Fas signaling implicated in development of psoriasis

September 1, 2006

Fas/Fas Ligand signaling, conventionally thought to be pro-apoptotic, can also send an activating signal that is an essential step in the development of psoriasis, according to results of a recent preclinical study by Amos Gilhar, M.D., of the Technion-Israel Institute of Technology, and associates.

Fas/Fas Ligand signaling, conventionally thought to be pro-apoptotic, can also send an activating signal that is an essential step in the development of psoriasis, according to results of a recent preclinical study by Amos Gilhar, M.D., of the Technion-Israel Institute of Technology, and associates.

"We found that lymphocyte induction of psoriasis is dependent upon the interaction of Fas Ligand (FasL) on activated lymphocytes and Fas (CD95) on keratinocytes," explains co-investigator Richard S. Kalish, M.D., Ph.D., of the State University of New York at Stony Brook, in an interview with Dermatology Times.

ALTERNATIVE PATHWAY

Previous studies have implicated TNF-alpha in the pathogenesis of psoriasis. This alternative pathway has been commonly observed in cells with high levels of anti-apoptotic mediators such as Bcl-xL, which is another hallmark of psoriasis.

"It was well-established that activated lymphocytes were capable of inducing psoriasis, though the mechanisms by which this happens were a black box," Dr. Kalish says.

Given the existence of the alternative Fas pathway and its association with events characteristic of psoriasis, Dr. Gilhar and colleagues hypothesized that Fas/FasL signaling by activated lymphocytes induces keratinocytes to produce inflammatory mediators, leading to the development of psoriasis.

ANIMAL MODEL

To investigate the association between Fas signaling and psoriasis, the study investigators first grafted noninvolved skin from nine patients with untreated psoriasis to beige-severe combined immunodeficiency (SCID) mice.

Eight weeks after engraftment, they induced psoriasis by injecting IL-2-activated autologous natural killer (NK) cells into the mice. The grafts were harvested and analyzed by histology and immunohistochemistry four weeks after the NK cell injections.

All grafts exhibited features consistent with psoriasis, including parakeratosis, hyperkeratosis, an absent granular layer, regular acanthosis (epidermal thickening), rete ridge elongation and increased dermal vascularization (Am J Pathol. 2006;168:170-175).

Treating the mice three and 10 days later with blocking antibodies directed against Fas or FasL prevented the development of the aforementioned psoriasis features. Injecting anti-Fas or anti-FasL monoclonal antibodies (mAbs) significantly reduced epidermal thickness of the grafts (P < .01). Anti-Fas also resulted in significantly reduced cell proliferation (P < .01).

IDENTIFICATION OF TARGET

To evaluate whether the anti-Fas treatment was acting on the epidermis or on the injected NK cells, the investigators pre-treated NK cells with anti-Fas for 30 minutes before washing and injecting the cells into the grafts.

The anti-Fas-treated NK cells were able to induce epidermal hyperplasia to the same extent as untreated NK cells, indicating that expression of Fas on the surface of epidermal cells, not NK cells, was the likely mechanism.

Epidermal cells from NK cell-treated grafts expressed inflammatory cytokines, including TNF-alpha and IL-15. However, expression of both mediators was substantially reduced by anti-Fas mAb injections (for TNF-alpha, P < .05). Expression of other immunological markers of psoriasis, including HLA-DR and ICAM-1 (P < .05 for both), was also inhibited by the introduction of anti-Fas into the graft. Anti-FasL mAb had less of an inhibitory effect compared with anti-Fas mAb.

Dr. Kalish adds that while there was no immediate therapeutic application for this finding, "This knowledge fills in an important blank in the pathogenesis of psoriasis which could potentially be exploited in the development of a therapy."

Disclosures: Drs. Gilhar and Kalish report no relevant financial disclosures.