Autoimmune Hepatitis in a Murine Autoimmune Polyendocrine Syndrome Type 1 Model Is Directed Against Multiple Autoantigens
Autoimmune Hepatitis in a Murine Autoimmune Polyendocrine Syndrome Type 1 Model Is Directed Against Multiple Autoantigens
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DOI：
10.1002/hep.27639
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发表时间：
2015-04-01
期刊：
影响因子：
13.5
通讯作者：
Jaeckel, Elmar
中科院分区：
文献类型：
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作者：
Hardtke-Wolenski, Matthias;Taubert, Richard;Jaeckel, Elmar
自身免疫性多内分泌综合征1型（APS-1）是由自身免疫调节因子（AIRE）基因突变引起的。小鼠研究表明，这导致T细胞阴性选择缺陷和外周器官与调节性T细胞（Tregs）早期播种缺陷。人和小鼠的Aire缺乏表现为针对多器官的自发自身免疫，20%的患者发展为自身免疫性肝炎（AIH）。为了研究APS-1中的AIH，我们在BALB/c小鼠背景下建立了人类AIH的小鼠模型，其中Aire在外显子2处被截断。24%的小鼠受到AIH的影响，其特征是淋巴浆细胞和门静脉周围肝脏浸润，自身抗体，转氨酶升高，以及慢性和进行性病程。疾病的表现依赖于特定的Aire突变和小鼠的遗传背景。虽然肝内Treg数量增加，增殖过度，但肝内CD4/CD8比值降低。适应性自身免疫反应的靶标是多特异性的，不像其他aps -1相关自身免疫性疾病那样集中于必需的自身抗原。AIH可以用强的松龙或多特异性treg过继性转移治疗。结论：APS-1患者AIH的发生与特定的Aire突变和遗传背景基因有关。自身免疫反应是多特异性的，可以通过类固醇或Tregs转移来控制。这可能为AIH患者提供新的治疗选择。(肝脏病学61:1295 2015;1305)
Autoimmune polyendocrine syndrome type 1 (APS-1) is caused by mutations of the autoimmune regulator (AIRE) gene. Mouse studies have shown that this results in defective negative selection of T cells and defective early seeding of peripheral organs with regulatory T cells (Tregs). Aire deficiency in humans and mice manifests as spontaneous autoimmunity against multiple organs, and 20% of patients develop an autoimmune hepatitis (AIH). To study AIH in APS-1, we generated a murine model of human AIH on a BALB/c mouse background, in which Aire is truncated at exon 2. A subgroup of 24% of mice is affected by AIH, characterized by lymphoplasmacytic and periportal hepatic infiltrates, autoantibodies, elevated aminotransferases, and a chronic and progressive course of disease. Disease manifestation was dependent on specific Aire mutations and the genetic background of the mice. Though intrahepatic Treg numbers were increased and hyperproliferative, the intrahepatic CD4/CD8 ratio was decreased. The targets of the adaptive autoimmune response were polyspecific and not focussed on essential autoantigens, as described for other APS-1-related autoimmune diseases. The AIH could be treated with prednisolone or adoptive transfer of polyspecific Tregs. Conclusion: Development of AIH in APS-1 is dependent on specific Aire mutations and genetic background genes. Autoimmune response is polyspecific and can be controlled by steroids or transfer with Tregs. This might enable new treatment options for patients with AIH. (Hepatology 2015;61:1295-1305)