Pathogen Infection as a Possible Cause for Autoimmune Hepatitis

Christen, Urs; Hintermann, Edith

doi:10.3109/08830185.2014.921162

Cited by 26 publications

(20 citation statements)

References 109 publications

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“…An additional strategy to induce AIH is based on the use of inflammatory viral vectors expressing Ags similar to, but not identical to, autoantigens, supporting the hypothesis of molecular mimicry of host structures by invading pathogens as a mechanism for the induction of autoimmune diseases (reviewed in Ref. 30). Using this strategy, it has been shown that self-antigens such as formiminotransferase cyclodeaminase or cytochrome P450 2D6 play an important role in the development of AIH (31).…”

Section: Discussionmentioning

confidence: 92%

Transient Expression of Transgenic IL-12 in Mouse Liver Triggers Unremitting Inflammation Mimicking Human Autoimmune Hepatitis

Gil-Fariña

Scala

Salido

et al. 2016

The Journal of Immunology

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The etiopathogenesis of autoimmune hepatitis (AIH) remains poorly understood. In this study, we sought to develop an animal model of human AIH to gain insight into the immunological mechanisms driving this condition. C57BL/6 mice were i.v. injected with adeno-associated viral vectors encoding murine IL-12 or luciferase under the control of a liver-specific promoter. Organ histology, response to immunosuppressive therapy, and biochemical and immunological parameters, including Ag-specific humoral and cellular response, were analyzed. Mechanistic studies were carried out using genetically modified mice and depletion of lymphocyte subpopulations. Adeno-associated virus IL-12–treated mice developed histological, biochemical, and immunological changes resembling type 1 AIH, including marked and persistent liver mononuclear cell infiltration, hepatic fibrosis, hypergammaglobulinemia, anti-nuclear and anti–smooth muscle actin Abs, and disease remission with immunosuppressive drugs. Interestingly, transgenic IL-12 was short-lived, but endogenous IL-12 expression was induced, and both IL-12 and IFN-γ remained elevated during the entire study period. IFN-γ was identified as an essential mediator of liver damage, and CD4 and CD8 T cells but not NK, NKT, or B cells were essential executors of hepatic injury. Furthermore, both MHC class I and MHC class II expression was upregulated at the hepatocellular membrane, and induction of autoreactive liver-specific T cells was detected. Remarkably, although immunoregulatory mechanisms were activated, they only partially mitigated liver damage. Thus, low and transient expression of transgenic IL-12 in hepatocytes causes loss of tolerance to hepatocellular Ags, leading to chronic hepatitis resembling human AIH type 1. This model provides a practical tool to explore AIH pathogenesis and novel therapies.

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Section: Discussionmentioning

confidence: 92%

Transient Expression of Transgenic IL-12 in Mouse Liver Triggers Unremitting Inflammation Mimicking Human Autoimmune Hepatitis

Gil-Fariña

Scala

Salido

et al. 2016

The Journal of Immunology

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“…(45) Environmental exposures play greater roles than genetics in shaping the immune repertoire, and specific environmental factors, such as viral infections or xenobiotic exposures, can act as environmental triggers for loss of self-tolerance to autoantigens in persons genetically susceptible to AIH. (46,47) patHogeNeSIS Autoreactive CD4 and CD8 T cells break selftolerance to hepatic autoantigens as the result of environmental triggers and inability of autoantigen-specific natural T regulatory cells (nTregs) and inducible T regulatory cells (iTregs) to prevent autoreactivity (48)(49)(50) (Fig. 1).…”

