|
1
|
Wu J, Lyu S, Guo D, Yang N, Liu Y. Protective effects of YCHD on the autoimmune hepatitis mice model induced by Ad-CYP2D6 through modulating the Th1/Treg ratio and intestinal flora. Front Immunol 2024; 15:1488125. [PMID: 39606230 PMCID: PMC11600021 DOI: 10.3389/fimmu.2024.1488125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 09/30/2024] [Indexed: 11/29/2024] Open
Abstract
Background Autoimmune hepatitis (AIH) is a chronic liver inflammatory disease mediated by autoimmune reactions, the pathogenesis of AIH is probably related to the imbalance of intestinal flora. Yinchenhao decoction (YCHD) has been used to relieve AIH. However, the mechanisms underpinning YCHD's hepatoprotective effects with the gut microbito have not been fully revealed. Objective To explore the potential mechanism of YCHD in treating AIH based on changes in the intestinal flora and Th1/Treg ratio in the spleen and hepatic hilar lymph nodes. Methods The AIH mice model induced by the adenovirus vectors that overexpress human cytochrome P450 family 2 subfamily D member 6 (Ad-CYP2D6) was established (untreated group). One week after the Ad-CYP2D6 injection, the AIH model mice were treated by administering YCHD by gavage for 14 days (YCHD-treated group). The therapeutic efficacy of YCHD on AIH was evaluated by detecting the histopathological changes of the liver, serum transaminases (ALT and AST), inflammatory factors (TNF-α,IL-17 and IFN-γ), and autoantibodies (including LKM-1 and LC-1). The ratio of Th1 to Treg within the spleen and hepatic hilar lymph nodes of the mice was detected by flow cytometry. The changes in the species and abundance of intestinal flora and intestinal flora metabolites were analyzed via 16S rRNA gene sequencing and gas chromatography-mass spectrometry (GC/MS) to reveal the protective mechanism of YCHD on liver injury. Result YCHD decreased the transaminase activity (AST and ALT), the content of autoantibodies (LC-1 and LKM-1), and the serum TNF-α, IL-12, and IL-17 levels in AIH mice. The degree of inflammatory infiltration in the YCHD-treated group was significantly less than that in the untreated group. YCHD can effectively reverse the abundance and diversity of intestinal flora in AIH mice and affect the release of short-chain fatty acids (SCFAs), especially butyric acid. Moreover, the flow cytometry results showed that YCHD could also decline the ratio of Th1/Treg, which probably be induced by SCFAs via the G protein-coupled receptor (GPR). Conclusion YCHD may affect the release of SCFAs by regulating the intestinal microbiota, thereby affecting the differentiation of Th1 and Treg, and achieving the effect of alleviating liver damage.
Collapse
Affiliation(s)
- Jiawen Wu
- College of Basic Medical Sciences, Shanxi University of Chinese Medicine, Jinzhong, China
- Basic Laboratory of Integrated Traditional Chinese and Western Medicine, Shanxi University of Chinese Medicine, Jinzhong, China
- Engineering Research Center of Cross Innovation for Chinese Traditional Medicine of Shanxi Province, Jinzhong, China
| | - Sixue Lyu
- College of Basic Medical Sciences, Shanxi University of Chinese Medicine, Jinzhong, China
- Basic Laboratory of Integrated Traditional Chinese and Western Medicine, Shanxi University of Chinese Medicine, Jinzhong, China
- Engineering Research Center of Cross Innovation for Chinese Traditional Medicine of Shanxi Province, Jinzhong, China
| | - Di Guo
- College of Basic Medical Sciences, Shanxi University of Chinese Medicine, Jinzhong, China
- Basic Laboratory of Integrated Traditional Chinese and Western Medicine, Shanxi University of Chinese Medicine, Jinzhong, China
- Engineering Research Center of Cross Innovation for Chinese Traditional Medicine of Shanxi Province, Jinzhong, China
| | - Na Yang
- College of Basic Medical Sciences, Shanxi University of Chinese Medicine, Jinzhong, China
- Basic Laboratory of Integrated Traditional Chinese and Western Medicine, Shanxi University of Chinese Medicine, Jinzhong, China
- Engineering Research Center of Cross Innovation for Chinese Traditional Medicine of Shanxi Province, Jinzhong, China
| | - Yang Liu
- College of Basic Medical Sciences, Shanxi University of Chinese Medicine, Jinzhong, China
- Basic Laboratory of Integrated Traditional Chinese and Western Medicine, Shanxi University of Chinese Medicine, Jinzhong, China
- Engineering Research Center of Cross Innovation for Chinese Traditional Medicine of Shanxi Province, Jinzhong, China
| |
Collapse
|
|
2
