Mutation keeps cells from stopping immune overreactions

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Scientists have discovered that a mutation in the FOXP3 gene may keep regulatory T cells, also called Treg cells, from correctly performing their function within the immune system.

Treg cells are a special kind of white blood cells or lymphocytes that prevent other immune cells from attacking the body’s own tissues, as well as controlling immune responses against microbes and other non-pathogenic agents, such as pollen, dust, or benign food groups. This is an important “self-check” built into the immune system to prevent excessive reactions.

“This discovery gives us key insights on how Treg cells are born and how they can be regulated.”

The findings could have a major impact in our understanding and treatment of all autoimmune diseases and most chronic inflammatory diseases such as arthritis and Crohn’s disease, as well as broader conditions such as asthma, allergies, and cancer.

Researchers made this discovery by investigating a rare human mutation in a gene called FOXP3. Although the importance of the FOXP3 gene in the proper function of Treg cells has been well documented, its mechanisms were still not fully understood by scientists.

“We discovered that this mutation in the FOXP3 gene affects the Treg cell’s ability to dampen the immune response, which results in the immune system overreacting and causing inflammation,” explains Ciriaco Piccirillo, the study’s lead author and senior scientist in infectious diseases and immunity in the Global Health Program at the Research Institute of the McGill University Health Centre. “This discovery gives us key insights on how Treg cells are born and how they can be regulated.”

The team was able to make their discovery using only a few drops of blood from a five-week-old newborn boy who died in 2009 from a rare and often fatal inherited genetic immune disorder called IPEX.

In the past 40 years, fewer than 200 cases of IPEX have been identified worldwide. Over 60 different mutations of the FOXP3 gene are known to cause IPEX and believed to result in non-functional Treg cells.

“What was unique about this case of IPEX was that the patient’s Treg cells were fully functional apart from one crucial element: its ability to shut down the inflammatory response,” says Piccirillo.

‘Treg’ cells stop immune system meltdown

“Understanding this specific mutation has allowed us to shed light on how many milder forms of chronic inflammatory diseases or autoimmune diseases could be linked to alterations in FOXP3 functions,” adds first author Khalid Bin Dhuban, a postdoctoral fellow in Piccirillo’s laboratory.

Piccirillo and his colleagues have already developed a molecule that could restore the Treg cells’ ability to control the immune system for patients with the same rare mutation. The drug has been tested in animal models and the researchers are hopeful they can also develop similar drugs that will apply for other conditions where Treg cells are known to be slightly defective such as arthritis, type 1 diabetes, multiple sclerosis, and lupus.

“Currently, we have to shut down the whole immune system with aggressive suppressive therapies in various autoimmune and inflammatory diseases,” explains Piccirillo. “Our goal is to increase the activity of these Treg cells in certain settings, such as autoimmune diseases, but we want to turn it down in other settings, such as cancer. With this discovery, we are taking a big step in the right direction.”

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The findings appear in the journal Science Immunology. The Canadian Institutes of Health Research, Canada Research Chair Program, National Institutes of Health, and the Abramson Family Cancer Research Institute funded this study.

Source: McGill University