Deeper understanding of dry eye surfaces

Various reports in the literature highlight inflammatory changes that can occur on the surface of the eye in the patient with dry eye. They are increased expression of immune activation markers (HLA Class II antigens, ICAM-1) by the conjunctival epithelium; conjunctival T cell infiltration; increased levels of inflammatory cytokines in the tears and conjunctiva; and increased concentration/activity of tear proteases (elastase, plasmin, and matrix metalloproteinases), explained Dr. Pflugfelder, the James and Margaret Elkins Chair and professor of ophthalmology, and director of the Ocular Surface Center, department of ophthalmology, Baylor College of Medicine, Houston.

"In experimental models of dry eye, all of these inflammatory changes would manifest in 5 to 12 days," Dr. Pflugfelder noted. "But in humans, it is a more heterogeneous population at different stages of disease, so detection of these markers is going to be variable."

Ocular surface epithelial disease occurs after stress signaling pathways are activated. This can lead to the production of cytokines and chemokines, "skin-like" cornified envelope proteins, and metalloproteinases that lyse attachments between epithelial cells, Dr. Pflugfelder said.

Investigators have discovered that both chemokines and cytokines can change the immune environment on the surface of the eye. When epithelial cells are dry or become traumatized from dry eye disease, proteins called chemokines are produced. These chemokines then recruit white blood cells from the vessels in the conjunctiva.

In addition, cytokines produced by the epithelial cells are activated and permeate the conjunctival blood vessels, causing the endothelial cells to become sticky. As the white blood cells travel through the blood vessels, they tend to stick to the wall and finally egress in response to the chemokines, he said.

"It is well known that patients with dry eye are more predisposed to developing sterile corneal infiltrates," Dr. Pflugfelder said. "So this may be one of the mechanisms by which the white blood cells are recruited into the corneal tissue."

In chronic dry eye, "skin-like" cornified envelope proteins are produced by the stressed ocular surface epithelial cells, changing the ocular surface from a well-lubricated state to one that resembles dry skin, he said. Under normal conditions, the ocular surface epithelia produce low levels of these cornified envelope proteins that are not closely linked together. But in the case of persistent dry eye, ocular surface cells produce much higher levels of these proteins that cross-link, forming a surface resembling skin.

"In the most severe dry eye, such as Stevens-Johnson syndrome, the ocular surface actually looks like skin and the person is usually rendered blind when it reaches that stage," Dr. Pflugfelder explained. "It has been found that certain inflammatory mediators can drive that process."

Matrix metalloproteinases also play a role in ocular surface inflammation as well as ulceration of the eye. In normal eyes, corneal epithelial cells produced by the stem cells at the limbus travel slowly toward the central cornea and then some are sloughed off. This process occurs in part by the help of these proteases, which break the attachments between the cells, he said.

"When there are more proteases, the cells loosen and detach more readily, causing a sloughing of the corneal surface-a hallmark of dry eye," Dr. Pflugfelder noted. "Production of these proteases is stimulated in large part by inflammatory mediators such as certain inflammatory cytokines."