|
Christen U, Hintermann E. Animal Models for Autoimmune Hepatitis: Are Current Models Good Enough? Front Immunol 2022; 13:898615. [PMID: 35903109 PMCID: PMC9315390 DOI: 10.3389/fimmu.2022.898615] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 06/22/2022] [Indexed: 11/13/2022] Open
Abstract
Autoimmune liver diseases like autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and IgG4-related cholangitis are chronic inflammatory diseases of the liver with an autoimmune background. The therapy of autoimmune hepatitis targets the autoreactive immune system and is largely dependent on the use of glucocorticoids and cytostatic drugs. In contrast, the treatment of cholestatic autoimmune liver diseases is restricted to the use of secondary or semi-synthetic bile acids, like ursodeoxycholic acid or obeticholic acid. Although the management of the disease using such drugs works well for the majority of patients, many individuals do not respond to standard therapy. In addition, chronic treatment with glucocorticoids results in well-known side effects. Further, the use of bile acids is a symptomatic therapy that has no direct immunomodulatory effect. Thus, there is still a lot of room for improvement. The use of animal models has facilitated to elucidate the pathogenesis of autoimmune liver diseases and many potential target structures for immunomodulatory therapies have been identified. In this review, we will focus on autoimmune hepatitis for which the first animal models have been established five decades ago, but still a precise treatment for autoimmune hepatitis, as obtainable for other autoimmune diseases such as rheumatoid arthritis or multiple sclerosis has yet to be introduced. Thus, the question arises if our animal models are too far from the patient reality and thus findings from the models cannot be reliably translated to the patient. Several factors might be involved in this discrepancy. There is first and foremost the genetic background and the inbred status of the animals that is different from human patients. Here the use of humanized animals, such as transgenic mice, might reduce some of the differences. However, there are other factors, such as housing conditions, nutrition, and the microbiome that might also play an important role. This review will predominantly focus on the current status of animal models for autoimmune hepatitis and the possible ways to overcome discrepancies between model and patient.
Collapse
|
|
3
|
Fasano R, Malerba E, Prete M, Solimando AG, Buonavoglia A, Silvestris N, Leone P, Racanelli V. Impact of Antigen Presentation Mechanisms on Immune Response in Autoimmune Hepatitis. Front Immunol 2022; 12:814155. [PMID: 35116039 PMCID: PMC8804214 DOI: 10.3389/fimmu.2021.814155] [Citation(s) in RCA: 13] [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: 11/12/2021] [Accepted: 12/31/2021] [Indexed: 12/21/2022] Open
Abstract
The liver is a very tolerogenic organ. It is continually exposed to a multitude of antigens and is able to promote an effective immune response against pathogens and simultaneously immune tolerance against self-antigens. In spite of strong peripheral and central tolerogenic mechanisms, loss of tolerance can occur in autoimmune liver diseases, such as autoimmune hepatitis (AIH) through a combination of genetic predisposition, environmental factors, and an imbalance in immunological regulatory mechanisms. The liver hosts several types of conventional resident antigen presenting cells (APCs) such as dendritic cells, B cells and macrophages (Kupffer cells), and unconventional APCs including liver sinusoidal endothelial cells, hepatic stellate cells and hepatocytes. By standard (direct presentation and cross-presentation) and alternative mechanisms (cross-dressing and MHC class II-dressing), liver APCs presents self-antigen to naive T cells in the presence of costimulation leading to an altered immune response that results in liver injury and inflammation. Additionally, the transport of antigens and antigen:MHC complexes by trogocytosis and extracellular vesicles between different cells in the liver contributes to enhance antigen presentation and amplify autoimmune response. Here, we focus on the impact of antigen presentation on the immune response in the liver and on the functional role of the immune cells in the induction of liver inflammation. A better understanding of these key pathogenic aspects could facilitate the establishment of novel therapeutic strategies in AIH.
