Genetics in Autoimmune Hepatitis

Donaldson, Peter

doi:10.1055/s-2002-35705

Cited by 112 publications

(81 citation statements)

References 71 publications

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“…In addition, our results showing that individual T cell subsets failed to recapitulate AIH development in recipient mice further supported the idea that complex interplay among lymphocyte cell subsets is required for disease development, with self-antigen recognition by autoreactive CD4 + T cells playing a key role in disease initiation. Consistent with this, susceptibility of human patients to AIH has been linked to deviant DRB1 alleles within the human leukocyte antigen (HLA) region (55)(56)(57). As these molecules present peptide antigens to CD4 + T cells, compromised antigen presentation by susceptibility alleles and recognition of liver self-antigens by naive T lymphocytes is thought to contribute to AIH pathogenesis.…”

Section: Discussionmentioning

confidence: 87%

Medullary thymic epithelial cell depletion leads to autoimmune hepatitis

Bonito

Aloman²,

Fiel³

et al. 2013

J. Clin. Invest.

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TRAF6, an E3 ubiquitin protein ligase, plays a critical role in T cell tolerance by regulating medullary thymic epithelial cell (mTEC) development. mTECs regulate T cell tolerance by ectopically expressing self-antigens and eliminating autoreactive T cells in the thymus. Here we show that mice with mTEC depletion due to conditional deletion of Traf6 expression in murine thymic epithelial cells (Traf6ΔTEC mice) showed a surprisingly narrow spectrum of autoimmunity affecting the liver. The liver inflammation in Traf6ΔTEC mice exhibited all the histological and immunological characteristics of human autoimmune hepatitis (AIH). The role of T cells in AIH establishment was supported by intrahepatic T cell population changes and AIH development after transfer of liver T cells into immunodeficient mice. Despite a 50% reduction in natural Treg thymic output, peripheral tolerance in Traf6ΔTEC mice was normal, whereas compensatory T regulatory mechanisms were evident in the liver of these animals. These data indicate that mTECs exert a cell-autonomous role in central T cell tolerance and organ-specific autoimmunity, but play a redundant role in peripheral tolerance. These findings also demonstrate that Traf6ΔTEC mice are a relevant model with which to study the pathophysiology of AIH, as well as autoantigen-specific T cell responses and regulatory mechanisms underlying this disease.

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Section: Discussionmentioning

confidence: 87%

Medullary thymic epithelial cell depletion leads to autoimmune hepatitis

Bonito

Aloman²,

Fiel³

et al. 2013

J. Clin. Invest.

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“…Among white northern Europeans and Americans, there is a well-recognized association between increased susceptibility to AIH and inheritance of DR3 and DR4. 14 The present study was undertaken to study the association of HLA alleles in patients with AIH type 1 and AIH type 2 from north Indian population.…”

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confidence: 99%

HLA DRB1 Alleles Discriminate the Manifestation of Autoimmune Hepatitis as Type 1 or Type 2 in North Indian Population

Kaur

Minz

Anand

et al. 2014

Journal of Clinical and Experimental Hepatology

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Background: Autoimmune hepatitis is a polygenic disorder of unknown etiology, where genetic factors affect the occurrence and clinical phenotype of the disease. It has been reported as a rare disease entity in the Indian subcontinent. This study was undertaken to investigate the association of HLA alleles with autoimmune hepatitis type 1 and type 2 in north Indian population and to analyze if distinct human leukocyte antigen (HLA) alleles help in characterization of the subtypes of autoimmune hepatitis. Methods: Sixty-eight patients with autoimmune hepatitis and 128 healthy controls were recruited in the study. Out of 68 patients, 55 were diagnosed with autoimmune hepatitis type 1 and 13 with autoimmune hepatitis type 2. The patients and the controls were typed for HLA class II alleles by PCR-SSP method. Results: HLA DRB1*04 and DRB1*08 were found to be significantly associated with autoimmune hepatitis type 1 in north Indian population. It was also observed that DRB1*04, DRB1*13 were significantly associated with pediatric autoimmune hepatitis type 1 and DRB1*08 was significantly associated with adult autoimmune hepatitis type 1. DRB1*14 was significantly associated with autoimmune hepatitis type 2. Conclusion: The study indicates that autoimmune hepatitis in north Indian population is associated with HLA alleles that may help to discriminate the subtypes as autoimmune hepatitis type 1 and type 2. The study also highlights the ethnic variations in the Indian subcontinent in context to the genetic association of HLA with autoimmune diseases. ( J CLIN EXP HEPATOL 2014;4:14-18)

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“…However, sporadic cases of AIH both in children and in adults are not associated with the common AIRE mutations, although different defects in the AIRE gene may result in phenotypically distinct syndromes of autoimmunity [64][65][66]. Thymic selection cannot provide complete protection against autoimmunity, particularly in individuals who express HLA haplotypes that make them more likely to recognize self-antigens despite adequate thymic selection; these include HLA-DR3 (A1-B8-DR3) and DR4, which increase susceptibility to type 1 AIH [67] and DR7 associated with type 2 AIH [68], and the development of immune responses against the hepatocyte enzyme, CYP2D6 [69,70].…”

Section: Genetic Susceptibilitymentioning

confidence: 99%

Autoimmune hepatitis: new paradigms in the pathogenesis, diagnosis, and management

2010

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Autoimmune hepatitis (AIH), primary biliary cirrhosis, and primary sclerosing cholangitis are the three major autoimmune diseases affecting the liver, and of these three, AIH is the most typical autoimmune disease being characterized by a T-cell-rich infiltrate, raised circulating c-globulins, autoantibodies, HLA associations, and links with other autoimmune diseases. It is the only one, of the three diseases, that responds well to immunosuppressive therapy. AIH is caused by dysregulation of immunoregulatory networks and the consequent emergence of autoreactive T cells that orchestrate a progressive destruction of hepatocytes leading untreated to liver failure. T cells play a major role in the immunopathogenesis, and both CD4? and CD8? T cells are involved together with effector responses mediated by NK cells, cd T cells, and macrophages. A number of triggering factors have been proposed including viruses, xenobiotics, and drugs, but none have been conclusively shown to be involved in pathogenesis.

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Genetics in Autoimmune Hepatitis

Cited by 112 publications

References 71 publications

Medullary thymic epithelial cell depletion leads to autoimmune hepatitis

Medullary thymic epithelial cell depletion leads to autoimmune hepatitis

HLA DRB1 Alleles Discriminate the Manifestation of Autoimmune Hepatitis as Type 1 or Type 2 in North Indian Population

Autoimmune hepatitis: new paradigms in the pathogenesis, diagnosis, and management

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