People with coronary artery disease are vulnerable to getting shingles, a painful skin rash. But why this is so has been a mystery.
Now, Stanford University School of Medicine researchers have traced the connection to a defective immune cell's sweet tooth.
In a study to be published online June 12 in the Journal of Clinical Investigation, the researchers learned that a set of immune cells whose aberrantly large appetite for glucose predisposes people to this heart condition also disables the immune response to viral infections -- and does so using the same immune-response-derailing technique often employed by cancer cells.
Our increasing vulnerability to shingles as we age speaks to our immune system not being as capable as when we're younger, said Cornelia Weyand, MD, professor and chief of immunology and rheumatology. "But how this would be related to heart disease has been an open question, until now," she said.
Shingles' incidence increases exponentially after age 50. About half of all people who are 80 years old have experienced a shingles attack. It's a leftover from childhood infection by varicella zoster, the virus that causes chickenpox. Even after our immune system defeats the active infection when we're young, the virus lives on inside our nerve ganglions. In older or immune-compromised people, the long-dormant virus can reactivate, crawl along the nerve fiber and emerge at nerve endings as a painful skin rash that's exceedingly difficult to treat.
In about 20 percent of shingles cases, the excruciating pain persists long after the rash clears up, said Weyand, the study's senior author. The lead authors are postdoctoral scholar Ryu Watanabe, MD, PhD, and former postdoctoral scholar Tsuyoshi Shirai, MD, PhD, now at Tokohu University in Japan.
"Coronary artery disease patients' glucose-guzzling macrophages, it turns out, exert the same paralyzing effect on T cells that cancers cells do, in much the same way," Weyand said.
A heart attack is born
An earlier study by Weyand's group showed that macrophages -- immune cells essential to battling infections and repairing injured tissue -- in patients with coronary artery disease boast excessive amounts of molecules involved in the uptake of glucose, forcing accelerated metabolism of the sugar.
Macrophages are attracted to wound sites, including coronary artery vessels bearing tiny scars or tears wrought by, say, high blood pressure. Weyand's earlier study demonstrated that while macrophages dwelling in arterial plaque may have good intentions, if they're predisposed to glucose gluttony they can go off-task, become inappropriately inflammatory and exacerbate the problem. The inflammatory macrophages both accelerate plaque buildup in coronary arteries and render that plaque brittle. It's when a chunk of labile plaque breaks off, suddenly blocking blood flow, that a heart attack is born. Coronary artery disease accounts for half of all deaths in the United States.
Macrophages also initiate helpful immune responses. The term "macrophage" derives from the Greek words for "big eater." These cells routinely gnaw on any pathogen they encounter, displaying bits of the ingested microbe on their surface for inspection by other immune cells called T cells, which can spearhead a targeted assault on the pathogen.
But, the new study showed, glucose-addicted macrophages that abound in atherosclerotic lesions are beyond incompetent at spurring T cells' antiviral activity. These aberrant macrophages actively discourage it.
So do tumor cells. Cancer-cell surfaces frequently manifest abundant amounts of a surface molecule, PD-L1, whose corresponding receptor, PD1, appears on T cells. The binding of PD1 to PD-L1 sets off a biochemical cascade inside a T cell, short-circuiting the fury it would otherwise mount on contact. Recent medical progress in understanding and exploiting this "immune checkpoint" mechanism has revolutionized cancer therapy.
"Blocking PD1/PD-L1 interaction is the object of a whole new wave of cancer-therapeutic interventions," said Weyand. "Many hundreds of clinical trials of this approach, which unleashes cancer patients' immune response to their cancer cells and unlike chemotherapy is not toxic to other cells, are underway."
Experiments by Weyand and her colleagues drew on the knowledge that macrophages, too, express PD-L1 on their surfaces.
Immune response restored
The investigators obtained blood and tissue samples from 113 patients with coronary artery disease who had sustained at least one heart attack and from 109 demographically matched healthy control subjects. From participants' blood samples, the scientists extracted cells called monocytes that begin life in the bone marrow, circulate in blood and, on taking up residence in a tissue, mature into full-blown macrophages. The scientists induced this maturation in culture.
"Your T cells' ability to stave off shingles is a good proxy for your overall ability to fight off new pathogens, the re-emergence of old ones or cancer," said Weyand. T cells targeting varicella zoster get aroused on contact with macrophages displaying pieces of this virus on their surfaces. So, the researchers fed viral bits to monocyte-derived macrophages from either the patients or the control subjects, and then gauged reactions of T cells incubated in a dish with these cells. One-third as many T cells exposed to virus-displaying macrophages from the patients mounted a reaction compared with T cells exposed to macrophages from the age-matched control subjects.
Antibodies that interfere with the PD1/PD-L1 checkpoint happen to be easy for researchers to come by, because these antibodies are in wide use today as cancer treatments. Adding such antibodies to the mix substantially restored T cells' erstwhile-diminished responsiveness to the patients' shingles-virus-primed macrophages.
Disabling the ability of the patients' macrophages to metabolize sugar likewise restored their capacity to incite T cell action. In particular, a small-molecule compound called ML265, which is now in clinical cancer trials, largely reversed PD-L1 overexpression on the surface of patients' macrophages. ML265 works by maintaining the appropriate configuration of an enzyme involved in glucose metabolism. In the presence of too much glucose-breakdown activity, Weyand's lab has previously shown, this enzyme suffers a breakdown of its own, initiating the chain reaction that causes macrophages to start spewing out pro-inflammatory chemicals.
In the new study, the scientists demonstrated that the enzyme's glucose-induced malfunction also sets off a different complicated biochemical cascade involving overproduction of a substance called BMP4. This, in turn, raises PD-L1 expression on macrophages' surfaces.
Just what makes macrophages go crazy for sugar in the first place is still an open question, Weyand said. But, she noted, 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," she said. But the new findings of the current study could lead to earlier detection and treatment of coronary artery disease.
Other Stanford study co-authors are postdoctoral scholars Hong Namkoong, PhD, and Hui Zhang, MD; medical student Benedikt Schaefgen; Gerald Berry, MD, professor of pathology; Jennifer Tremmel, MD, assistant professor of cardiovascular medicine; John Giacomini, MD, professor of cardiovascular medicine at the Veterans Affairs Palo Alto Health Care System; and Jorg Goronzy, MD, professor of immunology and rheumatology.
Scientists from Vanderbilt University also helped carry out the study.
The study was funded by the National Institutes of Health (grants AR042547, AI08906, HL117913, HL129941, AI108891, AG045779 and BX 001669) and the Cahill Discovery Fund.
Stanford's Department of Medicine also supported the work.
The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://med.stanford.edu/school.html. The medical school is part of Stanford Medicine, which includes Stanford Health Care and Stanford Children's Health. For information about all three, please visit http://med.stanford.edu.
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Journal of Clinical Investigation