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Plasmacytoid dendritic cells (PDCs) are a subpopulation of dendritic cells that make up approximately 0.1% of all mononuclear cells in the blood and are distinguished by their ability to produce large amounts of type 1 interferon. These cells respond to viral and microbial nucleic acids but are not normally activated by self-DNA. Few if any of these cells are present in normal skin, but they have been found in the dermis and epidermis in cutaneous lupus erythematosus, contact dermatitis, lichen planus, varicella, and psoriasis (in which they appear to facilitate the development of autoimmune psoriatic T cells). Because PDCs don’t usually respond to self-DNA, the production of large amounts of interferon in psoriasis has been mysterious.
These authors found that psoriatic plaques contained large amounts of the antimicrobial peptide LL37 (CAMP); this component of the innate immune system was not abundant in healthy skin or in uninvolved psoriatic skin. In culture, LL37 formed a complex with self-DNA that allowed it to enter the endosomal compartment of the plasmacytoid dendritic cells. There, LL37 bound to the toll-like receptor 9 (TLR9), another component of the innate immune system. TLR9 activation, in turn, potently stimulated the production in these cells of interferon-α. This was a highly specific phenomenon: Antimicrobial peptides other than LL37 did not stimulate the production of type 1 interferons, nor was it possible to stimulate interferon-α by binding to TLR7 instead of TLR9.
Lande R et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 2007 Oct 4; 449:564.
Comment
Although we have learned a great deal about the role of the immune system in the pathogenesis of psoriasis, how and why this process becomes activated have yet to be determined. This study suggests that LL37 accumulation in the skin lesions is a key factor in the T-cell activation in psoriasis and that TLR9 participates in this process. Pharmacologic agents that remove or inhibit LL37 may thus make effective psoriasis treatments. Dermatologists already know the potential of toll-like receptors to modulate skin disease; for example, imiquimod — an effective treatment for condyloma acuminata, actinic keratoses, and superficial basal cell carcinomas — binds to two other toll-like receptors, TLR7 and TLR8. As the authors point out, the finding that TLR9 is associated with psoriasis may help to explain the Koebner phenomenon: When self-DNA is released from wounded cells, it forms a complex with LL37 that binds to TLR9, causing the release of interferon-α in plasmacytoid dendritic cells, which facilitates T-cell activation.