Medullary thymic epithelial cells and central tolerance in autoimmune hepatitis development: novel perspective from a new mouse model

• Published in: International journal of molecular sciences 2015-01, Vol.16 (1), p.1980-2000
• Main Authors: Alexandropoulos, Konstantina, Bonito, Anthony J, Weinstein, Erica G, Herbin, Olivier
• Format: Article
• Language: English
• Subjects: Animals; Antigens; antinuclear antibodies; Autoimmune diseases; autoimmune hepatitis (AIH); autoimmune polyendocrine syndrome (APS); autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED); central tolerance; Central Tolerance - immunology; Disease Models, Animal; Epithelial Cells - pathology; Hepatitis; Hepatitis, Autoimmune - immunology; Immune system; medullary thymic epithelial cells; medullary thymic epithelial cells (mTECs); Mice; peripheral tolerance; regulatory T-cells; Review; soluble liver antigen; T-cells; T-Lymphocytes, Regulatory - immunology; Thymus Gland - pathology
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms16011980

Autoimmune hepatitis (AIH) is an immune-mediated disorder that affects the liver parenchyma. Diagnosis usually occurs at the later stages of the disease, complicating efforts towards understanding the causes of disease development. While animal models are useful for studying the etiology of autoimmune disorders, most of the existing animal models of AIH do not recapitulate the chronic course of the human condition. In addition, approaches to mimic AIH-associated liver inflammation have instead led to liver tolerance, consistent with the high tolerogenic capacity of the liver. Recently, we described a new mouse model that exhibited spontaneous and chronic liver inflammation that recapitulated the known histopathological and immunological parameters of AIH. The approach involved liver-extrinsic genetic engineering that interfered with the induction of T-cell tolerance in the thymus, the very process thought to inhibit AIH induction by liver-specific expression of exogenous antigens. The mutation led to depletion of specialized thymic epithelial cells that present self-antigens and eliminate autoreactive T-cells before they exit the thymus. Based on our findings, which are summarized below, we believe that this mouse model represents a relevant experimental tool towards elucidating the cellular and molecular aspects of AIH development and developing novel therapeutic strategies for treating this disease.