Pathogenesis of autoimmune hepatitis

doi:10.1016/j.bpg.2011.09.009

Best Practice & Research Clinical Gastroenterology

Volume 25, Issue 6, December 2011, Pages 653-664

https://doi.org/10.1016/j.bpg.2011.09.009 Get rights and content

The mechanisms underlying the pathogenesis of autoimmune hepatitis are not fully understood, though there is growing evidence that genetic predisposition, molecular mimicry and/or impairment of regulatory T-cells are involved in the initiation and perpetuation of the autoimmune liver attack. The histological picture of interface hepatitis, characterized by a dense portal mononuclear cell infiltrate, was the first to suggest an autoaggressive cellular immune attack in the pathogenesis of this condition. Liver damage is likely to be orchestrated by CD4^pos T-cells recognizing an autoantigenic liver peptide. For autoimmunity to arise, the peptide must be presented by antigen-presenting cells to naïve CD4^pos T-helper (Th0) cells. Once activated, Th0-cells can differentiate into Th1-, Th2-, or Th17-cells, initiating a cascade of immune reactions that are determined by the cytokines they produce. Autoantigen recognition and the above effector mechanisms are opposed by regulatory T-cells, a cell subset numerically and functionally impaired in autoimmune hepatitis.

Introduction

Autoimmune hepatitis (AIH), an immune-mediated liver disorder with a strong female preponderance, is characterized by hypergammaglobulinaemia, seropositivity for autoantibodies and interface hepatitis on histology. AIH responds to immunosuppressive treatment, which should be instituted as soon as the diagnosis is made. AIH can be divided in two subsets according to the autoantibodies detected at diagnosis: type 1 autoimmune hepatitis (AIH-1), associated with anti-nuclear antibody (ANA) and/or anti-smooth muscle antibody (SMA), and type 2 autoimmune hepatitis (AIH-2) characterized by positivity for anti-liver/kidney-microsomal-antibody-type-1 (anti-LKM-1) or anti-liver-cytosol-type-1 (anti-LC1). In spite of its global distribution, AIH prevalence and behaviour varies according to ethnicity. The aetiology of AIH is unknown, though both genetic and environmental factors are involved. Immune reactions against liver host antigens not adequately controlled by impaired regulatory T-cells are believed to be the major mechanism of liver damage.

Section snippets

Genetics

AIH is a “complex trait” disease that does not follow a Mendelian pattern of inheritance. Its mode of inheritance is unknown, though like other human complex trait disorders, it involves one or more genes, that acting alone or in concert, and interacting with environmental factors, increase or reduce the risk of the trait [1].

In AIH, the strongest genetic associations is with genes located within the major histocompatibility complex (MHC) – the human leukocyte antigen (HLA) region – on the

Immune mechanisms

The liver is regarded as a unique anatomical and immunological organ, continuously exposed to antigen-rich blood (containing pathogens, toxins, tumour cells and self-antigens) from the gastro-intestinal tract [28]. The liver is highly enriched in phagocytic cells, antigen-presenting cells (APC) and lymphocytes and is an active site for the production of cytokines, complement components and acute phase proteins [29]. Within the liver, many cell populations can act as APCs, namely endothelial

Animal models

The ideal AIH animal model, which should be characterized by a well-defined initiating event followed by chronic inflammation leading to fibrosis, is still lacking. Since in AIH-2 the autoantigen is well defined, researchers have focused their attention on this subtype of the disease. One model is based on immunizing C57BL/6 female mice with a plasmid containing cDNA for the antigenic region of human CYP2D6 and for formimino-transferase cyclodeaminase, targets of anti-LKM1 and anti-LC-1

Conflict of interest

None declared.

Acknowledgements

RL is supported by a Doctoral Grant from Fundação para a Ciência e Tecnologia, Portugal (reference SFRH/BD/65007/2009). MSL holds a Clinician Scientist Fellowship from the Medical Research Council, UK. GMV is supported by WellChild, Cheltenham, and the Children’s Liver Disease Foundation, Birmingham, UK. GMV and DV are supported by the Roger Dobson Fund and the Associazione Malattie Epatiche Autoimmuni (AMEA)

References (78)

