Nestle FO et al. (2005) Plasmacytoid predendritic cells initiate psoriasis through interferon-α production. J Exp Med 202: 135–143

Researchers have discovered a key innate immunity pathway for triggering psoriasis: interferon-α (IFN-α) derived from plasmacytoid predendritic cells (PDCs) activates and expands pathogenic T cells, causing development of skin lesions.

The investigators hypothesized that IFN-α produced by PDCs might contribute to the pathogenesis of psoriasis, supported by previous observations. To test this hypothesis, Nestle et al. first assessed the distribution of PDCs. They found that in normal controls there was no PDC accumulation in skin, but PDCs accumulated in plaque lesions, and surprisingly, in nearby uninvolved skin, in patients with psoriasis.

IFN-α mRNA levels in psoriatic lesions were the same as those in normal skin; however, psoriatic lesions showed increased expression of an IFN-α-inducible gene and a marker of IFN-α. This suggested that IFN-α had been produced earlier during the development of the psoriatic lesion, which was confirmed by tests in a mouse xenograft model of human psoriasis. To investigate the role of IFN-α in psoriasis, IFN-α and IFN-β signaling were blocked, resulting in complete inhibition of activation and expansion of pathogenic T cells. Immunostaining showed PDCs were the principal IFN-α-producing cell, and tests in mice showed PDC-derived IFN-α was necessary, and also sufficient, to drive psoriasis in prepsoriatic skin.

It was concluded that new strategies targeting PDCs and PDC-derived IFN-α should be considered for prevention and early therapeutic intervention in psoriasis.