Medullary thymic epithelial cells and central tolerance in autoimmune hepatitis development: novel perspective from a new mouse model.
Medullary thymic epithelial cells and central tolerance in autoimmune hepatitis development: novel perspective from a new mouse model.
复制标题
DOI：
10.3390/ijms16011980
复制
发表时间：
2015-01-16
影响因子：
5.6
通讯作者：
Herbin O
中科院分区：
文献类型：
--
作者：
Alexandropoulos K;Bonito AJ;Weinstein EG;Herbin O
自身免疫性肝炎（AIH）是一种影响肝实质的免疫介导的疾病。诊断通常发生在疾病的后期，使理解疾病发展原因的努力复杂化。虽然动物模型可用于研究自身免疫性疾病的病因学，但大多数现有的AIH动物模型不能概括人类疾病的慢性过程。此外，模拟AIH相关肝脏炎症的方法反而导致了肝脏耐受性，这与肝脏的高致耐受能力一致。最近，我们描述了一种新的小鼠模型，表现出自发性和慢性肝脏炎症，概括了已知的AIH的组织病理学和免疫学参数。该方法涉及肝脏外源性基因工程，干扰胸腺中T细胞耐受性的诱导，该过程被认为通过外源性抗原的肝脏特异性表达来抑制AIH诱导。这种突变导致专门的胸腺上皮细胞耗竭，这些细胞在离开胸腺之前呈递自身抗原并消除自身反应性T细胞。基于我们的发现，总结如下，我们认为这种小鼠模型代表了一种相关的实验工具，用于阐明AIH发展的细胞和分子方面，并开发用于治疗这种疾病的新的治疗策略。
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.
登录
查看更多内容
影响因子：
5.8
作者：
Clemente, MG;ObermayerStraub, P;Manns, MP
通讯作者：
Manns, MP
影响因子：
13.5
作者：
Ebrahimkhani, Mohammad R.;Mohar, Isaac;Crispe, Ian N.
通讯作者：
Crispe, Ian N.
影响因子：
30.5
作者：
Aschenbrenner, Katharina;D'Cruz, Louise M.;Klein, Ludger
通讯作者：
Klein, Ludger
影响因子：
56.9
作者：
Anderson, MS;Venanzi, ES;Mathis, D
通讯作者：
Mathis, D
影响因子：
30.5
作者：
Apostolou, I;Sarukhan, A;von Boehmer, H
通讯作者：
von Boehmer, H