Abnormal production of inflammatory mediators is believed to play an important role in the pathogenesis of psoriasis. Emerging data, both in mice and in humans, put the spotlight on a new subset of T helper (Th) cells, in part characterized by their production of IL-17 and accordingly named Th17 cells. Here, we review the development, characterization, and function of human Th17 cells as well as the crucial role of IL-23 in the context of Th17-cell-dependent chronic inflammation in psoriasis. We further discuss recent clinical trials targeting the IL-23/Th17 axis in psoriasis.
IL-23 and Th17 cells are key players in tissue immunosurveillance and are implicated in human immune-mediated diseases. Genome-wide association studies have shown that the IL23R R381Q gene variant protects against psoriasis, Crohn's disease and ankylosing spondylitis. We investigated the immunological consequences of the protective IL23R R381Q gene variant in healthy donors. The IL23R R381Q gene variant had no major effect on Th17 cell differentiation as the frequency of circulating Th17 cells was similar in carriers of the IL23R protective (A) and common (G) allele. Accordingly, Th17 cells generated from A and G donors produced similar amounts of Th17 cytokines. However, IL-23-mediated Th17 cell effector function was impaired, as Th17 cells from A allele carriers had significantly reduced IL-23-induced IL-17A production and STAT3 phosphorylation compared to G allele carriers. Our functional analysis of a human disease-associated gene variant demonstrates that IL23R R381Q exerts its protective effects through selective attenuation of IL-23-induced Th17 cell effector function without interfering with Th17 differentiation, and highlights its importance in the protection against IL-23-induced tissue pathologies.
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