Boston, Mass. – Scientists at Schepens Eye Research Institute have found that an inflammatory immune response, which is suppressed in the normal eye, may be an early, perhaps the first, step in the onset of a kind of glaucoma known as pigment dispersion glaucoma. They also found that replacing the inflammation-causing immune cells in the bone marrow with normal donor cells restored the eye’s “immune privileged state, inhibited inflammation in the eye, and ultimately prevented the glaucoma.
These findings, published in the current issue of the Journal of Experimental Medicine (May 19, 2003), are the first evidence of a direct link between abnormal inflammatory immune responses and any type of glaucoma, and may ultimately point to novel treatments for this and other types of glaucoma.
“This is just the tip of the iceberg”, says J. Wayne Streilein, MD, senior scientist at Schepens Eye Research Institute and senior author of the study. “We have long suspected that an inappropriate immune response or loss of “immune privilege” in the eye may be a precursor or the first trigger that sets certain blinding eye diseases on their inevitable course of destruction. This is the first formal evidence to support this theory”.
According to Streilein, the team chose to study this particular type of glaucoma because there was a mouse model available. A strain of mice with pigment dispersion glaucoma had been discovered five years ago by Dr. Simon John of the Jackson Laboratories in Maine, who also was able to identify two mutant genes connected with the disease. “Although we knew the genes, because of Dr. John’s seminal work, we still did not know the chain of events they caused,” said Streilein. “So we decided to explore whether these mice, whose progression toward pigment dispersion glaucoma was similar (although more rapid and intense) to that in humans, had abnormal immune responses in their eyes”, says Streilein.
Glaucoma is the second leading cause of blinding eye disease in the United States affecting well over 1 million Americans. There are a number of different types of glaucoma, in addition to pigment dispersion glaucoma, but all eventually cause the destruction of the optic nerve, blindness, and loss of quality of life for those afflicted.
Pigment dispersion glaucoma affects one to two percent of all glaucoma sufferers in the US. In the model mice, as in human sufferers of the disease, the iris, the dark tissue surrounding the pupil, begins to shed its black pigment (melanin) into the front part of the eye. This event is followed by increasing pressure within the eye, which eventually strangles the optic nerve and kills the retinal cells attached to it, causing blindness.
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The eye’s normal state (in mice and humans) is immune privileged, which means that the eye can protect itself from foreign invaders such as bacteria or transplanted tissue without permitting inflammatory immune responses typical of those that occur in most other parts of the body. This ability evolved because the eye is too delicate to withstand the inflammation caused by conventional immune responses. Conventional immunity can permanently damage tissues, and in organs such as the eye where damaged cells are not able to replenish themselves, immune injury causes permanent damage, even loss of vision. The immune privileged state in the eye is promoted by a number of factors (immunosuppressive molecules, blood:/eye barriers) that inhibit immune cells with the greatest potential to cause permanent damage.
In the study reported in JEM, Streilein, the study’s first author Dr. Jun Song Mo, a Schepens Eye Research Institute investigator, and their team, in collaboration with Dr. John and his team, examined the eyes of some of the model mice before the visible onset of the disease (when the iris begins to shed pigment) to determine if the eyes were actively suppressing the activation of T-Cells (white blood cells that cause inflammation.) Although normal eyes successfully suppress these T cells, Streilein and his collaborators found that the eyes of the model mice failed in this regard. And this failure preceded clinical evidence of pigment dispersion. Moreover, the diseased eyes contained bone-marrow-derived white blood cells that were programmed to cause inflammatory responses. It is relevant that one of the two genes known to be responsible for pigment dispersion glaucoma in mice is active in these same white blood cells. The team concluded, therefore, that the eyes of the genetically predisposed mice lost immune privilege before the pigment dispersion began.
“What this suggested to us”, says Streilein, “is that maybe the first thing that the genes for pigment dispersion glaucoma do is break down immune privilege and leave the eyes vulnerable to inflammation”.
The team then tested their theory further by replacing the bone marrow of mice destined to develop pigment dispersion glaucoma with bone marrow from normal mice. They found that following this procedure, the immune privileged status was maintained in the eyes, inflammation never developed, and pigment dispersion failed to occur. The mice are now being followed to determine if they are also “cured” of developing high pressure in the eyes and glaucoma.
“These results are very exciting and encouraging. We feel that this is a major breakthrough in understanding how this disease is triggered and may be cured”, says Streilein. “We are eager to understand more completely the interrelationship between loss of immune privilege and development of glaucoma. Moreover, we are also interested to know whether a similar immune dependency might occur in other blinding eye diseases, such as macular degeneration and retinitis pigmentosa.
The research team includes Drs. Simon W. M. John, Richard S. Smith, and Michael Anderson of Jackson Laboratories, and Drs. Jun Song Mo, Bruce R. Ksander, and Meredith Gregory of Schepens Eye Research institute.
The study titled “By Altering Ocular Immune Privilege, Bone Marrow-derived Cells Pathogenically Contribute to DBA/2J Pigmentary Glaucoma” (JEM, Volume 197, Number 10, May 19, 2003, Page 1335-1344) can be found on the JEM website at http://www.jem.org. The article can also be obtained by contacting email@example.com.
Founded in 1950 and based in Boston, the Schepens Eye Research Institute is an affiliate of Harvard Medical School and the largest independent eye research institute in the world.