by For nearly 140 years, the origin and behavior of an enigmatic cell type within lymph nodes, called a sharp-bodied macrophage, remained a mystery. Now, for the first time, scientists at the Garvan Institute for Medical Research have tracked the cell’s life cycle and function, with implications for our understanding of autoimmune disorders.
The autoimmune disease, which occurs when the immune system attacks the body, affects 5% of Australians and has a high chronic health burden worldwide, yet its causes are not well understood.
“In living organisms, death is happening all the time — and if you don’t clean up, the contents of dead cells can cause autoimmune diseases,” says lead author Professor Tri Phan, Head of the Intravital Microscopy and Gene Expression (IMAGE ) Laboratory and Co-Director of Precision Immunology Program at Garvan.
Macrophages in many parts of the body are responsible for removing foreign materials such as bacteria and viruses, but researchers have discovered that these body macrophages, found inside lymph nodes, specialize in cleaning up the immune system’s waste: the B cells that they multiply when you fight the infection.
During an immune response, a large number of B cells are generated within the lymph nodes and then tested for their ability to neutralize the infection. B cells that fail the test are destined to die, but on the way out, they can cause the body to attack itself. The contents of these cells — especially those in the central nucleus of the cell — are inflammatory and can inadvertently trigger some B cells to make antibodies against this waste, leading to autoimmunity. The removal of these wastes is therefore a critical housekeeping function.
The new research is published in the journal Cell.
Information about a tiny ecosystem
Scientists used state-of-the-art in vivo imaging techniques at the ACRF INCITe Center to observe how macrophages form inside lymph nodes and how they behave in real time. Their analysis shows that, unlike other cells of the immune system, the body’s macrophages do not hunt for their targets, but are spread out evenly and wait. When a dead or dying B cell approaches, the macrophage stretches and wraps around the target, pulling it in for engulfment.
“We know very little about macrophage ingestible bodies because it has not been possible until now, with next-generation two-photon microscopes, to get inside the microstructures inside an animal’s lymph nodes and watch the cells in action in real time. That’s why it took 140 years — since the body’s macrophages were first described in 1885 — to get to where we are now,” says Professor Phan.
“A lot of what we’re doing is like filming a David Attenborough documentary but on a microscopic scale — documenting the hidden lives of these rare cells ‘in the wild,’ to show how these cellular ecosystems work to keep us healthy,” said Abigail Grootveld. , a postdoctoral fellow at Garvan and co-first author of the study.
“This research is exciting because it helps us understand the causes of autoimmune conditions like lupus. Understanding why someone gets the disease in the first place, and why it keeps coming back, is an important step towards future treatments for these diseases,” says Wunna Kyaw . , a postdoctoral fellow at Garvan and co-first author of the study.
In systemic lupus, the immune system struggles to control the production of its fighter T cells and B cells. Their overactivity causes inflammation, autoantibodies and long-term damage throughout the body. This research suggests that body-eating macrophages, with their B cell cleanup function, could be responsible for setting the chain of events in motion if they fail.
So far, the study looked at what happens to macrophages in animal models of a healthy system. The researchers’ next step is to extend the experiment to an autoimmune model, to see if they can rescue the failing system and prevent autoimmunity at its root cause.
The research was carried out in collaboration with Associate Professor Oliver Bannard, Sir Henry Dale Fellow at the University of Oxford.
This research was supported by the Australian Cancer Research Foundation, the Ernest Heine Family Foundation and the National Health and Medical Research Council.
