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J Invest Dermatol. Author manuscript; available in PMC Jun 14, 2010.
Published in final edited form as:
PMCID: PMC2885349
NIHMSID: NIHMS210595

T-Helper 17 Cells in Psoriatic Plaques and Additional Genetic Links between IL-23 and Psoriasis

Abstract

T-helper 17 (Th17) cells are a newly appreciated T-cell subset, distinct from both Th1 and Th2 cells, that have been implicated in the pathogenesis of psoriasis and other autoimmune inflammatory diseases (Figure 1) (Fitch et al., 2007; Kastelein et al., 2007). IL-23 stimulates survival and proliferation of Th17 cells and thus serves as a key master cytokine regulator for these diseases.

Figure 1
Th17 cells are distinct from Th1 cells, differentiate in the presence of IL-1 and IL-6, proliferate in response to IL-23, and secrete a characteristic set of cytokines. (Modified from Fitch et al., 2007.)

In psoriasis lesions, IL-23 is overproduced by dendritic cells (Lee et al., 2004; Wilson et al., 2007) and keratinocytes (Piskin et al., 2006), and this cytokine stimulates Th17 cells within dermis to make “Th17 cytokines,” which include IL-17A, IL-17F, tumor necrosis factor (TNF)-α, IL-21, and IL-22 (Figure 1) (Fitch et al, 2007; Kastelein et al, 2007). IL-22—rather than IL-17A, for which Th17 cells are named—is emerging as the prototypic Th17 cytokine that is perhaps most specific for Th17 cells (Liang et al., 2006). Because it is a potent stimulus for keratinocyte proliferation (Wolk et al., 2006; Sa et al., 2007; Zheng et al., 2007), IL-22 has also gained prominence in the pathogenesis of psoriasis as a key effector Th17 cytokine (Fitch et al., 2007).

In this issue, Krueger and his group of investigators at Rockefeller University show for the first time the discrete presence of IL-17A-producing cells within the dermis of psoriatic plaques (Loweset al., 2008). Previously, Krueger’s and other groups had found increased levels of mRNA specific for the T-helper 17 (Th17) cytokines mentioned above, as well as increased mRNA levels for the IL-23 subunits, IL-12/23p40 and IL-23p19, in psoriasis (Lee et al., 2004; Chan et al., 2006; Wilson et al., 2007). To demonstrate IL-17A+ cells within psoriatic plaques, skin was biopsied, epidermis was separated from dermis using dispase, and leukocytes were allowed to spontaneously “crawl-out” of dermis placed into culture. These cells were then collected; stimulated for 4 hours with phorbol ester and ionomycin; labeled with antibodies directed against IL-17A, IFN-γ, and TNF-α; and analyzed by flow cytometry. Psoriasis plaque dermis contained a mean of 6.2% of cells secreting IL-17A, whereas dermis from normal-appearing skin contained a mean of 0.5% of cells making IL-17A. Dermal cells co-secreting IL-17A and TNF-α (5.1%) and dermal cells co-secreting IL-17A and IFN-γ (1.9%) were also significantly elevated in psoriasis as compared with normal-appearing skin (0.2 and 0.1%, respectively). The level of cells producing IFN-γ alone was statistically not higher in psoriatic dermis when compared with normal dermis. Taken together, these results suggest that there is a greater propensity for IL-17A-producing cells, rather than IFN-γ-producing cells, to be present in psoriatic plaques when compared to healthy skin. In a quantifiable manner, Th17 cytokine mRNA data in psoriatic plaques have now been linked with actual numbers of cells producing these cytokines within diseased tissue.

One caveat of this work is that it has become clear that IL-17A production alone does not necessarily correlate with the presence of a Th17 cell. In addition to Th17 cells, IL-17A can be produced by a subset of Th1 cells (Acosta-Rodriguez et al., 2007), natural killer T cells (Michel et al., 2007), γδ T cells (Lockhart et al., 2006), and dendritic cells (Coury et al., 2008). It will be important to perform additional multiparameter flow cytometric studies to more precisely identify the exact nature of the IL-17A-producing cells in psoriasis. IL-22, as mentioned above,

New genetic and immunologic studies suggest new therapeutic targets in psoriasis.

may be a more specific marker for Th17 cells. Thus, future coexpression and localization studies examining both IL-17A- and IL-22-secreting cells in psoriatic plaques will add other important pieces to the evolving characterization of the IL-23/Th17 inflammatory pathway in psoriasis.

In another paper in this issue, the genetics underpinning susceptibility to or protection from psoriasis was examined (Nair et al., 2008). Elder and his colleagues at the University of Michigan examined a cohort of North American and German Caucasians (1,810 psoriatics, 2,522 controls, and 509 pedigrees) for polymorphisms in a subset of IL-23- and IL-12-related genes, including those that encode for IL-23p19, IL-12/23p40, IL-12p35, IL-23R, IL-12Rβ1, and IL-12Rβ2. The choice of genes studied is important because IL-23 is a heterodimeric protein that consists of the unique IL-23p19 subunit paired with a second subunit called IL-12/23p40, whereas IL-12 is a related heterodimer consisting of the IL-12/23p40 subunit and a subunit called IL-12p35 (Figure 2) (Kastelein et al., 2007). The receptors for IL-23 and IL-12 are also related heterodimers; the IL-23 receptor consists of IL-23R and IL-12Rβ1 subunits, whereas the IL-12 receptor is composed of IL-12Rβ1 and IL-12Rβ2 subunits (Figure 2) (Kastelein et al., 2007). The conclusion of Nair and colleagues’ paper is that certain polymorphisms in genes that encode for IL-12/23p40 and IL-23R promote susceptibility to psoriasis, whereas other polymorphisms in the same two genes confer protection from developing psoriasis. This work confirms genetic associations first reported in 2002 for IL-12/23p40 and subsequently in two studies on IL-12/23p40 and IL-23R (Capon et al., 2007; Cargill et al., 2007). Thus, genes that encode for IL-12/23p40 and IL-23R are clearly linked to psoriasis.