Collapse
Affiliation(s)
- Rossella Fasano
- Department of Biomedical Sciences and Human Oncology, “Aldo Moro” University of Bari Medical School, Bari, Italy
- Medical Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Eleonora Malerba
- Department of Biomedical Sciences and Human Oncology, “Aldo Moro” University of Bari Medical School, Bari, Italy
| | - Marcella Prete
- Department of Biomedical Sciences and Human Oncology, “Aldo Moro” University of Bari Medical School, Bari, Italy
| | - Antonio Giovanni Solimando
- Department of Biomedical Sciences and Human Oncology, “Aldo Moro” University of Bari Medical School, Bari, Italy
- Medical Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Alessio Buonavoglia
- Department of Biomedical Sciences and Human Oncology, “Aldo Moro” University of Bari Medical School, Bari, Italy
| | - Nicola Silvestris
- Department of Biomedical Sciences and Human Oncology, “Aldo Moro” University of Bari Medical School, Bari, Italy
- Medical Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Patrizia Leone
- Department of Biomedical Sciences and Human Oncology, “Aldo Moro” University of Bari Medical School, Bari, Italy
| | - Vito Racanelli
- Department of Biomedical Sciences and Human Oncology, “Aldo Moro” University of Bari Medical School, Bari, Italy
- *Correspondence: Vito Racanelli,
| |
Collapse
|
|
4
|
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: 53] [Impact Index Per Article: 13.3] [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.
Collapse
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
| |
Collapse
|
|
5
|
Markotic A, Flegar D, Grcevic D, Sucur A, Lalic H, Turcic P, Kovacic N, Lukac N, Pravdic D, Vukojevic K, Cavar I, Kelava T. LPS-induced inflammation desensitizes hepatocytes to Fas-induced apoptosis through Stat3 activation-The effect can be reversed by ruxolitinib. J Cell Mol Med 2020; 24:2981-2992. [PMID: 32022429 PMCID: PMC7077556 DOI: 10.1111/jcmm.14930] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 12/05/2019] [Accepted: 12/15/2019] [Indexed: 12/12/2022] Open
Abstract
Recent studies have established a concept of tumour necrosis factor‐α (TNF‐α)/Fas signalling crosstalk, highlighting TNF‐α as a critical cytokine in sensitizing hepatocytes to death induced by Fas activation. However, in the exact inflammatory response, besides TNF‐α, many other mediators, that might modulate apoptotic response differentially, are released. To resolve the issue, we studied the effects of lipopolysaccharide (LPS), one of the crucial inductors of inflammation in the liver, on apoptotic outcome. We show that LPS‐induced inflammation diminishes the sensitivity of hepatocytes to Fas stimulus in vivo at caspase‐8 level. Analysis of molecular mechanisms revealed an increased expression of various pro‐inflammatory cytokines in non‐parenchymal liver cells and hepatocyte‐specific increase in Bcl‐xL, associated with signal transducer and activator of transcription 3 (Stat3) phosphorylation. Pre‐treatment with ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, prevented the LPS‐induced Stat3 phosphorylation and restored the sensitivity of hepatocytes to Fas‐mediated apoptosis. Furthermore, ruxolitinib pre‐treatment diminished the LPS‐induced Bcl‐xL up‐regulation without an inhibitory effect on LPS‐induced expression of pro‐inflammatory cytokines. In summary, although the reports are showing that the effects of isolated pro‐inflammatory mediators, such as TNF‐α or neutrophils, are pro‐apoptotic, the overall effect of inflammatory milieu on hepatocytes in vivo is Stat3‐dependent desensitization to Fas‐mediated apoptosis.
