Garvan team links molecule to stress

Researchers at Sydney's Garvan Medical Research Institute may have provided an explanation for the dramatic breakdown of champion Australian marathon runner Lisa Martin-Ondieki at the Barcelona Olympics in 1992.

A strong medal prospect, Ondieki was overcome by severe pain midway through the race and could not continue, despite being in peak physical condition. Her gruelling training schedule in the weeks leading up to the Olympics included running the full marathon course a week before the event.

Team doctors could find no sign of a viral or bacterial infection; highly trained athletes are unusually vulnerable to infection. Ondieki initially believed supporters of another runner had 'spiked' her electrolyte drink formula.

But new findings by the Garvan Institute's Assoc Prof Fabienne Mackay and Assoc Prof Herbert Herzog point to another possibility -- Ondieki may have suffered a severe inflammatory attack, brought on by the extreme physical and psychological stress of competing in the Olympic marathon.

Mackay and Herzog have discovered a molecule that appears to mediate the interaction of the central nervous system and immune system: the long-sought mind-body link.

Their findings support long-held scientific suspicions that the hormone-like molecule neuropeptide Y (NPY), which is over-secreted by neurons in the brain in response to stress, can disrupt normal immune function.

In a paper in the December issue of the Journal of Experimental Medicine, Mackay and Herzog describe how extreme stress -- both physical and psychological -- can unbalance the immune system, increasing a person's susceptibility to viral and bacterial infections, and even and cancer.

In severely stressed individuals, NPY can induce a painful inflammatory attack on muscles and organs, even in the absence of infection.

Herzog said NPY is an ancient molecule with multiple functions that act upon different organs and tissues, through a diverse class of receptors called Y receptors.

Y receptors in the hypothalamus, the seat of basic drives like hunger, thirst and sex, regulate appetite and food intake; Y receptors in the peripheral nervous system regulate heartbeat and breathing rate -- which both increase in response to stress.

NPY is also a neuroendocrine regulator, ramping up release of the stress hormone corticosterone from the adrenal glands. It also acts as a vasoconstrictor during stress, elevating blood pressure by binding to Y receptors in artery walls.

Mackay said NPY has also been suspected of being an immunomodulator, because circulating immune-system cells in the blood are exposed to high levels of the peptide during stress.

The Garvan researchers have now confirmed NPY's role as an immunomodulator, by showing that antigen-presenting cells (APCs), dendritic cells and macrophages express an NPY receptor called Y1.

Mackay said high levels of circulating NPY in the bloodstream, augmented by NPY secreted by the immune system itself, down-regulate Th1effector T lymphocytes, reducing the immune system's ability to fight infection or pre-cancerous cells expressing abnormal proteins.

This finding may explain why high stress levels in people with stressful lifestyles, including elite athletes experiencing high levels of physical and psychological stress, are more vulnerable to common respiratory and other infections.

Mackay said that during extreme stress, NPY inactivation of Th1 cells may be in some situations accompanied by up-regulation of Th2 cells, resulting in an imbalance between them.

As a result, hyperactivated Th2 cells over-secrete inflammatory cytokines, causing an inflammatory response similar to that seen in the early phases of a viral infection: symptoms may include fever, headache, backache and muscle pain and stiffness.

Mackay said the NPY-mediated response is normally beneficial; it only becomes a negative when NPY is chronically elevated to very high levels in severely stressed individuals.

"I've been thinking about this for the last five years," Mackay said. "A lot of people are chronically exposed to really high stress levels -- it's just a reality of modern life.

"We've now shown how high levels of NPY made in the brain during stress can shut down the immune response, and make people sick."

Mackay and Herzog said that the genes that code for NPY and its various receptors are known to be polymorphic, but they have not yet determined whether some individuals are more susceptible to stress and infection -- or more resistant -- because they naturally express more or less NPY, or vary in the sensitivity of their Y receptors to NPY.

They believe it is possible that chronic, high levels of stress may condition the immune system in the longer term, leaving people more vulnerable to inflammatory, auto-immune disorders like rheumatoid arthritis, type 1 diabetes, lupus, multiple sclerosis and Crohn's disease -- inflammatory bowel disorder.

"Researchers have looked at the possible involvement of the Y1 receptor in schizophrenia and depression, but not for inflammatory disorders," Mackay said.

She said it may be possible to prevent NPY binding to Y1 receptors on antigen-presenting cells, using a monoclonal antibody. Because the therapy would be selective for the Y1 receptor, it would not cross the blood-brain barrier and disrupt NPY's normal role in the brain.

"It's not impossible," Mackay said. "Our research team has already shown that it is possible to selectively block transmembrane receptors similar to Y1 using monoclonal antibodies."