A murine model of type 2 autoimmune hepatitis: Xenoimmunization with human antigens
A murine model of type 2 autoimmune hepatitis: Xenoimmunization with human antigens
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DOI：
10.1002/hep.20109
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发表时间：
2004-04-01
期刊：
影响因子：
13.5
通讯作者：
Alvarez, F
中科院分区：
文献类型：
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作者：
Lapierre, P;Djilali-Saiah, I;Alvarez, F
自身免疫性肝炎（AIH）的特征是免疫介导的肝实质损伤，其发病机制尚不清楚。2型AIH通过抗肝肾微粒体I型（抗LKM 1）和抗肝细胞溶质1型（抗LC 1）自身抗体的存在来鉴定。目前的研究表明，可以通过针对2型AIH自身抗原（P450 2D 6和甲酰亚胺转移酶-环脱氨酶）的DNA免疫产生AIH小鼠模型。将含有小鼠CTLA-4的N-末端区域和人CYP 2D 6（672- 1，377 bp）和人甲酰亚胺转移酶环脱氨酶（FTCD; 1，232 - 1，668 bp）的抗原区域的pCMV质粒用于C57 BL/6雌性小鼠的DNA免疫。免疫小鼠的丙氨酸氨基转移酶（ALT）水平升高，在注射后4个月和7个月达到峰值。在组织学上观察到门脉周围、门脉和小叶内肝脏炎性浸润。肝脏中主要为CD 4+淋巴细胞，但也有CD 8+和B淋巴细胞。在这些动物的肝脏和脾脏中均发现了细胞毒性特异性T细胞。小鼠产生针对特异性小鼠自身抗原的免疫球蛋白G2（IgG 2）亚类的抗LKM 1和抗LC 1抗体。ALT水平与抗LKM 1/抗LC 1抗体的存在和肝脏坏死性炎症的存在相关。总之，在小鼠中，针对人类自身抗原的DNA免疫破坏了耐受性并诱导了自身免疫性肝病。外来抗原和自身抗原之间的分子模拟解释了肝损伤。该模型与人类2型AIH相似，为进一步研究AIH的发病机制提供了实验依据。
Autoimmune hepatitis (AIH) is characterized by an immune-mediated injury of the hepatic parenchyma of unknown pathogenesis. Type 2 AIH is identified by the presence of anti-liver-kidney microsomes type I (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1) auto-antibodies. The current study shows that a murine model of AIH can be generated by DNA immunization against type 2 AIH self-antigens (P450 2D6 and formiminotransferase-cyclodeaminase). A pCMV plasmid containing the N-terminal region of mouse CTLA-4 and the antigenic region of human CYP2D6 (672-1,377 bp) and human formiminotransferase cyclodeaminase (FTCD; 1,232-1,668 bp) was used for DNA immunization of C57BL/6 female mice. Immunized mice showed elevated levels of alanine aminotransferase (ALT), with peaks at 4 and 7 months postinjection. Periportal, portal, and intralobular liver inflammatory infiltrates were observed at histology. Mainly CD4+ lymphocytes, but also CD8+ and B lymphocytes, were found in the liver. Cytotoxic-specific T cells were found in both the liver and spleen of these animals. Mice developed anti-LKM1 and anti-LC1 antibodies of immunoglobulin G2 (IgG2) subclass, against specific mouse autoantigens. The ALT levels correlated with both the presence of anti-LKM1/anti-LC1 antibodies and the presence of liver necroinflammation. In conclusion, in mice, DNA immunization against human antoantigens breaks tolerance and induces an autoimmune liver disease. Molecular mimicry between foreign and self-antigens explains the liver injury. This model of AIH resembles human type 2 AIH and will be helpful for the study of its pathogenesis.