Collapse
Affiliation(s)
- Antonio Markotic
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.,Center for Clinical Pharmacology, University Clinical Hospital Mostar, Mostar, Bosnia and Herzegovina
| | - Darja Flegar
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.,Department of Physiology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Danka Grcevic
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.,Department of Physiology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Alan Sucur
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.,Department of Physiology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Hrvoje Lalic
- Department of Physiology, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Petra Turcic
- Department of Pharmacology, Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
| | - Natasa Kovacic
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.,Department of Anatomy, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Nina Lukac
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.,Department of Anatomy, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Danijel Pravdic
- Department of Physiology, School of Medicine, University of Mostar, Mostar, Bosnia and Herzegovina.,University Clinical Hospital Mostar, Mostar, Bosnia and Herzegovina
| | - Katarina Vukojevic
- Department of Anatomy, Histology and Embryology, School of Medicine, University of Split, Split, Croatia.,Department of Medical Genetics, School of Medicine, University of Mostar, Mostar, Bosnia and Herzegovina
| | - Ivan Cavar
- Department of Physiology, School of Medicine, University of Mostar, Mostar, Bosnia and Herzegovina.,University Clinical Hospital Mostar, Mostar, Bosnia and Herzegovina
| | - Tomislav Kelava
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.,Department of Physiology, School of Medicine, University of Zagreb, Zagreb, Croatia.,Department of Physiology, School of Medicine, University of Mostar, Mostar, Bosnia and Herzegovina
| |
Collapse
|
|
6
|
Violatto MB, Casarin E, Talamini L, Russo L, Baldan S, Tondello C, Messmer M, Hintermann E, Rossi A, Passoni A, Bagnati R, Biffi S, Toffanin C, Gimondi S, Fumagalli S, De Simoni MG, Barisani D, Salmona M, Christen U, Invernizzi P, Bigini P, Morpurgo M. Dexamethasone Conjugation to Biodegradable Avidin-Nucleic-Acid-Nano-Assemblies Promotes Selective Liver Targeting and Improves Therapeutic Efficacy in an Autoimmune Hepatitis Murine Model. ACS NANO 2019; 13:4410-4423. [PMID: 30883091 DOI: 10.1021/acsnano.8b09655] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Steroids are the standard therapy for autoimmune hepatitis (AIH) but the long-lasting administration is hampered by severe side effects. Methods to improve the tropism of the drug toward the liver are therefore required. Among them, conjugation to nanoparticles represents one possible strategy. In this study, we exploited the natural liver tropism of Avidin-Nucleic-Acid-Nano-Assemblies (ANANAS) to carry dexamethasone selectively to the liver in an AIH animal model. An acid-labile biotin-hydrazone linker was developed for reversible dexamethasone loading onto ANANAS. The biodistribution, pharmacokinetics and efficacy of free and ANANAS-linked dexamethasone (ANANAS-Hz-Dex) in healthy and AIH mice were investigated upon intraperitoneal administration. In ANANAS-treated animals, the free drug was detected only in the liver. Super-resolution microscopy showed that nanoparticles segregate inside lysosomes of liver immunocompetent cells, mainly involved in AIH progression. In agreement with these observational results, chronic low-dose treatment with ANANAS-Hz-Dex reduced the expression of liver inflammation markers and, in contrast to the free drug, also the levels of circulating AIH-specific autoantibodies. These data suggest that the ANANAS carrier attenuates AIH-related liver damage without drug accumulation in off-site tissues. The safety and biodegradability of the ANANAS carrier make this formulation a promising tool for the treatment of autoimmune liver disorders.
Collapse
Affiliation(s)
- Martina Bruna Violatto
- Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche “Mario Negri” IRCCS, Milano, 20156, Italy
| | | | - Laura Talamini
- Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche “Mario Negri” IRCCS, Milano, 20156, Italy
| | - Luca Russo
- Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche “Mario Negri” IRCCS, Milano, 20156, Italy
| | - Simone Baldan
- Department of Pharmaceutical and Pharmacological Sciences , University of Padova , Padova , 35131 , Italy
| | - Camilla Tondello
- Department of Pharmaceutical and Pharmacological Sciences , University of Padova , Padova , 35131 , Italy
| | - Marie Messmer
- Pharmazentrum Frankfurt/ZAFES , Goethe University Hospital Frankfurt , Frankfurt am Main , 60488 , Germany
