Figure provides our working hypothesis for the immunopathogenesis of psoriasis. This model contains elements from earlier proposals (13
). Multiple signaling pathways are envisioned to contribute to the pathological process whereby symptomless skin is converted to psoriatic plaques. An initial activating signal is portrayed as perturbing epidermal keratinocytes (13
). Mild skin trauma, such as a cut or abrasion, in which epidermal keratinocytes are damaged can trigger psoriasis (this is known as the Köbner phenomenon) and a change in the epidermal maturation pathway. Exactly what happens in keratinocytes to create a “danger signal” is unclear (51
), but several possible molecular events may occur to activate resting dendritic APCs (52
), followed by delivery of an antigenic signal to T cells (so-called signal no. 1). These possible events include perturbation of the barrier function of skin with release of preformed or rapidly produced cytokines such as IL-1 and TNF-α (53
); exposure of DCs constitutively expressing MHC class II molecules such as HLA-DR in the epidermis and/or dermis to bacterial products from skin flora (54
), including superantigens (55
); release of heat shock proteins from epidermal keratinocytes that could bind to CD91 expressed by dendritic APCs (56
); exposure of keratinocytes and dendritic APCs to glycolipids that bind to CD1d (57
); and engagement of Toll-like receptors on dendritic APCs by unspecified molecular determinants (59
The next step involves delivery of additional costimulatory signals (signal no. 2), which is likely to involve CD28 and B7 family members including B7.1 (CD80) and B7.2 (CD86) based on in vitro and in vivo studies (37
). New B7-related family members (and their ligands) have been identified, and it will be interesting to determine whether they also play a role in the pathogenesis of psoriasis. Once T cells and dendritic APCs are fully activated, they can create a “cytokine storm” composed of numerous cytokines, chemokines, and growth factors, as summarized in the lower right panel of Figure . A vicious cycle can then be envisioned in which keratinocytes, endothelial cells, neutrophils, and immunocytes in the vicinity become activated and conspire in the creation of a psoriatic plaque. Macrophages are also present, and it remains to be determined whether they are functioning to enhance the inflammatory response or to limit local immune reactions.
One of the first questions addressed by investigators was whether a polarized Th1- versus Th2-type cytokine-production profile would apply to human diseases. Initial analysis of psoriatic plaques with rather limited cytokine analysis revealed a Th1-type profile (61
). IFN-γ, TNF-α, and IL-12, but not IL-4, IL-5, or IL-10, were documented within psoriatic plaques at the mRNA and protein levels. As investigators probed the interactions among the Th1-type cytokines in vitro, it became apparent that there was synergy between IFN-γ and TNF-α with regard to production of adhesion molecules such as ICAM-1, and chemotactic polypeptides such as IL-8 or monocyte chemotactic activating factor-1 (MCAF-1). The challenging task of integrating the in vitro and in vivo findings into a coherent cytokine network that had spatial and temporal validity was first undertaken in 1991 (17
). This initial portrayal of the cytokine network in psoriasis placed TNF-α at center stage as a key primary cytokine involved in the induction and maintenance of plaques. Polymorphisms in genes regulating cytokine production have been identified for TNF-α and other inflammatory mediators (63
). Given pleiotropic effects by which TNF-α influences a wide variety of cell types in both skin and joints of psoriatic patients, several pharmaceutical companies began targeting this cytokine, using two approaches. However, before we enter the therapeutic arena, additional details of the cytokine network are presented.
During the past decade, numerous reports have provided additional molecular details concerning the cytokine network in psoriatic plaques including chemokines, growth factors, and signal transduction pathways. With the advent of high-throughput cDNA-based microarrays, this list has grown exponentially (65
). Space constraints do not permit a complete summary of all of these mediators; however, some of the most prominent components are listed in Figure . Besides these mediators, consideration of high-mobility group B1 (HMGB1) protein binding to its receptor, receptor for advanced-glycation end products (RAGE) (65
), is warranted, since HMGB1 influences cytokines such as TNF-α. In other chronic inflammatory diseases, HMGB1 is also considered an important regulator (67
). Production of cytokines derived from APCs includes TNF-α (68
) and IL-23 (69
). T cells are the likely source for IFN-γ, IL-15 (71
), and IL-17 (73
), whereas keratinocytes can produce IL-1, IL-6, and IL-8, as well as IL-18 (74
) and IL-20 (75
). Besides these cytokines, numerous chemokines and chemokine receptors are present in psoriatic plaques. When chemokines bind to their respective receptors, they activate the cells, which may be important not only for recruitment into the skin, but also for their local release of cytokines and growth factors.
Chemokines and chemokine receptors of interest in the immunopathogenesis of psoriasis include TARC (CCL17), MIG (CXCL9), IP10 (CXCL10), MDC (CCL22), and RANTES (CCL5), as recently reviewed by Krueger (4
), as well as CXCR2, CXCR3, CCR4, CCL27-CCR10, MIP3α (CCL20), MIP3β (CCL19), and CCR6. In addition, nitric oxide is present, which may contribute to an angiogenic tissue reaction, accompanied by many growth factors present at elevated levels within psoriatic plaques, including TGF-α, IGF-1, keratinocyte growth factor (KGF), VEGF, nerve growth factor (NGF), amphiregulin, and IL-20 (4
). Given the plethora of these cytokines, chemokines, and growth factors, it should not be surprising that the end result is a thick, erythematous scaly plaque. In general, activated CD4+ T cells are primarily located in the dermis and CD8+ T cells in the psoriatic epidermis, accompanied by tangled collections of dendritic APCs predominantly located in the dermis.
Besides those molecules listed, potentially important signaling pathways including NF-κB, STAT-1, STAT-3, and IFN-α–inducible proteins are also now on the radar screen of psoriasis research (65
). Not only can high-throughput cDNA-based technology be used to identify specific transcripts that are elevated in psoriatic plaques; sequential analysis of plaques following treatment can be completed to explore the pharmacogenomics of psoriasis (65
). Knowing which transcripts are reduced as lesions improve provides potential new therapeutic targets for future clinical trials, as detailed in the last section of this review. In the next section, additional lessons regarding the immunopathogenesis of psoriasis, derived from two different animal models, are reviewed. Besides xenogeneic animal models, transgenic murine models are important, as exemplified by a recent report in which genetic inactivation of a chemokine receptor 2 unexpectedly provoked a severe disease state similar to human RA, rather than the predicted reduction in inflammation (76