Abnormal Immune Response May Cause Glaucoma

[Guest guest]

Abnormal Immune Response May Play Major Role in Glaucoma, Study Says

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, 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 of the Laboratories in Maine, who also was able to

identify two mutant genes connected with the disease. " Although we knew the

genes, because of Dr. '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.

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. 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. , S. , and

of Laboratories, and Drs. Jun Song Mo, Bruce R.

Ksander, and Meredith of Schepens Eye Research institute.