| | - Edith Hintermann
- Pharmazentrum Frankfurt/ZAFES , Goethe University Hospital Frankfurt , Frankfurt am Main , 60488 , Germany
| | - Alessandro Rossi
- Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche “Mario Negri” IRCCS, Milano, 20156, Italy
| | - Alice Passoni
- Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche “Mario Negri” IRCCS, Milano, 20156, Italy
| | - Renzo Bagnati
- Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche “Mario Negri” IRCCS, Milano, 20156, Italy
| | - Stefania Biffi
- Institute for Maternal and Child Health-IRCCS "Burlo Garofolo″ , Trieste , 34137 , Italy
| | - Chiara Toffanin
- Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche “Mario Negri” IRCCS, Milano, 20156, Italy
| | - Sara Gimondi
- Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche “Mario Negri” IRCCS, Milano, 20156, Italy
| | - Stefano Fumagalli
- Department of Neuroscience, Istituto di Ricerche Farmacologiche “Mario Negri” IRCCS, Milano, 20156, Italy
| | - Maria-Grazia De Simoni
- Department of Neuroscience, Istituto di Ricerche Farmacologiche “Mario Negri” IRCCS, Milano, 20156, Italy
| | - Donatella Barisani
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, 20900, Italy
| | - Mario Salmona
- Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche “Mario Negri” IRCCS, Milano, 20156, Italy
| | - Urs Christen
- Pharmazentrum Frankfurt/ZAFES , Goethe University Hospital Frankfurt , Frankfurt am Main , 60488 , Germany
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, 20900, Italy
| | - Paolo Bigini
- Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche “Mario Negri” IRCCS, Milano, 20156, Italy
| | - Margherita Morpurgo
- Department of Pharmaceutical and Pharmacological Sciences , University of Padova , Padova , 35131 , Italy
| |
Collapse
|
|
7
|
Christen U, Hintermann E. Pathogens and autoimmune hepatitis. Clin Exp Immunol 2018; 195:35-51. [PMID: 30113082 DOI: 10.1111/cei.13203] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2018] [Revised: 07/30/2018] [Accepted: 08/06/2018] [Indexed: 12/12/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a severe form of hepatitis resulting in the autoimmune-mediated destruction of the liver parenchyma. Whereas many of the immunopathogenic events have been elucidated and some of the drivers of the disease have been identified, little is known about the aetiology of the disease. There are certain risk factors, such as particular human leucocyte antigen (HLA) haplotypes, that enhance the susceptibility for AIH or influence the severity of the disease. However, as for many other autoimmune diseases, the mere presence of such risk factors does not warrant the occurrence of the disease. Not all individuals carrying risk factors develop AIH, and not all patients with AIH are carriers of high-risk alleles. Thus, additional environmental factors need to be considered as triggers for AIH. Environmental factors include diet, sunlight exposure, stress, medication and hygiene, as well as pathogen infections and vaccinations. This review discusses if pathogens should be considered as triggers for the initiation and/or propagation of AIH.
Collapse
Affiliation(s)
- U Christen
- Pharmazentrum Frankfurt / ZAFES, Goethe University Hospital, Frankfurt am Main, Germany
| | - E Hintermann
- Pharmazentrum Frankfurt / ZAFES, Goethe University Hospital, Frankfurt am Main, Germany
| |
Collapse
|
|
8
|
Christen U, Hintermann E. Autoantibodies in Autoimmune Hepatitis: Can Epitopes Tell Us about the Etiology of the Disease? Front Immunol 2018; 9:163. [PMID: 29503645 PMCID: PMC5820307 DOI: 10.3389/fimmu.2018.00163] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 01/18/2018] [Indexed: 12/12/2022] Open
Abstract
Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC) are serious autoimmune liver diseases that are characterized by a progressive destruction of the liver parenchyma and/or the hepatic bile ducts and the development of chronic fibrosis. Left untreated autoimmune liver diseases are often life-threatening, and patients require a liver transplantation to survive. Thus, an early and reliable diagnosis is paramount for the initiation of a proper therapy with immunosuppressive and/or anticholelithic drugs. Besides the analysis of liver biopsies and serum markers indicating liver damage, the screening for specific autoantibodies is an indispensable tool for the diagnosis of autoimmune liver diseases. Such liver autoantigen-specific antibodies might be involved in the disease pathogenesis, and their epitope specificity may give some insight into the etiology of the disease. Here, we will mainly focus on the generation and specificity of autoantibodies in AIH patients. In addition, we will review data from animal models that aim toward a better understanding of the origins and pathogenicity of such autoantibodies.