D. Vergani et al.
Pathogenesis of autoimmune hepatitis
Clin Liver Dis
(2002)
M.D. Strettell et al.
Allelic basis for HLA-encoded susceptibility to type 1 autoimmune hepatitis
Gastroenterology
(1997)
P.T. Donaldson
Genetics of autoimmune and viral liver diseases; understanding the issues
J Hepatol
(2004)
C. Duarte-Rey et al.
HLA class II association with autoimmune hepatitis in Latin America: a meta-analysis
Autoimmun Rev
(2009)
Y. Ma et al.
Polyclonal T-cell responses to cytochrome P450IID6 are associated with disease activity in autoimmune hepatitis type 2
Gastroenterology
(2006)
I. Djilali-Saiah et al.
Linkage disequilibrium between HLA class II region and autoimmune hepatitis in pediatric patients
J Hepatol
(2004)
I. Djilali-Saiah et al.
HLA class II influences humoral autoimmunity in patients with type 2 autoimmune hepatitis
J Hepatol
(2006)
I. Vorechovsky et al.
Genetic linkage of IgA deficiency to the major histocompatibility complex: evidence for allele segregation distortion, parent-of-origin penetrance differences, and the role of anti-IgA antibodies in disease predisposition
Am J Hum Genet
(1999)
D. Vergani et al.
Genetically determined low C4: a predisposing factor to autoimmune chronic active hepatitis
Lancet
(1985)
A.J. Czaja et al.
Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis
Gastroenterology
(1999)

K. Yoshizawa et al.

Genetic analysis of the HLA region of Japanese patients with type 1 autoimmune hepatitis

J Hepatol

(2005)

A. Vogel et al.

Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis

Hepatology

(2002)

M.S. Longhi et al.

Aetiopathogenesis of autoimmune hepatitis

J Autoimmun

(2010)

S. Vento et al.

Antigen specific suppressor cell function in autoimmune chronic active hepatitis

Lancet

(1984)

M.S. Longhi et al.

Impairment of CD4(+)CD25(+)regulatory T-cells in autoimmune liver disease

J Hepatol

(2004)

M.S. Longhi et al.

Effect of CD4 + CD25 + regulatory T-cells on CD8 T-cell function in patients with autoimmune hepatitis

J Autoimmun

(2005)

J.L. Riley et al.

Human T regulatory cell therapy: take a billion or so and call me in the morning

Immunity

(2009)

B.M. McFarlane et al.

Serum autoantibodies reacting with the hepatic asialoglycoprotein receptor protein (hepatic lectin) in acute and chronic liver disorders

J Hepatol

(1986)

Y. Ma et al.

Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease

Hepatology

(2002)

L. Wen et al.

T-cell-directed hepatocyte damage in autoimmune chronic active hepatitis

Lancet

(1990)

P.T. Donaldson

Genetics of liver disease: immunogenetics and disease pathogenesis

Gut

(2004)

P.T. Donaldson

Genetics in autoimmune hepatitis

Semin Liver Dis

(2002)

P.T. Donaldson et al.

Susceptibility to autoimmune chronic active hepatitis: human leukocyte antigens DR4 and A1-B8-DR3 are independent risk factors

Hepatology

(1991)

A.J. Czaja et al.

Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis

Immunol Rev

(2000)

A.J. Czaja et al.

Genetic bases of autoimmune hepatitis

Dig Dis Sci

(2002)

D. Vergani et al.

Autoimmune hepatitis

Semin Immunopathol

(2009)

G.V. Gregorio et al.

Autoimmune hepatitis in childhood: a 20-year experience

Hepatology

(1997)

K. Agarwal et al.

Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis

Hepatology

(2000)

D. Vergani et al.

Aetiopathogenesis of autoimmune hepatitis

World J Gastroenterol

(2008)

K. Agarwal et al.

A functional Fas promoter polymorphism is associated with a severe phenotype in type 1 autoimmune hepatitis characterized by early development of cirrhosis

Tissue Antigens

(2007)

D. Mathis et al.

Aire Annu Rev Immunol

(2009)

M.J. Simmonds et al.

Genetic insights into disease mechanisms of autoimmunity

Br Med Bull

(2004)

A. Liston et al.

Gene dosage–limiting role of Aire in thymic expression, clonal deletion, and organ-specific autoimmunity

J Exp Med

(2004)

A. Liston et al.

Genetic lesions in T-cell tolerance and thresholds for autoimmunity

Immunol Rev

(2005)

V. Racanelli et al.

The liver as an immunological organ

Hepatology

(2006)

I.R. Mackay

Hepatoimmunology: a perspective

Immunol Cell Biol

(2002)

I.N. Crispe

The liver as a lymphoid organ

Annu Rev Immunol

(2009)

K.T. Nouri-Aria et al.

Effect of corticosteroids on suppressor-cell activity in "autoimmune" and viral chronic active hepatitis

N Engl J Med

(1982)

H.J. Hodgson et al.

