Scientists in Italy have, for the first time, been able to watch how white blood cells use tiny tentacles to identify and kill liver cells in living animals infected with hepatitis B, leading to the hope of new therapies for fighting infection and possibly cancer.
Hepatitis B, a debilitating liver infection, affects around 300 million people around the world and kills 780 000 people each year. There is no specific treatment for acute hepatitis B, which is why it's so important to investigate.
The researchers were able to make a real-time video recording of the process after developing new imaging techniques, including extremely sensitive microscopes.
It revealed that the white blood cells, known as lymphocytes, seek and destroy diseased liver cells using microscopic protuberances to probe through natural holes in the walls of capillaries.
The tiny holes – about a 10 000th of a millimetre across – make the liver capillaries different to most others in the body.
When the white blood cell probing through the hole – or ‘fenestra’ – detects the antigen it is programmed to find, such as for hepatitis B, it goes on the attack, killing the infected cell.
Professor Luca Guidotti and Dr Matteo Iannacone, the EU's European Research Council grant recipients who co-led the research at the San Raffaele Scientific Institute in Milan, Italy, said it was a big surprise to see the lymphocyte doing these tasks from inside the capillary.
‘A surprising finding is that the lymphocyte doesn’t need to get out of the capillary to do all this,’ said Prof. Guidotti. ‘It just has to use its little protrusions.’
New imaging techniques, including multi-photon microscopes, are revealing how white blood cells protrude through holes in capillary walls. Video: Matteo Iannacone
Dr Iannacone said the researchers were also able to observe how the process is hampered by liver damage caused by chronic hepatitis B.
This damage, liver fibrosis, affects the capillary holes, which can become smaller or even blocked, interfering with the efforts of the white blood cells to detect and kill problem cells. That could help to explain why long-term hepatitis B can play a leading role in liver cancer.
‘It could be that this process of liver fibrosis interferes with antigen recognition, and impairs the immune surveillance that white blood cells perform with respect to infected cells or tumour cells,’ Dr Iannacone said.
A lot of earlier work on how white blood cells identify and attack targets was done in vitro, where groups of cells can be observed. But the lack of a living capillary wall made it impossible to reproduce the microcirculation shown to be so important in the process.
‘Lots of the findings we made were totally unexpected, achieved only because of the power of the technology.’
Professor Luca Guidotti, San Raffaele Scientific Institute, Milan, Italy
Observing the living vessel wall in real time showed for the first time the role in these immune mechanisms of blood platelets, which are usually involved in blood clotting.
Platelets streaming through the liver can briefly form tiny clumps on the wall of a capillary, and a passing lymphocyte in the bloodstream will stick to the clump, attach itself to the vessel wall and then ‘crawl’ very slowly back and forth, using its tentacles to probe for infected cells through the holes. The platelets then detach themselves and perhaps repeat the process downstream.
‘Lots of the findings we made were totally unexpected, achieved only because of the power of the technology,’ Prof. Guidotti said.
The 3D imaging methods developed by the researchers included multi-photon microscopes that are so sensitive that they have to be two floors below ground on a three-tonne table, which is suspended to avoid vibration.
‘Without this special setting, a truck driving even a kilometre away would cause too much vibration for the recording of this imaging,’ Prof. Guidotti said.
Further technology to help scientists look deeper into living processes is being supported by EU-funding, including that being developed by the CSRR project, coordinated by the Institute of Photonic Sciences, near Barcelona, Spain.
The CSRR researchers, funded by the EU's Marie Skłodowska-Curie actions, have been developing systems to match live-cell images with super-resolution nanoscopy images. The process, developed using real-time imaging of herpes virus infections, allows researchers to extract biologically significant information that they would not be able to get through more conventional imaging methods.
And EU support has also contributed to understanding the processes by which stem cells specialise in living organisms, becoming different types of cells such as skin, heart, blood or bone. The DIFFEBIMG project, coordinated by the University of Tel Aviv, Israel, has developed live imaging to observe these processes, which could have implications for transplant medicine.
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