By David N. Leff
Nobody dies of psoriasis.
The unsightly, acutely discomfiting skin disease affects 1 percent to 2 percent of the U.S. population - 5.5 million suffering Americans. "I think it's a very emotionally debilitating kind of disease," observed cell biologist and physiologist Yasmin Chandrasekher at ZymoGenetics Inc. in Seattle.
"It certainly has severe effects on people's lives," she continued, "including a lot of pain, itching, motion in joints and so on. But I don't think you'd consider it life-threatening. However," Chandrasekher added, "I think dermatologists who see psoriasis patients will insist that it is not a disease to be taken trivially, because it has a big life impact - affecting how you look - besides all the pain and discomfort that goes with it."
The thick layering of silvery, metallic, iridescent scales topping psoriatic plaques is generally ascribed to increased proliferation of epidermal cells, accompanied by inflammation. Psoriasis is no respecter of skin areas. It's common on the scalp and over joints, especially knees and elbows. But it also turns up on the sacrum - the broad, flat base of the back - as well as buttocks, penis, underarms, fingernails and toenails and navel.
Psoriatic arthritis, which strikes 5 percent of people with the disease, is a more devastating variant pathology. It can cripple any of the synovial joints, and involve tendon and ligament attachment to bone, as well as deforming the spine.
Chandrasekher is senior author of a paper in the current issue of Cell, dated Jan. 12, 2001. Its title: "Interleukin 20: Discovery, receptor, identification and role in epidermal function." Molecular biologist Hal Blumberg is its first author.
"We identified the novel cytokine, interleukin-20, on chromosome 1's long arm," Chandrasekher told BioWorld Today, "and were able to find and identify its receptor. This is a heterodimer, consisting of two dissimilar subunits - IL-20R-alpha and beta. Beyond that we have taken it further and have gotten some insights into the biology, specifically in this case showing that transgenic mice that overexpress IL-20 had shiny, wrinkled skin strikingly similar to human psoriasis. When we looked for IL-20 receptor expression in normal human tissue, the levels of both receptor subunits were extremely low or undetectable, but in human psoriatic skin samples from seven patients they were considerably elevated."
Jury Still Out On IL-20 Culpability - If Any
"This," added Blumberg, "is something that points our IL-20 in the direction of skin and psoriasis. I think what's interesting is that it gives us an example of a new cytokine and cytokine receptor system, which seems to be modulated in the skin. There's a clear enthusiasm that it may be playing some role in psoriasis," he cautioned, "but it's too early yet to draw any firm conclusions in that direction."
At the University of Washington, co-authors of the Cell paper provided the ZymoGenetics team with normal and psoriatic fresh, snap-frozen human tissue samples, clinically annotated by stage of disease and part of the body. These were full-thickness punch biopsies 2 to 3 millimeters in diameter by 3 to 4 mm deep in the epidermis and dermis. The co-authors compared these samples with transgenic mice they had engineered to overexpress the two IL-20 receptor subunits. They found upregulation of those subunits in a variety of human psoriatic tissues, but not in normal skin.
Little is known about the etiology of psoriasis. It's believed to be a T-cell-mediated disease, involving multiple genes, which confer on it a familial risk factor.
The ZymoGenetics group, Chandrasekher said, is "currently interested in using an antagonist drug, and doing some animal studies in SCID mice with xenotransplants of human psoriatic skin, to evaluate further whether this would be a useful way of antagonizing the pathogenesis of the disease. In these models," she said, "we would transplant involved psoriatic skin compared to normal skin, and then treat with the antagonist. The analysis is done looking for a clearing of the psoriatic features, at the visual level and by histology, looking for markers for the keratinocytes [cells of the living epidermis] and immune cells.
"We're looking at agonists of soluble receptors, and at neutralizing antibodies," Chandrasekher recounted. "I think it would be fair to say that there are a variety of ways we could go about it. There isn't just one particular mode that we're going to go forward with."
Psoriatic Skin Flunks Barrier Test
Biochemist Beverley Dale is a co-author on the university team cooperating with the company. "My lab," she told BioWorld Today, "focuses on epidermal differentiation, and on proteins involved in the skin's barrier function. My role in the psoriasis work was looking at how the mice overexpressed IL-20, and how their skin differentiation changed.
"On normal skin," Dale explained, "we humans have a tough surface. It's tough because of the proteins that are in those cells, and the way they interact with each other. Some of that toughness," she went on, "makes our skin do what it's supposed to do - allow it to resist mechanical abrasion, and keep our bodies from losing water. So the outside surface of healthy human skin has a wonderful barrier function.
"In psoriasis," Dale pointed out, "that barrier is not as good. The psoriatic plaque and the scales build up, but it doesn't function like the normal surface of the skin. So in psoriasis there's not a good barrier to water loss, for instance, or mechanical abrasion. It's not a normal surface, but a much more delicate one that doesn't function as a barrier."
As for her insight into the application of ZymoGenetics' IL-20 finding in clinical practice, Dale observed, "They are very interested in trying to develop a drug that would react with - or prevent, interfere with - the action of the IL-20 receptors. With the idea," she pointed out, "that these receptors are so overexpressed, there's way too much of them in psoriasis. The idea is that they must be contributing to the disease, although we still don't know how.
"So if their function could be blocked by some kind of inhibitory substance, that could be very beneficial. This is a paradigm," Dale observed, "a way of looking, because so much of biology, and so much of the way the tissues work, depend on receptor-ligand interaction. So there are a number of cases," Dale concluded, "in which it's a very effective medical treatment to interfere with that interaction - which would help in disease."