Autoimmunity may be due to failure of debris-clearing macrophages

Tingible body macrophages in lymph nodes are tasked with cleanup

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by Lindsey Shapiro |

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A failure of tingible body macrophages (TBMs), a type of immune cell tasked with cleaning up its environment, might play a role in the development of autoimmune diseases like lupus, according to a recent study.

These cells have long been poorly understood due to technical challenges in identifying them and tracking their behavior. Using new and improved techniques, researchers found that TBMs are produced in lymph nodes, and work to clear other immune cells that are dying off.

Researchers think it’s possible that a failure in that process could underlie the onset of autoimmunity, which will be the focus of future studies.

“This research is exciting because it helps us to understand causes of autoimmune conditions like lupus,” Wunna Kyaw, a PhD student at the Garvan Institute of Medical Research, in Australia, and one of the study’s first authors, said in an institute press release. “Understanding why somebody gets the disease in the first place and why it keeps coming back, is an important step towards future treatments for these diseases.”

The study, “Apoptotic cell fragments locally activate tingible body macrophages in the germinal center,” was published in the journal Cell.

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Macrophages are immune cells that engulf and clear unneeded materials

Like other autoimmune diseases, lupus arises when the body’s immune system mistakenly attacks its own cells, but the mechanisms haven’t been fully worked out.

Macrophages are a type of immune cell that engulf and clear foreign materials, as well as the body’s own cellular waste that’s faulty or unneeded, helping to ensure that the immune system doesn’t become overactive and react against these waste products.

During an immune response, antibody-producing B-cells are created in large quantities within lymph nodes, in an area called a germinal center, where they are tested for their ability to properly fight off infection before being sent out.

If they fail or are faulty in any way — a common occurrence — they’re primed for cell death (apoptosis). A specialized type of macrophages, TBMs, are responsible for clearing out the waste generated from this cell death. If these rejected B-cells aren’t cleared properly, they can trigger autoimmune attacks.

“In living organisms, [cell] death happens all the time — and if you don’t clean up, the contents of the dead cells can trigger autoimmune diseases,” said Tri Phan, PhD, the study’s senior author. Phan is a conjoint professor at the University of New South Wales, senior research fellow, and co-lead of the precision immunology program at Garvan.

In animal models, mice lacking a protein important for signaling to TBMs (that they should engulf dead cells) produce self-reactive antibodies and enter in a lupus-like autoimmune state.

While it’s possible that faulty TBMs play a role in driving lupus and other autoimmune conditions, scientists know relatively little about these cells, which were first discovered about 140 years ago.

Since they’re hidden deep within lymph nodes, technological limitations didn’t previously allow researchers to track their behavior in real time.

In the study, researchers used a special type of microscopy that can track TBMs in live healthy mice, starting from their formation in the lymph nodes.

“A lot of what we do is like shooting a David Attenborough documentary but at a microscopic scale — capturing the hidden life of these rare cells ‘in the wild’, to show how these cellular ecosystems work to keep us healthy,” said Abigail Grootveld, a PhD student at Garvan and one of the study’s first authors.

Using that approach, the team found that macrophages are activated in the lymph nodes in response to local cell death, and mature into TBMs capable of clearing the debris.

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TBMs seem to be more passive than most immune cells

While most immune cells chase down their targets, TBMs seem to be more passive. Instead of moving around looking for dying cells, they sit throughout the lymph nodes, using processes, or specialized arm-like extensions, spreading from their surface to survey their environment.

Conversely, dead or dying B-cell fragments are mobile and move around lymph nodes. When they approach a stationary TBM, the macrophage pulls it in and ingests it.

Results show that this so-called “lazy” search strategy by TBMs is very efficient at capturing dying cell fragments.

A genetic analysis of the cells identified as TBMs reveal that they had increased activity of genes involved in clearing apoptotic cells.

These observations indicate that “apoptotic B cells … trigger activation and maturation of … macrophages into classical TBMs to clear apoptotic debris and prevent antibody-mediated autoimmune diseases,” the researchers wrote.

According to the team, an important next step is to understand how these cells behave in animal models of autoimmune diseases like lupus. Then, they can see whether the system can be rescued if it fails, preventing autoimmunity at its start.