Foxp3 gene methylation. Results Levels of liver function biomarkers were significantly increased in the AIH group compared to the HC group (p<0.05). Levels of ANA and ASMA were significantly enhanced in the AIH group compared to the HC group (p<0.05). Other auto-antibodies, including anti-AHA, anti-ribosome P protein, and anti-RO-52, were also discovered in the AIH group. Severe lymphocytic infiltration and inflammatory cells clustering were discovered in AIH patients. There were significantly fewer CD4+CD25+ T cells in the AIH group, and interleukin 6 (IL-6) and IL-10 levels were significantly decreased compared to the HC group (p<0.05). CD127+ Treg and Foxp3+ Treg expressions were decreased in the AIH group compared to the HC group (p<0.05). Foxp3 in Treg cells of AIH patients exhibited higher methylation frequency compared to that of HC patients (p<0.05). Conclusions Foxp3+ regulatory T cells were involved in pathological processes by activating methylation modification in autoimmune hepatitis patients.
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Affiliation(s)
- Jiang Chen
- Yibin Traditional Chinese Medicine Hospital, Yibin, Sichuan, China (mainland)
| | - Wen Liu
- Yibin Traditional Chinese Medicine Hospital, Yibin, Sichuan, China (mainland)
| | - Wenjing Zhu
- The No. 2 People's Hospital of Yibin, Yibin, Sichuan, China (mainland)
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21
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Fas, FasL and Foxp3 gene expression in post-liver transplant autoimmune hepatitis patients with and without acute rejection. Clin Exp Hepatol 2019; 5:103-108. [PMID: 31501785 PMCID: PMC6728859 DOI: 10.5114/ceh.2019.85076] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 10/14/2018] [Indexed: 12/19/2022] Open
Abstract
Aim of the study In this study we investigated Fas, FasL and Foxp3 expression in relation to liver graft rejection and its severity in autoimmune hepatitis (AIH) patients. Material and methods Twenty-three AIH patients including five post-transplant patients with acute rejection (AR) and 18 patients without AR (non-AR) were studied for Fas, FasL and Foxp3 gene expression in peripheral blood mononuclear cells on days 1, 3 and 7 after transplantation by real-time PCR. The relationships between gene expression and clinical features were determined. Results Real-time PCR showed various Fas gene expression levels with no significant difference between the days in AR patients (p = 0.52). In non-AR patients, Fas level increased from 0.98 ±0.24 fold on the first day to 1.89 ±0.42 fold on day 3 after transplantation (p < 0.01). In this group of patients, we also found a significant increase in FasL expression on day 7 (29.91 ±6.89 fold) compared to day 1 (13.50 ±7.44 fold, p < 0.05). Foxp3 gene expression in both groups showed decreased levels during the first week after transplantation. The decreased Foxp3 expression in AR patients was correlated with rejection activity index (r = 0.86, p < 0.0001). Conclusions Increased Fas and FasL gene expression levels in non-AR patients and decreased Foxp3 gene expression in both groups suggested the important role of these molecules in the alloreactive response after liver transplantation in AIH patients. Foxp3 expression might be useful for monitoring rejection severity.
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22
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Zafari P, Yari K, Mostafaei S, Iranshahi N, Assar S, Fekri A, Taghadosi M. Analysis of Helios gene expression and Foxp3 TSDR methylation in the newly diagnosed Rheumatoid Arthritis patients. Immunol Invest 2018; 47:632-642. [PMID: 29851536 DOI: 10.1080/08820139.2018.1480029] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
BACKGROUND The control of auto-reactive cells is defective in rheumatoid arthritis (RA). Regulatory T (Treg) cells which play a key role in the modulation of immune responses have an impaired function in RA. Foxp3 is a master regulator of Treg cells which its expression is under the tight control of epigenetic mechanisms. In the current study, we analyzed the epigenetic modulation of the Foxp3 Treg-specific demethylated region (TSDR) and Helios gene expression to determine Treg cells alteration in RA patients. METHODS We have recruited 20 newly diagnosed patients with RA and 41 healthy controls in our study. The measurement of Foxp3 and Helios gene expression was performed by the real-time PCR technique and the methylation level of TSDR was analyzed by bisulfite treatment and quantitative methylation-specific PCR (Q-MSP). RESULTS We found that RA patients had significantly lower level of Foxp3 gene expression and TSDR demethylation compared to healthy subjects (P < 0.001 and P = 0.006, respectively). Inversely, the Helios gene expression was elevated significantly in RA patients group (P = 0.048). We also observed a significant correlation between Foxp3 and Helios gene expression (P = 0.016) as well as a significant correlation between FoxP3 expression and demethylation rate of TSDR (P = 0.010). CONCLUSION Our results suggested that both epigenetic modifications and Helios gene expression may have important roles in the pathogenesis of RA through their effects on Foxp3 gene expression.
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Affiliation(s)
- Parisa Zafari
- a Student Research Committee, Medical school , Kermanshah University of Medical Sciences , Kermanshah , Iran.,b Faculty of Medicine , Kermanshah University of Medical Sciences , Kermanshah , Iran
| | - Kheirollah Yari
- c Medical Biology Research Center , Kermanshah University of Medical Sciences , Kermanshah , Iran.,d Zagros Bioidea Laboratory , Razi University Incubator , Kermanshah , Iran
| | - Shayan Mostafaei
- e Rheumatology Research Center , Tehran University of Medical Sciences , Tehran , Iran
| | - Nasrin Iranshahi
- a Student Research Committee, Medical school , Kermanshah University of Medical Sciences , Kermanshah , Iran.,b Faculty of Medicine , Kermanshah University of Medical Sciences , Kermanshah , Iran
| | - Shirin Assar
- f Clinical Research Development Center , Imam Reza Hospital, Kermanshah University of Medical Sciences , Kermanshah , Iran
| | - Adel Fekri
- a Student Research Committee, Medical school , Kermanshah University of Medical Sciences , Kermanshah , Iran.,b Faculty of Medicine , Kermanshah University of Medical Sciences , Kermanshah , Iran
| | - Mahdi Taghadosi
- g Department of Immunology , Kermanshah University of Medical Sciences , Kermanshah , Iran
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