Protein that helps immune cells infiltrate MS brain ID’d in mice
Surprise finding in lab may lead to new ways to prevent inflammatory attacks
In a surprise discovery, researchers found that deleting a protein called integrin alpha-3 blocked harmful immune cells from accessing the brain — and prevented the onset of symptoms — in a mouse model of multiple sclerosis (MS).
Now, the researchers say that targeting this protein might be one way of preventing the inflammatory attacks that lead to neurological damage in MS.
“These findings demonstrate that integrin [alpha-3] is … an attractive therapeutic target for MS,” the scientists wrote.
Their study, “Integrin [alpha-3] promotes TH17 cell polarization and extravasation during autoimmune neuroinflammation,” was published in Science Immunology.
Investigating a gene and finding a different key mechanism
In MS, immune cells circulating in the bloodstream gain access to the central nervous system, or CNS, comprising the brain and spinal cord. Once they infiltrate the brain, they can launch inflammatory attacks that damage otherwise healthy tissues.
One of these infiltrating immune cells is known as T helper 17 cells — or simply, Th17 cells — which normally fight off harmful invaders such as bacteria. But in autoimmune diseases, they become wrongfully activated, mediating damaging attacks.
As such, therapeutic strategies to prevent Th17 cell migration into the CNS could be a promising treatment approach, according to researchers.
To specifically target this process, however, there is a need to better understand the factors that help these cells reach the brain.
While conducting research on another subject, scientists at Duke University, in North Carolina, determined that the protein integrin alpha-3 seems to be involved in this process in MS. They found that the protein was abundant on the Th17 cell surface in an MS mouse model.
“We were studying the role of another gene when we stumbled upon integrin [alpha-3] ,” Maria Ciofani, PhD, an associate professor at Duke and one of the study’s senior authors, said in a university news story.
When integrin alpha-3 was deleted in the mouse MS model, the development of MS-like symptoms in the mice was suppressed. Normally, these mice would progressively experience muscle weakness, and eventually, limb paralysis.
But without integrin alpha-3, “they were walking around like nothing happened,” according to Ciofani.
“When we looked carefully, we found that none of the Th17 cells were entering the central nervous system,” Ciofani said, adding that researchers took the “opportunity to look at the machinery that controls these cells.”
We found that when it’s missing, the Th17 cells don’t develop as effectively, and more importantly, they face difficulties entering the central nervous system. This means less damage.
The team found that the cells were not able to penetrate the blood brain barrier, a selective membrane that protects the CNS from potentially harmful molecules and invaders in circulation.
Through additional experiments, the scientists identified that integrin alpha-3 helps to stabilize the immune synapse — the site where Th17 cells interact with other immune cells that help activate them. Essentially, integrin alpha-3 enabled Th17 cells to grow and become more inflammatory.
“We found that when it’s missing, the Th17 cells don’t develop as effectively, and more importantly, they face difficulties entering the central nervous system. This means less damage,” Ciofani said.
Altogether, the results indicated that the harmful effects of Th17 cells in MS may rely on integrin alpha-3, making it a potential treatment target in MS, according to the researchers.
This approach will not be the first that aims to block immune cell infiltration as a way of treating MS.
The approved MS therapy Tysabri (natalizumab) works by blocking a protein called alpha 4 beta 1 integrin that’s found on the surface of certain T-cells, helping them cross the blood-brain barrier.
However, Tysabri has its side effects and is only available through a restricted access program in the U.S. due to an elevated risk of developing progressive multifocal leukoencephalopathy, a rare and serious brain infection. As such, new treatments targeting the blood-brain barrier crossing by T-cells are needed, the release stated.
The researchers noted that one issue with blocking integrin alpha-3 is the potential for an increased risk of infections, given the importance of Th17 cells in normal immune function.
“One concern about targeting integrin [alpha-3] is that these Th17 cells are vital for our body’s defense against infections,” Ciofani said.
“We’ve done preliminary tests to see if [suppressing] integrin [alpha-3] stops Th17 cells from performing their protective roles, and so far, it seems they can still do their jobs,” Ciofani added, however.
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