Glaucoma blinds millions of people a year, but little is known of its causes.

Exciting new findings, from the laboratory of Dr. Simon John at the Jackson Laboratory, pinpoint a specific biological process as a causative agent, and suggest that a single dose of radiation directed into the eye may protect that eye from glaucoma. For life. The research, just published in the Journal of Clinical Investigation, provides new clues to the causes of glaucoma and points to therapeutic strategies that could be used to protect people from some forms of the disease.

In 2005, scientists in Dr. Johns lab made a startling discovery. The group was in the midst of an experiment on mice that inherit glaucoma. They had exposed some of the mice to radiation, for the purpose of performing bone marrow transplants. Strikingly, the irradiated mice were fully protected from glaucoma. The protective treatment was 96% effective and lifelong. While it was apparent that radiation was the key factor, the scientists did not know how radiation exerted the protective effect, or even where the effect was exerted. The new work published by Dr. John, with Dr. Gareth Howell as lead author, answers these questions and more.

Glaucoma is a degenerative disease of the eye, in which the optic nerve is progressively destroyed, leading to blindness. The disease is complex and takes various forms. In the mice studied by Howell and colleagues, pressure inside the eye becomes abnormally high, causing damage to the optic nerve, a pattern that is typical of many forms of human glaucoma.

The new results show that a single dose of radiation protects the optic nerve from damage, even though the pressure inside the eye is still elevated. The scientists show that the protective effect of radiation occurs in the eye itself. Working with x-ray physicists, the group devised an apparatus that could direct an x-ray beam into one eye of a mouse. Remarkably, this treatment could confer protection from glaucoma in that one eye; the other eye, if it was not irradiated, displayed the typical disease progression.

But how does radiation do this? Howell and colleagues first examined changes in gene expression in the optic nerve during the early stages of disease in the glaucoma-prone mice. From this large dataset, which the researchers made freely available online, they discerned a telltale pattern: genes involved in inflammation and in a particular immune process called leukocyte transendothelial migration were altered in a way that makes inflammation less likely in radiation-treated eyes. The process involves the migration of immune cells from the blood into a tissue. In a series of experiments, the researchers showed that a particular type of immune cell enters the optic nerve early in glaucoma. These cells, called monocytes, specialize in early immune responses such as the engulfment of invaders or debris and the activation of subsequent events in the immune response to damage or infection. Monocytes can also act by secreting damaging molecules to kill pathogens, but the recent data strongly suggest that in glaucoma, these damaging molecules can damage healthy cells. A single radiation treatment almost completely blocks the migration of monocytes into the optic nerves of glaucoma-prone mice. Adding back one of these damaging molecules caused glaucoma-like changes in irradiated eyes. Howell and colleagues believe that infiltrating monocytes are the potential triggers of the destructive events that lead to glaucoma.

The new results implicate a specific immune process as a central cause of many glaucomas, and point to some possible interventions. Most promising is radiation itself, delivered to the eye alone. Might this work in humans, after all the necessary safety and efficacy tests are performed? It seems likely: it was recently discovered that high radiation was associated with significantly lower levels of glaucoma in atomic-bomb survivors in Japan. Howell and colleagues suspect that low-level radiation treatments can be designed and tested as protective actions against glaucoma, raising the possibility of a simple and effective means of preventing blindness in millions of people.