Collapse
Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Frankfurt am Main, Germany
| | - Edith Hintermann
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Frankfurt am Main, Germany
| |
Collapse
|
|
9
|
Ferreira CP, Cariste LM, Santos Virgílio FD, Moraschi BF, Monteiro CB, Vieira Machado AM, Gazzinelli RT, Bruna-Romero O, Menin Ruiz PL, Ribeiro DA, Lannes-Vieira J, Lopes MDF, Rodrigues MM, de Vasconcelos JRC. LFA-1 Mediates Cytotoxicity and Tissue Migration of Specific CD8 + T Cells after Heterologous Prime-Boost Vaccination against Trypanosoma cruzi Infection. Front Immunol 2017; 8:1291. [PMID: 29081775 PMCID: PMC5645645 DOI: 10.3389/fimmu.2017.01291] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 09/26/2017] [Indexed: 12/27/2022] Open
Abstract
Integrins mediate the lymphocyte migration into an infected tissue, and these cells are essential for controlling the multiplication of many intracellular parasites such as Trypanosoma cruzi, the causative agent of Chagas disease. Here, we explore LFA-1 and VLA-4 roles in the migration of specific CD8+ T cells generated by heterologous prime-boost immunization during experimental infection with T. cruzi. To this end, vaccinated mice were treated with monoclonal anti-LFA-1 and/or anti-VLA-4 to block these molecules. After anti-LFA-1, but not anti-VLA-4 treatment, all vaccinated mice displayed increased blood and tissue parasitemia, and quickly succumbed to infection. In addition, there was an accumulation of specific CD8+ T cells in the spleen and lymph nodes and a decrease in the number of those cells, especially in the heart, suggesting that LFA-1 is important for the output of specific CD8+ T cells from secondary lymphoid organs into infected organs such as the heart. The treatment did not alter CD8+ T cell effector functions such as the production of pro-inflammatory cytokines and granzyme B, and maintained the proliferative capacity after treatment. However, the specific CD8+ T cell direct cytotoxicity was impaired after LFA-1 blockade. Also, these cells expressed higher levels of Fas/CD95 on the surface, suggesting that they are susceptible to programmed cell death by the extrinsic pathway. We conclude that LFA-1 plays an important role in the migration of specific CD8+ T cells and in the direct cytotoxicity of these cells.
Collapse
Affiliation(s)
- Camila Pontes Ferreira
- Molecular Immunology Laboratory, Center of Molecular and Cellular Therapy, São Paulo, Brazil.,Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Leonardo Moro Cariste
- Molecular Immunology Laboratory, Center of Molecular and Cellular Therapy, São Paulo, Brazil.,Department of Biosciences, Federal University of São Paulo, São Paulo, Brazil
| | - Fernando Dos Santos Virgílio
- Molecular Immunology Laboratory, Center of Molecular and Cellular Therapy, São Paulo, Brazil.,Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Barbara Ferri Moraschi
- Molecular Immunology Laboratory, Center of Molecular and Cellular Therapy, São Paulo, Brazil.,Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | | | | | - Ricardo Tostes Gazzinelli
- René Rachou Research Center, Fiocruz, Minas Gerais, Brazil.,Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, United States
| | - Oscar Bruna-Romero
- Department of Microbiology, Immunology and Parasitology, Federal University of Santa Catarina, Florianópolis, Brazil
| | | | | | - Joseli Lannes-Vieira
- Biology Interactions Laboratory, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil
| | - Marcela de Freitas Lopes
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Mauricio Martins Rodrigues
- Molecular Immunology Laboratory, Center of Molecular and Cellular Therapy, São Paulo, Brazil.,Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - José Ronnie Carvalho de Vasconcelos
- Molecular Immunology Laboratory, Center of Molecular and Cellular Therapy, São Paulo, Brazil.,Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.,Department of Biosciences, Federal University of São Paulo, São Paulo, Brazil
| |
Collapse
|
|
10
|
Muratori P, Lenzi M, Cassani F, Lalanne C, Muratori L. Diagnostic approach to autoimmune hepatitis. Expert Rev Clin Immunol 2017; 13:769-779. [PMID: 28480763 DOI: 10.1080/1744666x.2017.1327355] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease which, if left without treatment, can evolve into cirrhosis and possibly liver failure. The diagnosis of AIH is hampered by the lack of specific and reliable markers of the disease and a number of clinical, biochemical, immunological, histological and genetic factors should be considered to reach a confident diagnosis Areas covered: Clinical expression of AIH, histological features, serological and genetic profiles, differential diagnosis, overlap with other autoimmune liver diseases, assessed on the basis of personal experience and review of published literature in the last 10 years through a systematic Medline search (keywords: autoimmune hepatitis, diagnosis) Expert commentary: Notwithstanding numerous efforts to identify simple and reliable markers of the disease, the diagnosis of AIH is still based on the combination of histological, immunological and biochemical features and often can represent a real challenge for the hepatologist.
