LJI Scientists Discover Defect That Stops T Cells from Fighting MAC Bacteria

Then there are those rare people who get very, very sick.

MACs are ‘opportunistic’ pathogens, explains Dr. Cecilia Lindestam Arlehamn, research assistant professor at the La Jolla Institute for Immunology (LJI). Some people have risk factors, such as cystic fibrosis or structural lung disease, that make them more likely to develop symptoms after MAC exposure. No one knows exactly what difference it makes.

Lindestam Arlehamn’s lab has discovered immune cell defects associated with the risk of developing MAC disease.as her team reports The forefront of immunologyIndividuals who show symptoms of MAC infection have fewer specialized Th1* (Th1 “star”) cells, and thus lose the ability to mount an effective immune response against bacteria.

Lindestam Arlehamn, a colleague at the University of Washington who worked closely on the study, explains:

This study may be a step towards identifying biomarkers for predicting the risk of progressive lung disease and response to treatment in patients with MAC disease.

When T cells don’t fight back

In 2020, Lindestam Arlehamn received funding to investigate how T cells fight disease through the Tullie and Rickey Families SPARK Award. By analyzing her T cells from previously MAC-infected people, it was hoped that we could identify the major targets, or epitopes, that MAC-infected cells are susceptible to attack by the immune system.

T cells are normally important for fighting infection, but a study by Lindestam Arlehamn reveals that the human T cell response to MAC infection is very limited, revealing MAC-specific epitopes. I couldn’t.

Such limited T cell responses to pathogens are highly unusual. MAC-infected research volunteers seemed to have very little “immune memory” of being sick. highlighted unexpected cellular defects that can occur. “It was also very interesting,” he says Lindestam Arlehamn.

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Lindestam Arlehamn looked at global gene expression (which genes are “switched on”) in response to MAC infection and found significant differences in blood samples from previously MAC-infected people and healthy controls. I noticed that there is

People with MAC appeared to have an immunological defect in which they had a low number of special “helper” immune cells called Th1* cells in the body, which are normally the body’s pathogens. It helps warn cells of danger to fight against.

Lindestam Arlehamn and her colleagues were the first to show that Th1* cells are particularly important for fighting infections. mycobacteria Attack from MAC or Either Mycobacterium tuberculosis.

Their study is the first to suggest that this Th1* deficiency may lead to increased disease susceptibility. They think that without enough Th1* cells, it is likely that some key immune cells will never get the message that the MAC is about to invade. This is because MAC-susceptible individuals have an overactive innate immune response (specific cells trigger inflammation early in the disease process) and a poorly functioning adaptive immune response (activated T cells that actually stop the disease). lack of ).

For some people, this lack of immune defense can be intolerable. There is a possibility. Depletion of Th1* cells can hit double-hit, adding immune system dysfunction to already weak lung defenses. “That might explain it in part,” says Lindetham his Aareham.

Next steps to fight MAC

Lindestam Arlehamn now wants to see if there is a defect in humans that leads to a loss of Th1* cells before MAC exposure. She plans to look at samples taken from people early in the progression of the disease to see if the lack of Th1* is characteristic of them. We would like to study samples from people exposed to MAC sources of

“If you live with someone who has MAC disease, you may have it too,” she says. We would like to see if we can define specific her T-cell responses for these individuals, to see the difference between those who get sick and those who do not. ”

This study may help researchers understand exactly how MACs go from harmless to highly pathogenic.

This study was supported by the National Institutes of Health (grant R21 AI125777, NIH/NIAID K24 AI137310, P30 DK089507, UL1TR000423, S10 RR027366, S10 OD016262), the U.S. Food and Drug Administration (R01 FD006848), the Cystic Fibrosis Foundation, and the Tully Family. and the Ricky family received the SPARK Award for Innovation in Immunology at the La Jolla Institute of Immunology.