肝炎：肝功能衰竭可归因于血液供应受损

StephenW

Hepatitis: Liver failure attributable to compromised blood supply

Technical University of Munich (TUM)
IMAGE

IMAGE: Percy Knolle, Professor for Molecular Immunology at TUM, investigates the cause of liver failure. view more

Credit: Andreas Heddergotte / Technical University of Munich

In severe cases, a viral hepatitis infection can result in liver failure. A team from the Technical University of Munich (TUM) has now discovered how this occurs: by immune cells attacking cells in the vascular system, which disrupts the organ's blood and nutrient supply. This is responsible for the overwhelming damage that causes the liver to fail. Using an animal model, the researchers were then able to identify an agent to prevent this lethal process.

An infection of the liver with viral hepatitis, such as the hepatitis B virus, can progress in very different ways: the liver inflammation (hepatitis) can heal again without any problems; become chronic and require lifelong medication; or take a fulminant - i.e. potentially fatal - course. In the latter case, the immune-mediated damage to the liver is so severe that the organ fails, leaving a liver transplant as the last remaining treatment option.

Hepatitis viruses target the liver cells, or hepatocytes. The immune system tries to bring the infection under control by attacking and destroying the infected liver cells with the help of certain immune cells, known as killer T-cells. It was previously assumed that this process was also responsible for the severe organ damage that accompanies acute hepatitis. Now, though, Dr. Dirk Wohlleber, Research Group Leader at TUM, and Percy Knolle, Professor of Molecular Immunology, have arrived at a completely different explanation. In collaboration with colleagues from the universities of Würzburg and Bonn (Germany), they discovered that this organ failure is not in fact caused by the death of liver cells, but by defects in the vascular (blood vessel) system.

Blood supply disrupted by immune cells

The liver is home to important cells called liver sinusoidal endothelial cells, or LSECs for short. These connect the cells of the liver to the vascular system and regulate the exchange of nutrients and oxygen with the blood. They also have the ability to present small fragments of viruses on their outer membrane, in a similar way to immune system cells. The researchers observed that the killer T-cells specifically detected these viral particles, mistaking the LSECs for infected liver cells and destroying them. To this end, they used proteins that integrate into the cell membrane of the target cell and form a pore. Known as perforins, these proteins perforate the membrane and destroy the cell.

"We observed that the elimination of LSECs by the immune cells has an enormous impact on the liver tissue. Blood flow within the liver is hugely disrupted, with large numbers of liver cells - even those not infected - dying as a result. This immune response has a much more dramatic effect than the attack on liver cells that are actually infected," Wohlleber explains. This discovery was made possible by a new mouse model specially developed by the researchers to replicate the fulminant course of viral hepatitis.

Perforin inhibitors as a therapeutic tool

"Only now that we have pinpointed the actual destructive mechanism in acute hepatitis can we consider new treatment strategies and specifically target this process," underscores Knolle. Using their mouse model, the researchers were able to show that a new active substance can prevent fulminant hepatitis. This is a perforin inhibitor, which stops the killer T-cells from forming pores and thus safeguards the LSECs from attack. This agent successfully protected the mice from developing fulminant hepatitis, since the LSECs remained intact, preserving the blood supply to the liver cells.

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Publication

M. Welz, S. Eickhoff, Z. Abdullah, J. Trebicka, K.H. Gartlan, J.A. Spicer, A.J. Demetris, H. Akhlaghi, M. Anton, K. Manske, D. Zehn, B. Nieswandt, C. Kurts, J.A. Trapani, P. Knolle, D. Wohlleber & W. Kastenmüller: Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis, Nature Communications, November 15, 2018, DOI: 10.1038/s41467-018-07213-x (open access) https://www.nature.com/articles/s41467-018-07213-x

StephenW

肝炎：肝功能衰竭可归因于血液供应受损

慕尼黑工业大学（TUM）
图片

图片：TUM的分子免疫学教授Percy Knolle研究了肝功能衰竭的原因。查看更多

图片来源：Andreas Heddergotte /慕尼黑工业大学

在严重的情况下，病毒性肝炎感染可导致肝功能衰竭。来自慕尼黑工业大学（TUM）的一个团队现在已经发现了这种情况：免疫细胞攻击血管系统中的细胞，破坏器官的血液和营养供应。这是造成肝脏衰竭的巨大损害的原因。使用动物模型，研究人员随后能够识别一种药物以防止这种致命过程。

病毒性肝炎（如乙型肝炎病毒）对肝脏的感染可以以非常不同的方式发展：肝脏炎症（肝炎）可以再次愈合而没有任何问题;变得慢性并需要终身服药;或采取暴发 - 即可能致命的 - 当然。在后一种情况下，免疫介导的对肝脏的损害是如此严重以至于器官失效，留下肝移植作为最后剩余的治疗选择。

肝炎病毒靶向肝细胞或肝细胞。免疫系统试图通过在某些免疫细胞（称为杀伤性T细胞）的帮助下攻击和破坏受感染的肝细胞来控制感染。之前认为这一过程也是伴随急性肝炎的严重器官损害的原因。然而，现在，TUM研究组组长Dirk Wohlleber博士和分子免疫学教授Percy Knolle得出了完全不同的解释。他们与来自维尔茨堡和波恩（德国）大学的同事合作，发现这种器官衰竭实际上并不是由肝细胞死亡引起的，而是由血管（血管）系统的缺陷引起的。

血液供应被免疫细胞破坏

肝脏是重要细胞的家园，称为肝窦内皮细胞，简称LSECs。它们将肝细胞连接到血管系统，并调节营养和氧气与血液的交换。它们还能够以与免疫系统细胞类似的方式在其外膜上呈现小片段病毒。研究人员观察到杀伤性T细胞特异性地检测到这些病毒颗粒，将LSEC误认为感染的肝细胞并将其破坏。为此，他们使用整合到靶细胞的细胞膜中并形成孔的蛋白质。这些蛋白质被称为穿孔素，穿透膜并破坏细胞。

“我们观察到免疫细胞对LSECs的消除对肝脏组织有巨大的影响。肝脏内的血液流动受到严重破坏，大量肝细胞 - 甚至那些未感染的肝细胞 - 因此死亡。这种免疫反应Wohlleber解释说：“对实际感染的肝细胞的攻击具有更为显着的效果。”这一发现是由研究人员专门开发的一种新型小鼠模型实现的，该模型用于复制病毒性肝炎的暴发过程。

穿孔素抑制剂作为治疗工具

“只有现在我们已经确定了急性肝炎的实际破坏机制，我们才能考虑新的治疗策略，并专门针对这一过程，”Knolle强调说。利用他们的小鼠模型，研究人员能够证明一种新的活性物质可以预防暴发性肝炎。这是一种穿孔素抑制剂，可阻止杀伤性T细胞形成毛孔，从而保护LSEC免受攻击。该药物成功地保护了小鼠免于发生暴发性肝炎，因为LSEC保持完整，保留了肝细胞的血液供应。

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出版物

M. Welz，S。Eickhoff，Z。Abdullah，J。Trebicka，K.H。 Gartlan，J.A。斯派塞，A.J。 Demetris，H。Akhlaghi，M。Anton，K。Manske，D。Zehn，B。Nieswandt，C。Kurts，J.A。 Trapani，P。Knolle，D。Wohlleber和W.Kastenmüller：Perforin抑制在暴发性病毒性肝炎期间免受致命的内皮损伤，Nature Communications，2018年11月15日，DOI：10.1038 / s41467-018-07213-x（开放获取）https ：//www.nature.com/articles/s41467-018-07213-x