It's sometimes said that dermatologists do one of two things (though it's not dermatologists who say it): Faced with a skin disease that's too dry, they try to wet it; if the disease is too wet, they try to dry it. There's some wisdom in this general approach, says James G. Krueger, head of the Laboratory for Investigative Dermatology at Rockefeller University. But it also suggests the lack of sophisticated treatments for many skin conditions. "A hairdryer or a sponge doesn't make a very good therapeutic. We need to do better. We need to be more specific."
In experiments published this month in The Journal of Allergy and Clinical Immunology, Krueger and colleagues drilled down on the molecular nitty-gritty that distinguishes the two most common forms of inflammatory skin disease, atopic eczema and psoriasis. The researchers say that the ability to distinguish between the disorders' genetic and immunological signatures opens the door for more narrowly targeted therapies sorely needed by the millions of people afflicted worldwide.
A team of researchers led by Visiting Fellow Emma Guttman and Research Associate Mayte Suαrez-Fariρas used extensive genetic tests to detail the gene expression patterns in skin samples of both diseases and normal skin. They also dissected the activity that each of the diseases jump-starts in the immune system, defining the unique signaling molecules -- called cytokines -- that T cells produce in the face of each threat to direct the immune response. The scientists confirmed previously recognized immunological distinctions, but they found even more remarkable differences in the expression of genes that control the differentiation of skin cells, establishing a new paradigm for precisely classifying the diseases.
Atopic eczema is a disease that chronically inflames and irritates patches of skin, often causing "wet" lesions. It runs in families, is associated with respiratory allergies such as asthma and afflicts about 100 million people worldwide, up to 25 percent of some populations of children. Psoriasis, which is also chronic and usually produces red and scaly "dry" rashes, is even more prevalent, striking two to three percent of people around the world. The diseases generally do not respond to the same treatments, except for systemic immune suppression, which becomes dangerous if prolonged and is not approved by the Food and Drug Administration. Other existing treatments are inadequate, Guttman says.
Earlier genetic testing of eczema and psoriasis did not use enough samples to produce the statistical power needed to definitively establish how each disease differs from normal skin, the researchers say. Up to this point, scientists have focused in particular on a defect in one gene associated with some cases of eczema -- filaggrin.
Filaggrin, however, is only one of 150 to 200 genes that comprise the epidermal differentiation complex, which directs the formation of the skin's defensive barriers and cell growth more generally. The new research shows that the expression of many of these genes is suppressed in eczema, especially in those genes responsible for producing the hard, insoluble envelope surrounding skin cells. One gene, loricrin, is expressed at only two percent of its level in normal skin. Psoriasis, by contrast, generally increases the expression of many of these genes, the researchers found.
Until now, animal models have guided the development of new therapies for human skin disorders. However, it has been difficult to determine if a model simulates psoriasis, atopic eczema or some other inflammatory disorder. And so far, treatments that have shown promise in animals by and large have not translated to humans. The new research may be a game-changer. "What we've got is a means to critically evaluate the models of these diseases in animals in a way that wasn't possible before," says Krueger, who is also director of Rockefeller's Milstein Medical Research Program.
By detailing the gene expression profile of each disease and zeroing in on a key difference in how they operate at the molecular level, the research also suggests new possibilities -- narrow-acting immunosuppression drugs or treatments for the barrier around skin cells, for instance -- that might strike individual vulnerabilities in the diseases without harming the patients. "Atopic eczema is widely prevalent and understudied. We've begun a process that may take years to come to fruition, but this is where you start to look for better treatment targets," Krueger says. "You find the fundamental defects, and that's what we've done."
- Guttman-Yassky et al. Broad defects in epidermal cornification in atopic dermatitis identified through genomic analysis. The Journal of Allergy and Clinical Immunology, 2009; 124 (6): 1235 DOI: 10.1016/j.jaci.2009.09.031
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