People who have heart disease get shingles more often than others, and the reason has eluded scientists since they first discovered the link. A new study has found a connection, and it lies in a defective white cell with a sweet tooth.
Shingles is a reactivation of the same virus — varicella zoster — that causes chickenpox. It can recur in people who had the infection earlier in their lives, causing a painful skin rash that can last up to a month. One in 3 people in the US develop shingles in their lifetime. The virus lives in the nerves but is usually held back by the immune system, so tends to crop up when someone is stressed, or another infection weakens their immune system. If you haven't had chickenpox, you won't get shingles, but why heart disease patients are more prone to shingles has been a real mystery.
A study by senior author Cornelia Weyand, of the Stanford University School of Medicine, published June 12 in the Journal of Clinical Investigation reports on how a particular set of glucose-gobbling immune cells disables the immune response to viral infections.
Macrophages are scavengers of the immune system. They are attracted to microbes and to wound sites where they can meet and eat invaders to get rid of them. This same process happens in a diseased heart.
When the inner wall of an artery becomes damaged — like from high blood pressure — fats, calcium, and cholesterol in the blood can accumulate at the site of the damage. That accumulation triggers immune cells to come to the site, including macrophages. But, the well-intended inflammatory macrophages become part of the problem. They eat the cholesterol, develop into foam cells, and become plaque. The artery wall thickens and hardens; the blood vessel narrows and reduces blood flow. Parts of plaques can break off into the bloodstream. From there, they can travel to the heart where they plug cardiac vessels, stop blood flow and cause a heart attack.
An earlier study by Weyand found that some of the macrophages that come to the scene of an arterial wall injury may be defective. They can have a big appetite for glucose and function in ways that may create even more problems. Those macrophages no longer signal other white blood cells called T cells to do their job, kill viruses. They do the opposite, discouraging the activity. That happens because of a protein on their surface of the sugar-loving macrophages called PD-L1.
PD-L1 is a protein found on the surface of some cells, including cancer cells. On normal cells, PD-L1 helps to block T cells of the immune system from reacting to them, allowing them to live. It's called an "immune checkpoint" protein. Cancer cells display PD-L1 to circumvent the immune system from attacking them and live, so an immune therapy called checkpoint inhibitors — that inhibits PD-L1 — has sprung up.
The research team investigated whether PD-L1 on macrophages had something to do with the connection between heart disease and shingles by studying how they react to these checkpoint inhibitors.
The investigators got blood and tissue samples from 113 patients with coronary artery disease who had at least one heart attack. They also got samples from 109 healthy control subjects. From the blood samples, the team isolated immune cells called monocytes. These are the same cells that migrate to tissue when needed and become macrophages. The scientists turned the monocytes into macrophages in the lab.
Macrophages can turn the immune system on when they eat bacteria or viruses and display bits of the viruses on their surface. That provokes T cells to react. So, the researchers did that experiment in the lab. When they fed the macrophages herpes zoster virus and presented them to T cells, only one-third as many T cells from the cardiac patients became activated to fight the virus as T cells exposed to macrophages from the control subjects. The macrophages from the cardiac patients didn't get the T cells to respond to kill the virus.
When the researchers mixed checkpoint inhibitors in the experiment to inhibit PD-L1, the cardiac patients' macrophages were able to activate the T cells, showing that the lack of response to the shingles virus was due to PD-L1 on the macrophages. The researchers were also able to activity whey they disabled the ability of the patients' macrophages to metabolize sugar, demonstrating that it was the sugar-loving macrophages in the cardiac patients that used PD-L1 to inhibit T cells' reaction to the shingles virus.
Weyand isn't sure how the defect develops in the macrophages, but she noted that the defect shows up in monocytes before they take up residence in tissues and mature into macrophages.
"Finding out why this happens is the next frontier," said Weyand in a press release from Stanford University School of Medicine.
The authors are hopeful the new findings could lead to earlier detection and treatment of coronary artery disease. New treatments may also allow us to prevent some viral infections, like shingles, that cardiac patients get more frequently.
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