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Connexin 26 overproduction prompts 'feedback loop'


The impaired epidermal barrier itself can trigger the inflammation process, allowing allergens and chemicals to get through and set off the immune response.

Bethesda, Md. - Therapies for psoriasis and eczema typically focus on the suppression of hyperactive immune system responses, which are blamed for causing the skin erosion of the diseases, but new research indicates that a reversal of roles may also be at play.

In fact, the impaired epidermal barrier itself can trigger the inflammation process, allowing allergens and chemicals to get through and set off the immune response, which in turn causes even more skin barrier erosion, and a nasty cycle of erosion and inflammation occurs, according to the research from the National Human Genome Research Institute (NHGRI).

The culprit in the initial skin barrier erosion has been narrowed to a specific gap junction protein - connexin 26 (Cx26), which forms connections between skin cells to heal wounds, according to the findings, published in the May issue of The Journal of Clinical Investigation.

Under normal conditions, Cx26 typically upregulates when there is a wound, opening channels to engage communication between layers of cells that run deep and generate the healing process.

Once the keratinocytes in the skin are re-epithelialized, the protein then downregulates, according to the researchers.

With Cx26 already shown to be overproduced in psoriatic plaque, the researchers developed a line of transgenic mice designed to overproduce the protein in order to further investigate the protein's role in psoriasis. Significantly, the researchers found that the mice developed psoriatic-type skin sores precisely like those seen on humans with psoriasis. (J. Clin. Invest., doi: 10.1172/JCI27186)

"We kept the expression of the Cx26 channels open and it turned out the skin still believed it was in the wound healing and not a wound remodeling state," says Julia A. Segre, Ph.D., an investigator in the NHGRI's genetics and molecular biology branch and senior author of the paper.

"It never reestablished the epidermal barrier or remodeled to look like normal skin. It just stayed in that hyperactive state and started to look like psoriasis," she says.

The overproduction of Cx26 in humans may work the same way - compromising the epidermal barrier and causing a hyperproliferative state in the immune system, which blasts the epidermal barrier with a too-rapid influx of skin cells.

No 'chicken or egg' smoking gun

While the research offers an intriguing insight into the role of the impaired epidermal barrier in psoriasis, Dr. Segre stops short of suggesting that an impaired barrier could be the exclusive causative action in the disease.

"This isn't so much a 'chicken or the egg' situation as it is what I would call a feedback loop," she explains. "The immune cells have an effect on the keratinocytes, and vice versa, but the two things may not be exclusive.

"With these animal models, we may not get at the initiating event, but what we're trying to find out is what the pathways are that we could most easily target to medically manage this disorder," she says.

The findings suggest that a potential management approach could be to simply develop a temporary artificial barrier for the skin to block incoming allergens, hence preventing the inflammatory response and breaking the cycle.

A lotion, for instance, that provided an epidermal barrier could keep the immune system at bay while the skin had enough time to restore a normal barrier.

But Dr. Segre says there is a big reason why psoriasis has been such a tough disease to manage: Any attempted treatments are taking on the Goliath of evolution, with the body's response to an impaired skin barrier representing influences that were encoded in our genomes thousands of years ago.

"Before antibiotics, an impaired epidermal barrier really was a serious risk, and many of our defenses to that were programmed well before the medical advances we have," Dr. Segre says.

"Even though medical treatments have progressed tremendously in the past 100 years, our genomes can't evolve at that rapid of a rate."

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