Section: Genetic Predispositionsmentioning

confidence: 99%

Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases

et al. 2020

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US children, 9%-12% (14-16) UK children, 38% (13) Age at presentation Peripubertal and adults Usually under 14 years (153) Mode of presentation Chronic symptoms common Acute onset (~40%) Ascites or GI bleeding rare Acute liver failure possible (555,556) Asymptomatic in 25%-34% Relapse frequent (108) Acute in 25%-75% Acute severe in 2%-6% Laboratory features Hypergammaglobulinemia IgA levels may be reduced (153) Autoantibodies ANA Anti-LKM1 SMA, anti-actin [Anti-LC1, Anti-LKM3] SLA Concurrent immune diseases Autoimmune thyroiditis Autoimmune thyroiditis Rheumatic diseases Diabetes mellitus IBD Vitiligo Autoimmune overlap with PSC (ASC in children) Common in children Rare Atypical pANCA-positive Atypical pANCA-negative Overlap with PBC Seen in adults (not children) Not reported Cirrhosis at presentation Adults, 28%-33% (especially elderly) Rare Children, ≤33% Remission after drug withdrawal Possible Rare, usually need long-term immunosuppression Abbreviations: GI, gastrointestinal; IgA, serum immunoglobulin A. *Removed from marketplace. Abbreviation: anti-PD-L1, antibody to programmed death protein ligand 1. taBle 6. Features of Drug-Induced aIH-like Injury and aIH Clinical Features Drug Induced AIH-Like Injury AIH Gender Mainly women (187) Female predominance, but men also affected (2,384,467) Acute onset Majority (>60%) (231) <20% (2,136) Hypersensitivity (fever, rash, eosinophilia) Up to 30% (231,232,613) Unusual (2,384,467) Temporal relationship with drug Positive (231-234) Negative (2,56,188) HLA DRB1*03:01 or DRB1*04:01 association None (236) Common (29) Concurrent autoimmune diseases Unusual (187) Present in 14%-44% (129,149-152) Cirrhosis at presentation Rare (187) 28%-33% (9,104-107) Management Stop offending drug ± glucocorticoids (187,231,232) Glucocorticoids with AZA (2,384,467) Relapse after drug withdrawal Rare (187) 60%-87% (243,244) Progression to cirrhosis Rare (187) 7%-40% (105) Survival without transplantation 90%-100% (187,232) 10-year survival, 89%-91% (105,451

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“…Several case studies have revealed associations between pathogenic infections and the occurrence of AIH [2,3,7] . The presence of cross-reactive autoantibodies and the existence of structural similarities between AIH autoantigens and pathogens (i.e., molecular mimicry) provide a plausible explanation of how tolerance to liver autoantigens might be broken by infectious pathogens [8] . Experimental designs of AIH have clearly demonstrated that viral and bacterial superantigens can induce relapse and exacerbations of a T cell-mediated autoimmune process [9] .…”

Section: Discussionmentioning

confidence: 99%

Transient Exacerbation After Infections in Patients With Autoimmune Hepatitis

Maruyama¹,

Koda

2018

Journal of Gastroenterology and Hepatology Research

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and after infections in 20 patients with definite AIH, 33 with probable AIH, 24 with primary biliary cholangitis (PBC), 30 with chronic hepatitis C [CH(C)], and 23 control subjects. RESULTS: During the study period, 19 of the 20 patients (95%) with AIH experienced one or more signs of liver dysfunction after infection. Seventy-three (59%) out of the 124 total occurrences of infections in 19 patients met the criteria for transient exacerbation of liver dysfunction. The incidence of liver dysfunction and the serum IgG levels after infection were significantly higher in the patients with definite AIH than in the patients with probable AIH, PBC and CH(C), and in the control subjects. Serum IgG level was a significant independent predictor of liver dysfunction. CONCLUSION: The present study results suggested that infection was one cause of exacerbation of liver dysfunction in patients with AIH, and that serum IgG level was a significant independent predictor of exacerbation of liver dysfunction after infection.

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Pathogen Infection as a Possible Cause for Autoimmune Hepatitis

Cited by 26 publications

References 109 publications

Transient Expression of Transgenic IL-12 in Mouse Liver Triggers Unremitting Inflammation Mimicking Human Autoimmune Hepatitis

Transient Expression of Transgenic IL-12 in Mouse Liver Triggers Unremitting Inflammation Mimicking Human Autoimmune Hepatitis

Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases

Transient Exacerbation After Infections in Patients With Autoimmune Hepatitis

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