Medullary Thymic Epithelial Cells and Central Tolerance in Autoimmune Hepatitis Development: Novel Perspective from a New Mouse Model

Abstract

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.

Medullary thymic epithelial cells and CD8α + dendritic cells coordinately regulate central tolerance but CD8α + cells are dispensable for thymic regulatory T cell production

“…We previously generated conditional knockout mice in which Traf6, a known regulator of mTEC development, was specifically deleted in TECs using FoxN1-Cre knock-in mice (Traf6ΔTEC mice) [14, 19]. Deletion of Traf6 in TECs led to a marked reduction in the numbers of mature mTECs and a 50% reduction in the numbers of tTregs [19].…”

“…In contrast, results from a related study did not support a role for CD8α + cDCs in tTreg cell production [13]. In addition, while defective antigen expression and presentation by mTECs results in autoimmunity development in mice and humans [14, 15], the role of tDCs in the development of peripheral autoimmunity is controversial [16, 17]. While Ohnmacht et al showed that DC depletion led to impaired negative selection and fatal autoimmunity, Birnberg et al found normal negative selection and no autoimmune manifestations following DC ablation.…”

The Pathogenesis of Autoimmune Liver Disease

“…In comparison, thymic medullary TECs (mTECs) express different self-antigens to eliminate auto-reactive T-cells (central tolerance) and regulate the production of regulatory Tcells (Tregs). These Tregs work peripherally to dampen the immune response (peripheral tolerance) [22] .…”

“…AIH is a chronic immune-mediated liver disease characterized by hepatitis, the presence of autoantibodies and elevated IgG [1] . Histological features include portal inflammation and interface hepatitis along with lymphocytic infiltrates of both B-and T-lymphocytes [2] . AIH, unlike PBC and PSC, is classically very sensitive to immunosuppression.…”

Expression of cell cycle and apoptosis regulators in thymus and thymic epithelial tumors

“…and a high Ki67 proliferation index [80 %, whereas in A thymomas the Ki67 proliferation index was low (\80 %) [56]. These observations might be related to the findings that tumor TEC as neoplastic counterparts of normal TEC may promote thymocyte proliferation and differentiation through the elaboration of cytokines and chemokines and that thymomas have the capacity to promote the intratumoral maturation of T cells from immature precursors [115][116][117][118][119][120][121][122].…”