Researchers revealed the B cell mechanism of autoimmunity triggered by the clearance of susceptible macrophages in lymph nodes

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The origin and behavior of a mysterious cell type within lymph nodes, so-called “tingible body macrophages”, has been a mystery for nearly 140 years. Now, in a new study, researchers from Australia’s Garvan Institute for Medical Research have for the first time tracked the life cycle and function of this cell, which has implications for our understanding of autoimmune diseases. The relevant research results were published online in the journal Cell on March 2, 2023, with the title “Apoptotic cell fragments locally activate tingible body macrophages in the germinal center”.

Autoimmune diseases, which occur when the immune system attacks the body, affect 5 percent of Australians and have a high chronic health burden globally, but the causes are not well understood. Professor Tri Phan, co-corresponding author of the paper and head of the Intravital Microscopy and Gene Expression Laboratory at the Garvan Institute of Medical Research, said, “In organisms, death occurs all the time, and if it is not cleaned up, the contents of dead cells can trigger autoimmune diseases.”

Macrophages in many parts of the body are responsible for clearing foreign material such as bacteria and viruses, but the authors found that these infectious macrophages, found in lymph nodes, specialize in cleaning up the immune system’s own waste: proliferating when the body fights infection of B cells.

During an immune response, large numbers of B cells are produced within the lymph nodes and then tested for their ability to neutralize infection. B cells that fail the test are doomed to die, but in the process of disappearing they trigger the body to attack themselves. The contents of these cells — specifically those in the nucleus — are inflammatory and can inadvertently activate some B cells, causing them to produce antibodies against the waste product in themselves, leading to autoimmunity. Therefore, the removal of these wastes is a critical housekeeping function.

New insights into a microscopic ecosystem

These authors used state-of-the-art intravital imaging at the ACRF INCITe Center to observe how susceptible macrophages form within lymph nodes and how they behave in real-time. Their analysis showed that, unlike other immune cells, susceptible macrophages did not chase their targets, but spread out evenly, waiting for opportunities. When a dead or dying B cell approaches, susceptible macrophages reach out, wrap around the target cell, pull it inside, and engulf it.

Prof. Phan said, “We know very little about chromatin-susceptible macrophages because it has not been possible to pinpoint the microstructure inside the lymph nodes of living animals until now with next-generation two-photon microscopy to observe the actions of these cells in real-time. This is why It took us 140 years — starting with the first description of chromosomal macrophages in 1885 — to get to where we are now.”

Abigail Grootveld, co-first author of the paper and a doctoral student at the Garvan Institute for Medical Research, said, “A lot of what we do is like filming David Attenborough’s documentary, but only under the microscope — capturing the uniqueness of these rare cells ‘in the wild’ to show how these cellular ecosystems work to keep us healthy.”

This research is exciting because it helps us understand what causes autoimmune diseases like lupus. Understanding why someone gets the disease in the first place and why it continuously relapse is an important step in the future of treating these diseases.

Abigail Grootveld

In systemic lupus, the immune system struggles to control its production of T cells and B cells. Their overactivity leads to inflammation, autoantibodies, and long-term damage within the body. The new study shows that susceptible body macrophages, which have a cleanup function of B cells, may trigger a cascade of health-threatening events if they become dysfunctional.

So far, the new study explored what happens to susceptible macrophages in animal models with healthy immune systems. The next step for these authors is to expand their experiments to models of autoimmunity to see if they can rescue a dysfunctional immune system and prevent autoimmunity at its source.

Abigail K. Grootveld et al. Apoptotic cell fragments locally activate tingible body macrophages in the germinal center. Cell, 2023, doi:10.1016/j.cell.2023.02.004.

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