Alteration in suppressor cell activity in chronic active hepatitis

Proc Natl Acad Sci U S A

(1978)

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Citation Excerpt :
Whatever the initial trigger, it is probable that such a high number of activated inflammatory cells causes liver damage. There are different pathways that an immune attack can follow to inflict damage on the hepatocyte (Fig. 1) [4]. Autoantigen recognition is controlled by regulatory mechanisms.
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease affecting all ages, characterised by elevated transaminase and immunoglobulin G levels, positive autoantibodies, interface hepatitis on histology and good response to immunosuppressive treatment. If untreated, it has a poor prognosis. The aim of this review is to analyse AIH therapeutic interventions with reference to our knowledge of the pathogenesis of AIH. Standard treatment, based on steroids and azathioprine, leads to disease remission in 80–90% of patients. Alternative first-line treatment with budesonide is effective in adults, but less so in the juvenile form of AIH; first-line treatment with ciclosporin does not provide convincing advantages compared to standard treatment. Second-line treatments are needed for patients not responding or intolerant to first-line standard management. Mycophenolate mofetil is the most widely used second-line drug, and has good efficacy particularly for patients intolerant to azathioprine, but is teratogenic. Only few and heterogeneous data on calcineurin inhibitors and m-TOR inhibitors are available. Biologicals, including anti-tumour necrosis factor- α and anti-CD20 monoclonal antibodies, have given ambivalent results and may have severe side-effects. Clinical trials with new therapeutic options aiming at targeting B lymphocytes and proinflammatory cytokines, or expanding regulatory T cells to restore tolerance are ongoing
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Autoimmune hepatitis (AIH) is a rare indication for liver transplantation (LT). Data on the long-term outcomes of living-related LT for AIH are limited and inconsistent. The present study aimed to assess the long-term outcomes of deceased donor LT (DDLT) and living donor LT (LDLT) for AIH.
All patients who received transplants for AIH-related cirrhosis from 2001 to 2018 were included in this study.
Seventy-four patients (31 male, 43 female) received LT. The average follow-up was 7.9 ± 6.9 years (median = 7.2 years), average age was 34.3 ± 13.8 years, and average Model for End-Stage Liver Disease (MELD) score was 23.6 ± 8.5. Thirty-six (49.3%) patients received a graft from a living donor, and 83% of patients were maintained on steroids. The 1-, 3-, 5-, and 10-year survival rates of patients were 91%, 89%, 87%, and 82% and of grafts were 89%, 88%, 86%, and 76%, respectively. In univariate analysis, MELD score (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01-1.17; P = .028), donor age (OR per 5 years, 1.45; 95% CI, 1.07-2.02; P = .021), donor type (OR LDLT vs DDLT, 0.19; 95% CI, 0.04-0.67; P = .017), and renal function (OR glomerular filtration rate <60 vs ≥60 mL/min/m², 7.41; 95% CI, 1.88-31.25; P = .004) were significant predictors of graft survival; however, none of the factors remained significant in multivariate analysis.
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2Pathogenesis of autoimmune hepatitis

Introduction

Section snippets

Genetics

Immune mechanisms

Animal models

Conflict of interest

Acknowledgements

Clin Liver Dis

Gastroenterology

J Hepatol

Autoimmun Rev

Gastroenterology

J Hepatol

J Hepatol

Am J Hum Genet

Lancet

Gastroenterology

J Hepatol

Hepatology

J Autoimmun

Lancet

J Hepatol

J Autoimmun

Immunity

J Hepatol

Hepatology

Lancet

Genetics of liver disease: immunogenetics and disease pathogenesis

Gut

Genetics in autoimmune hepatitis

Semin Liver Dis

Susceptibility to autoimmune chronic active hepatitis: human leukocyte antigens DR4 and A1-B8-DR3 are independent risk factors

Hepatology

Genetic susceptibilities for immune expression and liver cell injury in autoimmune hepatitis

Immunol Rev

Genetic bases of autoimmune hepatitis

Dig Dis Sci

Autoimmune hepatitis

Semin Immunopathol

Autoimmune hepatitis in childhood: a 20-year experience

Hepatology

Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis

Hepatology

Aetiopathogenesis of autoimmune hepatitis

World J Gastroenterol

A functional Fas promoter polymorphism is associated with a severe phenotype in type 1 autoimmune hepatitis characterized by early development of cirrhosis

Tissue Antigens

Aire Annu Rev Immunol

Genetic insights into disease mechanisms of autoimmunity

Br Med Bull

Gene dosage–limiting role of Aire in thymic expression, clonal deletion, and organ-specific autoimmunity

J Exp Med

Genetic lesions in T-cell tolerance and thresholds for autoimmunity

Immunol Rev

The liver as an immunological organ

Hepatology

Hepatoimmunology: a perspective

Immunol Cell Biol

The liver as a lymphoid organ

Annu Rev Immunol

Effect of corticosteroids on suppressor-cell activity in "autoimmune" and viral chronic active hepatitis

N Engl J Med

Alteration in suppressor cell activity in chronic active hepatitis

Proc Natl Acad Sci U S A

2
Pathogenesis of autoimmune hepatitis