Outside-in. Genetic defects in skin cells, rather than immune factors, may trigger psoriasis.

Probing the Cause of Psoriasis

Is psoriasis a skin disease or an immune system disorder? The answer--key to developing an effective therapy--has remained elusive. Now genetic evidence indicates that psoriasis begins as a skin disorder that can also trigger an immune system response.

Psoriasis, a noncontagious, lifelong disease characterized by skin lesions, red patches, white blisters, and sometimes arthritic inflammation, afflicts about 4.5 million adults in the United States. Researchers have been of two minds about the cause. One theory argues that it progresses from a haywire immune system response, signaled by elevated T-cells found in psoriatic lesions. But the disease may also be a genetic skin disorder, a theory supported by observed mutations in skin cell DNA. That skin disorder may then trigger an immune system response.

To gain better insight, researchers led by molecular pathologist Erwin Wagner of the Research Institute of Molecular Pathology in Vienna, Austria, set out to induce human psoriasislike symptoms in mice. They found they could do this by inhibiting two genes: JunB and c-Jun, both known to regulate cell proliferation and mutations. This pointed strongly to a genetic trigger for the disease.

Then, to examine what role the immune system plays in psoriasis, the researchers inhibited T-cell response in the genetically deficient mice. They found that although the animals' arthritic inflammations and associated bone destruction largely disappeared, the skin lesions were still present, though milder. The researchers saw a similar response when they blocked another immune system trigger thought to be associated with the disease, TNF-alpha.

Overall, the findings suggest that psoriasis is fundamentally a skin disorder, though the immune system's T cells and TNF-alpha exacerbate the disease's inflammatory symptoms, the team reports 15 September in Nature. Though the study reinforces the idea that skin cells are more than passive "brick-and-mortar" walls shielding against disease, there is likely to be a complicated interplay of triggers between the immune system and mutated skin cells, notes immunologist Brian Nickoloff of Loyola University of Chicago Medical Center. However, he adds, the study makes an important clinical contribution by helping to identify new therapeutic targets.

Related sites
Erwin Wagner's site
Brian Nickoloff's site
National Psoriasis Foundation