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J Autoimmun. 2017 Mar;78:39-45. doi: 10.1016/j.jaut.2016.12.001. Epub 2016 Dec 11.

The influence of genetic predisposition and autoimmune hepatitis inducing antigens in disease development.

Author information

1
Dept. of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Germany. Electronic address: Wolenski.Matthias@mh-hannover.de.
2
Dept. of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Germany.
3
Inst. of Pathology, Hannover Medical School, Germany.
4
Diabetes Center, University of California-San Francisco, San Francisco, United States.
5
Dept. of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Germany; Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Germany.

Abstract

Autoimmune hepatitis (AIH) is defined as a chronic liver inflammation with loss of tolerance against hepatocytes. The etiology and pathophysiology of AIH are still poorly understood because reliable animal models are limited. Therefore, we recently introduced a model of experimental murine AIH by a self-limited adenoviral infection with the AIH type 2 antigen formiminotransferase cyclodeaminase (FTCD). We could demonstrate that break of humoral tolerance towards liver specific autoantigens like FTCD and cytochrome P450 2D6 (CYP2D6) is not dependent on the genetic background. However, the development of AIH in autoantibody positive animals is determined by genetic background genes. We could also show that the break of humoral tolerance is necessary but not sufficient for the development of AIH. In contrast the break of tolerance against the ubiquitously expressed nuclear antigens (ANAs) is strictly dependent on genetic predisposition. Priming with the UGA suppressor tRNA-associated protein (soluble liver antigen; SLA) is a strong inducer of ANA reactivity, but not sufficient to cause AIH development thereby questioning the importance of anti-SLA immune response as an important driver in AIH. Monogenetic mutations such as Aire-deficiency can cause AIH in otherwise genetically resistant strains.

CONCLUSION:

The results have important implications for our understanding of the pathophysiology of AIH development and for the interpretation of humoral antibody responses in AIH.

KEYWORDS:

Autoantibodies; Autoimmune hepatitis; Cytochrome P450 2D6; Experimental murine autoimmune hepatitis; Formiminotransferase cyclodeaminase; Genetic predisposition; Soluble liver antigen

PMID:
27974250
DOI:
10.1016/j.jaut.2016.12.001
[Indexed for MEDLINE]

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