Findings from multiple types of studies point to IL-23 as a master cytokine in the pathogenesis of psoriasis.
Speaking at MauiDerm '09, Dr. Blauvelt reviewed data from immunologic, genetic, and preclinical and clinical therapeutic studies supporting the concept that psoriasis is a Th17-dependent disease in which IL-23 acts as a master cytokine.
"Much of this story has yet to be unraveled, but it is important for dermatologists to be knowledgeable about the basic science because new biologics acting as anti-IL-12/IL-23 agents will soon be in our hands," Dr. Blauvelt says.
"The idea that IL-23 may be a master cytokine is very exciting, considering that about 1,400 genes have been identified so far as being upregulated in psoriasis.
"Sorting through all of those alterations to identify potential therapeutic targets presents a complex challenge that could be circumvented by identifying the initiator," says Dr. Blauvelt, who is also chief, dermatology service, VA Medical Center, Portland, Ore.
Histologic studies showing that there is an overabundance of the IL-23-producing dendritic cells in the dermis of psoriatic skin represents one line of evidence of the importance of IL-23.
In addition, there has been substantial research showing that the cytokines produced by the Th17 cells induce the keratinocyte pathology that is characteristic of psoriasis.
"In contrast to early concepts on the pathogenesis of psoriasis, current evidence indicates that the keratinocytes are not the primary pathologic cell, but rather, an endpoint manifestation of upstream immunologic dysregulation," Dr. Blauvelt says.
The fact that IL-23 and IL-12 (the main cytokine driving Th1 proliferation) share a common subunit, p40, has complicated delineation of the roles of these two cytokines in psoriasis pathogenesis.
However, the picture has been clarified by looking at unique cytokine subunits, and these studies have shown that psoriatic plaques contain very high levels of p19, which is associated exclusively with IL-23, but not of p35, which is a unique subunit of IL-12.
Dr. Blauvelt notes that a recently published paper from James Krueger, M.D., Ph.D., and colleagues reported on the findings from flow cytometry studies performed to define T-cell populations in psoriatic lesions by characterizing cytokine profiles.
The results indicated there were elevated levels of both Th17 and Th1 cells in psoriatic plaques relative to normal skin and that a reduction in the numbers of Th17 and Th1 cells occurred in association with clinical improvements with effective therapy.
Using the same assay methodology, the investigators did not find any increase in circulating Th17 or Th1 cells.
However, recognizing that the methodology used might underestimate T cell numbers in skin, Dr. Blauvelt and colleagues employed immunohistochemical techniques to quantify levels of Th17.
With this approach, they found that Th17 cells accounted for a high proportion of T cells in the psoriatic skin, about one-third of the T-cell population, and they also documented significant increases in the numbers of Th17 cells in the blood of psoriatic patients compared with healthy controls.
"Genetic polymorphisms in p19, p40 and IL-23R that have been identified in psoriatics suggest they have a genetic tendency to make more IL-23, which supports our finding of increased levels of Th17 cells in the blood in addition to lesional skin," Dr. Blauvelt says.