Collapse
Affiliation(s)
- Paolo Muratori
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
| | - Marco Lenzi
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
| | - Fabio Cassani
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
| | - Claudine Lalanne
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
| | - Luigi Muratori
- a Center for the Study and Treatment of Autoimmune Diseases of the Liver and Biliary System , Policlinico di Sant'Orsola, University of Bologna , Bologna , Italy
| |
Collapse
|
|
11
|
Christen U, Hintermann E. Immunopathogenic Mechanisms of Autoimmune Hepatitis: How Much Do We Know from Animal Models? Int J Mol Sci 2016; 17:ijms17122007. [PMID: 27916939 PMCID: PMC5187807 DOI: 10.3390/ijms17122007] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 11/22/2016] [Accepted: 11/23/2016] [Indexed: 12/14/2022] Open
Abstract
Autoimmune hepatitis (AIH) is characterized by a progressive destruction of the liver parenchyma and a chronic fibrosis. The current treatment of autoimmune hepatitis is still largely dependent on the administration of corticosteroids and cytostatic drugs. For a long time the development of novel therapeutic strategies has been hampered by a lack of understanding the basic immunopathogenic mechanisms of AIH and the absence of valid animal models. However, in the past decade, knowledge from clinical observations in AIH patients and the development of innovative animal models have led to a situation where critical factors driving the disease have been identified and alternative treatments are being evaluated. Here we will review the insight on the immunopathogenesis of AIH as gained from clinical observation and from animal models.
Collapse
Affiliation(s)
- Urs Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany.
| | - Edith Hintermann
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Theodor-Stern Kai 7, 60590 Frankfurt am Main, Germany.
| |
Collapse
|
|
12
|
Hua Y, Lu P, Ji JL, Shao JG, Wang LJ. Transgenic animal models of type 2 autoimmune hepatitis. Shijie Huaren Xiaohua Zazhi 2015; 23:4652-4657. [DOI: 10.11569/wcjd.v23.i29.4652] [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] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is a chronic liver disease putatively caused by loss of tolerance to hepatocyte specific autoantigens. It is currently divided into types 1 and 2, based on the expression of autoantibodies. Autoantigenic epitopes have been identified only for the less frequent type 2 AIH. Many type 2 AIH mouse models have been well developed in recent years. This review focuses on some kinds of well-established type 2 AIH mouse models.
Collapse
|
|
13
|
Gatselis NK, Zachou K, Koukoulis GK, Dalekos GN. Autoimmune hepatitis, one disease with many faces: Etiopathogenetic, clinico-laboratory and histological characteristics. World J Gastroenterol 2015; 21:60-83. [PMID: 25574080 PMCID: PMC4284362 DOI: 10.3748/wjg.v21.i1.60] [Citation(s) in RCA: 128] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 10/30/2014] [Accepted: 11/19/2014] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis (AIH) is an unresolving progressive liver disease of unknown etiology characterized by hypergammaglobulinemia, autoantibodies detection and interface hepatitis. Due to the absence of specific diagnostic markers and the large heterogeneity of its clinical, laboratory and histological features, AIH diagnosis may be potentially difficult. Therefore, in this in-depth review we summarize the substantial progress on etiopathogenesis, clinical, serological and histological phenotypes of AIH. AIH has a global distribution affecting any age, both sexes and all ethnic groups. Clinical manifestations vary from asymptomatic to severe or rarely fulminant hepatitis. Hypergammaglobulinemia with selective elevation of IgG is found in most cases. Autoimmune attack is perpetuated, possibly via molecular mimicry, and favored by the impaired control of T-regulatory cells. Histology (interface hepatitis, emperipolesis and hepatic rosette formation) and autoantibodies detection although not pathognomonic, are still the hallmark for a timely diagnosis. AIH remains a major diagnostic challenge. AIH should be considered in every case in the absence of viral, metabolic, genetic and toxic etiology of chronic or acute hepatitis. Laboratory personnel, hepato-pathologists and clinicians need to become more familiar with disease expressions and the interpretation of liver histology and autoimmune serology to derive maximum benefit for the patient.
Collapse
|