Figure 2
Schematic of the related heterodimers IL-23 and IL-12 and their related heterodimeric cytokine receptors, indicating (in red circles) the subunits where polymorphisms in genes encoding these proteins have been linked to development of psoriasis. (Modified ...

At least three ingredients are still lacking in the overall picture of genetics studies and psoriasis. First, the IL-12/23p40 and IL-23R genetics data in humans have not been compared and contrasted with functional data from biologic experiments. It is predicted that these in vitro studies will demonstrate that certain genetic changes in IL-12/23p40 and IL-23R will lead to enhanced IL-23 production and IL-23 receptor-mediated signaling and thus be correlative with psoriasis susceptibility in humans. In contrast, other mutations that result in decreased IL-23 production and IL-23 receptor-mediated signaling in vitro are predicted to be associated with protection from developing psoriasis in individuals who carry these particular polymorphisms. Second, genotype–phenotype studies have yet to be completed, although many are underway. For instance, will certain IL-12/23p40 and IL-23R polymorphisms correlate with certain disease presentations (e.g., guttate vs. pustular psoriasis) or with severity of disease? Third, do the polymorphisms described by Elder and others confer therapeutic responsiveness to drugs that target IL-12/23p40, such as ustekinumab (Krueger et al., 2007) and ABT-874 (Kimball et al., 2008)? Such pharmacogenomic studies now appear to be within reach of cutaneous biologists and investigative dermatologists.

In the ongoing discussion of whether psoriasis represents a “Th1 disease” (as has been espoused for many years), a “Th17 disease,” or some combination of both, the most recent data emerging from many investigators studying various aspects of this immunologic puzzle suggest that IL-23 and Th17 cells are key mediators of disease pathogenesis (Fitch et al., 2007; Lowes et al., 2007; Nickoloff, 2007). In other words, IL-23, which makes Th17 cells survive and proliferate, has emerged as a master cytokine in the new paradigm of psoriasis pathogenesis. Although the IL-12/23p40 genetic data discussed above do not clearly implicate IL-23 more than IL-12, or vice versa, the IL-23R genetic data clearly point to IL-23 as a central cytokine in psoriasis (Capon et al., 2007; Cargill et al., 2007; Nair et al., 2008). Similarly, psoriasis patients treated with monoclonal antibodies directed against IL-12/23p40 demonstrate substantial clinical responses (Krueger et al., 2007; Kimball et al., 2008), yet the relative importance of IL-23 vs. IL-12 in disease maintenance is not distinguished. Of note, however, pharmaceutical companies’ interest in drugs that specifically target IL-23 and Th17 cells is high. New-age biologics that specifically block components of the IL-23/Th17 inflammatory pathway, such as IL-23p19, IL-23R, IL-17A, and IL-22, are examples of compounds that are making their way through the pharmaceutical industry’s developmental pipelines. It will be interesting to learn whether the drugs that are targeted more to the IL-23/Th17 cell inflammatory pathway will be as effective for psoriasis as the less selective anti-IL-12/23p40 monoclonal antibodies. It is predicted that inhibition of IL-23 will lead to death of Th17 cells and long-lasting abrogation of psoriasis. Finally, determining the biologic effects of such drugs (both dual IL-23/IL-12 inhibitors and selective IL-23 inhibitors) on normal cellular processes and examining overall drug safety profiles will be important to ensure adequate risk–benefit ratios for patients.

It is an exciting time to be working in psoriasis. Recent pioneering research in cellular immunology has led to the discovery of IL-23 and Th17 cells (Kastelein et al., 2007). These seminal studies, in combination with new information on murine models of psoriasis (Gudjonsson et al., 2007), data from human skin affected by psoriasis (Lowes et al., 2008), advances in genetics (Nair et al., 2008), and the development of novel targeted therapeutics for patients with psoriasis (Krueger et al., 2007; Kimball et al., 2008), have converged into a fertile mix of new and useful knowledge about psoriasis. Although much work remains to be done, investigators studying psoriasis now appear poised to unravel many of the remaining mysteries of this enigmatic disease.

ACKNOWLEDGMENTS

I appreciate the many discussions on this topic with members of my laboratory, including Erin Fitch, Stephen E. Kurtz, and Erin G. Harper. This work was supported by a Veterans Affairs Merit Award and National Institutes of Health grant 1 R21 AR054495-01A1.

Footnotes

CONFLICT OF INTEREST

The author is a scientific consultant, speaker, and clinical study principal investigator for Centocor and Abbott.

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