NEWS: Unraveling mechanisms that trigger psoriasis

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Unraveling mechanisms that trigger psoriasis



Sep 19, 2005



Norra MacReady

Vienna, Austria - A new mouse model suggests that epidermal changes

alone can initiate both the skin and joint symptoms seen in psoriasis

and psoriatic arthritis, according to a report in the September 15,

2005 issue of Nature [1].

" The major clinical implication is that the primary lesions in

psoriasis occur in the epidermis, and the immune system reacts and

potentiates the effects, " senior author Dr Erwin F Wagner (Institute

of Molecular Pathology, Vienna, Austria) tells rheumawire. Based on

these findings, it might be possible to beef up the activity of anti-

TNF drugs by combining them with agents that specifically address the

skin disorder, Wagner adds.

" Outside-in " hypothesis

The findings shed new light on how psoriasis is triggered, comments a

Nature press release highlighting the paper. There have been two

opposing views, with one camp regarding psoriasis as an immune

disorder that affects the skin (the " inside-out " hypothesis), while

the other proposes that it is a skin disorder with immunological

repercussions (the " outside-in " hypothesis). Genetic evidence from

the study shows that the skin lesions develop independently of immune

cells, supporting the outside-in hypothesis.

Wagner and colleagues used a double-knockout mouse, with the genes

JunB and c-Jun deleted from epidermal cells. All of the animals with

this mutation develop histological and molecular hallmarks of

psoriasis and psoriatic arthritis that mimic the human disorders more

closely than previous mouse models, the researchers write.

To develop the model, they crossed mice carrying JunB and c-Jun

alleles with transgenic K5-Cre-ERT mice. They then treated the

offspring with tamoxifen for five days starting at eight weeks of

age, which produced deletions of JunB and c-Jun in the epidermis.

By two weeks after the last injection, all of these mice had

developed scaly plaques on their ears, paws, and tails that closely

resembled the characteristic lesions of human psoriasis. On

histological examination, the epidermis was thickened and had

prominent rete ridges, with hyperkeratosis and parakeratosis in the

upper layers. Subepidermal vascularization was increased.

The mice also developed arthritic lesions, with periostitis and

massive bone destruction, similar to the psoriatic arthritis seen in

humans.

In the new model, deletion of epidermal JunB and c-Jun was necessary

for both conditions, while TNF and T-cells were essential for the

development of joint but not skin symptoms.

The close resemblance between mouse and human skin lesions and the

downregulation of JunB proteins in affected, but not healthy, skin

were unexpected findings, Wagner tells rheumawire. He was also struck

by the speed and consistency with which the lesions appeared. Earlier

models did not have skin lesions completely approximating those of

human patients, he says, and they did not develop arthritis at all.

This contrasts with clinical findingsup to 40% of psoriasis

patients develop arthritis lesions.

" These results provide strong genetic evidence that the development

of the skin phenotype does not fully depend on T cells or TNF-

signaling through [tumor necrosis factor receptor 1] TNFR1, although

both are contributors to the disease development and severity, " the

investigators conclude. They also found genetic evidence for

psoriatic arthritis being primarily mediated by TNF signaling, data

that " strongly support " the recently approved TNF inhibitors as novel

therapeutics for psoriasis and psoriatic arthritis, they comment.

Heightened immune activity

The investigators also found evidence of heightened immune activity.

Along with the neutrophil-rich inflammatory infiltrate in the

epidermis typical of psoriasis, they noted an increased number of

macrophages in the dermis, microabscesses in the epidermis, and

intraepidermal T cells.

T cells abound in the affected skin of human patients, and the fact

that these individuals respond to immunosuppressive drugs supports

the idea that T cells somehow figure in the development of the

disease. However, whether they are a cause or a consequence is unclear.

To test the role of the T cell in the pathogenesis of psoriasis, they

induced deletions of JunB and c-Jun in Rag2-knockout mice, which lack

B and T cells. Those mice did develop psoriatic skin lesions, but the

lesions were milder than those in the mice with normal Rag2 activity,

suggesting that B and T cells make a minor contribution to the

development of skin symptoms in psoriasis.

The Rag2-deficient animals also had much milder joint inflammation

and no bone destruction, leading Wagner and his colleagues to

conclude that " a functional contribution of immune cells was a

prerequisite for the development of arthritic lesions. "

The mere presence of T cells in psoriatic skin does not necessarily

mean those cells are involved in its etiology, the authors write.

Drugs like cyclosporine A, which are thought to act specifically on T

cells, actually affect other cells as well, including neutrophils.

Cyclosporine A also inhibits keratinocyte proliferation, which could

help account for its salutary effects.

T cells also appear to be nonessential to the chemokine and cytokine

profile typical of psoriasis, as Rag2-deficient mice had a profile

similar to that of the JunB- and c-Jun-deficient mice, they write.

http://www.jointandbone.org/viewArticle.do?primaryKey=563955