Expression of B and T lymphocyte attenuator (BTLA) in macrophages contributes to the fulminant hepatitis caused by murine hepatitis virus strain-3
Expression of B and T lymphocyte attenuator (BTLA) in macrophages contributes to the fulminant hepatitis caused by murine hepatitis virus strain-3
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巨噬细胞中 B 和 T 淋巴细胞衰减因子 (BTLA) 的表达导致鼠肝炎病毒 3 株引起的暴发性肝炎
DOI：
10.1136/gutjnl-2012-302239
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发表时间：
2013-08-01
期刊：
影响因子：
24.5
通讯作者：
Wu, Yuzhang
中科院分区：
文献类型：
--
作者：
Yang, Chengying;Chen, Yongwen;Wu, Yuzhang
目的 暴发性病毒性肝炎（FH）仍然是一个严重的临床问题，其潜在发病机制尚不清楚。 B 和 T 淋巴细胞衰减蛋白 (BTLA) 是一种含有免疫球蛋白结构域的蛋白质，能够维持外周耐受性并限制免疫反应过程中的免疫病理损伤。然而，其在 FH 中的确切作用仍有待研究。设计BTLA缺陷型（BTLA−/−）小鼠及其野生型同窝小鼠感染鼠肝炎病毒3型（MHV-3），并测量和比较组织损伤、细胞凋亡、血清肝酶、纤维蛋白原样蛋白2（FGL2）和细胞因子产生的水平。研究了 MHV-3 感染后有或没有过继转移巨噬细胞的存活率。结果感染 MHV-3 的 BTLA−/− 小鼠的 FGL2 产生、肝脏和脾脏损伤以及死亡率显着降低。这种效应是由于 BTLA−/− 小鼠中 MHV-3 感染的巨噬细胞发生快速、TRAIL（TNF 相关凋亡诱导配体）依赖性凋亡所致。巨噬细胞的早期损失导致致病性肿瘤坏死因子α（TNFα）和FGL2水平降低以及病毒滴度降低。 TNFα 在 MHV-3 诱导的病理学中的重要性通过 TNFα 治疗的 MHV-3 感染的 BTLA−/− 小鼠死亡率增加得到证明，而 TNFα−/− 小鼠对感染具有抵抗力。此外，将巨噬细胞过继转移至 BTLA−/− 小鼠体内会引起敏化，而阻断 BTLA 则可保护野生型小鼠免受病毒诱导的 FH 死亡。结论 BTLA 通过增强巨噬细胞活力和功能促进病毒诱导的 FH 发病。靶向 BTLA 可能是治疗 FH 的一种新策略。
Objectives Fulminant viral hepatitis (FH) remains a serious clinical problem for which the underlying pathogenesis remains unclear. The B and T lymphocyte attenuator (BTLA) is an immunoglobulin-domain-containing protein that has the capacity to maintain peripheral tolerance and limit immunopathological damage during immune responses. However, its precise role in FH has yet to be investigated. Design BTLA-deficient (BTLA−/−) mice and their wild-type littermates were infected with murine hepatitis virus strain-3 (MHV-3), and the levels of tissue damage, cell apoptosis, serum liver enzymes, fibrinogen-like protein 2 (FGL2) and cytokine production were measured and compared. Survival rate was studied after MHV-3 infection with or without adoptive transferring macrophages. Results FGL2 production, liver and spleen damage, and mortality were significantly reduced in BTLA−/− mice infected with MHV-3. This effect is due to rapid, TRAIL (TNF-related apoptosis-inducing ligand)-dependent apoptosis of MHV-3-infected macrophages in BTLA−/− mice. The early loss of macrophages resulted in reduced pathogenic tumour necrosis factor α (TNFα) and FGL2 levels and lower viral titres. The importance of TNFα in MHV-3-induced pathology was demonstrated by increased mortality in TNFα-treated MHV-3-infected BTLA−/− mice, whereas TNFα−/− mice were resistant to the infection. Moreover, adoptively transferring macrophages to BTLA−/− mice caused sensitisation, whereas blocking BTLA protected wild-type mice from virus-induced FH mortality. Conclusions BTLA promotes the pathogenesis of virus-induced FH by enhancing macrophage viability and function. Targeting BTLA may be a novel strategy for the treatment of FH.