Parenchymal expression of CD40 exacerbates adenovirus-induced hepatitis in mice.

The healthy adult human liver expresses low levels of MHC II and undetectable levels of immune co-stimulatory molecules. However, high levels of MHC class II, CD40 and B7 family molecules are expressed in the activated Kupffer cells and hepatocytes of patients having viral hepatitis. The precise role of these molecules in viral clearance and immune-mediated liver injury is not well understood. We hypothesize that parenchymal CD40 expression enhances T-cell recruitment and effector functions, which may facilitate viral clearance and alleviate liver injury. To test this hypothesis, we generated novel, liver-specific, conditional CD40 transgenic mice, and challenged them i.v. with recombinant replication-deficient adenovirus carrying Cre recombinase (AdCre). Wild-type mice infected with AdCre developed a relatively mild course of viral hepatitis and recovered spontaneously. CD40 expression in the liver of transgenic animals, however, resulted in CD80 and CD86 expression. Dysregulation of population dynamics and effector functions of intrahepatic lymphocytes results in severe lymphocytic infiltration, apoptosis, necroinflammation, and serum alanine transferase (ALT) elevation in a dose-dependent fashion. To our surprise, an early expansion followed by a contraction of intrahepatic lymphocytes, especially CD8+ and NK cells, accompanied by increased granzyme B and IFN-γ production, did not lead to a faster viral clearance in CD40 transgenic mice. Conclusion: Our results demonstrated that hepatic CD40 expression does not accelerate adenoviral clearance, but rather exacerbates liver injury. This study unveils a previously unknown deleterious effect of hepatic CD40 in adenovirus-induced liver inflammation.

健康成人肝脏低水平表达主要组织相容性复合体II（MHC II），且免疫共刺激分子水平无法检测到。然而，在病毒性肝炎患者的活化库普弗细胞和肝细胞中，高水平的MHC II类、CD40以及B7家族分子会表达。这些分子在病毒清除和免疫介导的肝损伤中的确切作用尚未完全清楚。我们假设实质细胞CD40的表达增强了T细胞的募集和效应功能，这可能有助于病毒清除并减轻肝损伤。为了验证这一假设，我们培育了新型的肝脏特异性条件性CD40转基因小鼠，并通过静脉注射携带Cre重组酶的重组复制缺陷型腺病毒（AdCre）对其进行攻击。感染AdCre的野生型小鼠发生了相对较轻的病毒性肝炎病程，并自发恢复。然而，转基因动物肝脏中的CD40表达导致了CD80和CD86的表达。肝内淋巴细胞群体动力学和效应功能的失调导致严重的淋巴细胞浸润、细胞凋亡、坏死性炎症以及血清丙氨酸氨基转移酶（ALT）呈剂量依赖性升高。令我们惊讶的是，肝内淋巴细胞（尤其是CD8 +和NK细胞）早期扩增随后收缩，同时伴有颗粒酶B和干扰素 - γ产生增加，但这并未导致CD40转基因小鼠中病毒清除加快。结论：我们的研究结果表明，肝脏CD40表达不会加速腺病毒的清除，反而会加剧肝损伤。这项研究揭示了肝脏CD40在腺病毒诱导的肝脏炎症中一种先前未知的有害作用。