September 10, 2004

Gene that fights off bacteria helps maintain normal eyesight

The same gene functions in vision and immune system

Ann Arbor, MI -- Scientists have learned that a family of genes long known to be integral to the immune system also plays a role in vision, perhaps preventing certain blinding diseases. The gene, TLR4, enables the eye to clear old outer segments, a function that is essential for maintaining normal vision. The gene belongs to a group of toll-like receptors (TLRs), which dispose of bacteria and other foreign matter in cells throughout the body.

In the fluorescence image at right, the anti-TLR4 antibody surrounds the outer segments of the photoreceptor, shown in red.

According to Howard R. Petty, Ph.D., a biophysicist for the University of Michigan Kellogg Eye Center, the discovery will give scientists new ways of thinking about the chain of molecular events that lead to eye disease. Dr. Petty and his colleagues are the first to link TLR4 to the eye; his findings are reported in the August issue of the Journal of General Physiology.To maintain vision, the eye must continuously dispose of the aging or damaged outer segments of photoreceptor cells. This takes place in the layer of cells known as the retinal pigment epithelium. “The process is a little like recycling,” Dr. Petty explains. “As outer segments of photoreceptor cells become worn out, new outer segments are generated to replace them. If the eye cannot efficiently dispose of its worn out segments, a person will go blind.”

As scientists learn more about this gene, they may find new avenues for studying such diseases as retinitis pigmentosa (RP) and age-related macular degeneration (AMD), says Dr. Petty. In RP, the damaged outer segments accumulate in the eye tissue, resulting in near or total blindness. If further studies show that TLR4 is associated with RP, scientists can begin to look at genetic therapies based on enabling TLR4 to perform its cleansing function. Dr. Petty is already conducting research to learn more about TLR4 and how its proteins interact with other elements involved in clearing outer segments.

Other studies have shown that TLRs play a role in stimulating oxidants. When oxidants accumulate in eye tissue, they cause retina cells to die. The build-up most likely occurs in small incremental steps, and may be a factor in AMD.

Dr. Petty is fascinated by this “ancient” gene and its parallel roles in the eye and in the immune system. Scientists have known for years that TLRs participate in the immune system of Drosophila, or fruit fly.  “We are looking at one of the oldest genes to participate in immune defense,” says Dr. Petty. “Fruit flies do not have antibodies; these evolved much later. So with TLR we are talking about innate immunity.”

“Nature likes to economize,” observes the Kellogg scientist. “Maybe it’s not all that surprising that we have found a set of genes that are central to corresponding processes involving two different systems. The bottom line is that the TLR genes are there to get rid of things that don’t belong.”

The paper, Toll-Like Receptor 4 (TLR4) of Retinal Pigment Epithelial Cells Participates in Transmembrane Signaling in Response to Photoreceptor Outer Segments, is available on line at www.jgp.org

In addition to Dr. Petty, other authors from University of Michigan Department of Ophthalmology and Visual Sciences are: Andrei L. Kindzelskii, M.D., Ph.D., Victor M. Elner, M.D., Ph.D., Susan G. Elner, M.D., Dongli Yang, M.D., Ph.D. and Bret A. Hughes, Ph.D.

Contact: Betsy Nisbet, 734.647.5586, bsnisbet@umich.edu.