Immunology of Psoriasis

The skin is the front line of defense against insult and injury and contains many epidermal and immune elements that comprise the skin-associated lymphoid tissue (SALT). The reaction of these components to injury allows an effective cutaneous response to restore homeostasis. Psoriasis vulgaris is the best-understood and most accessible human disease that is mediated by T cells and dendritic cells. Inflammatory myeloid dendritic cells release IL-23 and IL-12 to activate IL-17-producing T cells, Th1 cells, and Th22 cells to produce abundant psoriatic cytokines IL-17, IFN-γ, TNF, and IL-22. These cytokines mediate effects on keratinocytes to amplify psoriatic inflammation. Therapeutic studies with anticytokine antibodies have shown the importance of the key cytokines IL-23, TNF, and IL-17 in this process. We discuss the genetic background of psoriasis and its relationship to immune function, specifically genetic mutations, key PSORS loci, single nucleotide polymorphisms, and the skin transcriptome. The association between comorbidities and psoriasis is reviewed by correlating the skin transcriptome and serum proteins. Psoriasis-related cytokine-response pathways are considered in the context of the transcriptome of different mouse models. This approach offers a model for other inflammatory skin and autoimmune diseases.

Structure of Skin Skin consists of three major tissue segments. The epidermis is composed mainly of keratinocytes, but with an integral population of dendritic antigen-presenting cells termed Langerhans cells (LCs). The dermis is largely composed of collagenous connective tissue with blood vessels, but it also contains numerous other cell types including immune cells and has several associated appendages such as hair follicles, sweat glands, and sebaceous glands. The adipose tissue or subcutis makes up the third layer. As illustrated in Figure 1a , the epidermis is formed by keratinocytes that undergo a progressive differentiation program (homeostatic growth) in which proliferative cells in the basal layer differentiate into spinous and then granular keratinocytes. Granular layer keratinocytes express several molecules associated with innate immunity, such as antimicrobial peptides (AMPs) including S100A7 (psoriasin), S100A8 (calgranulin A), S100A9 (calgranulin B), lipocalin 2, β-defensin, and cathelicidin (CAMP/LL-37) ( 1 , 2 ). With further differentiation, granular keratinocytes transition to corneocytes that have lost their nuclei, but they gain a cross-linked protein membrane structure termed the cornified envelope, between which many layers of neutral lipids are deposited. Effectively, the cornified layer creates a physical barrier to outward water loss as well as to inward bacterial penetration.

Activation of skin-resident T cells could lead to the production of IFN-γ, IL-17, or IL-22, depending on the nature of the activation stimulus or antigen. This can lead to induction of cytokine-specific chemokines, which then amplify specific effector responses. In this manner, Th1 activation, leading to increased production of IFN-γ, induces synthesis of chemokines (CXCL9, CXCL10, and CXCL11) that can recruit more Th1 cells. Likewise, activation of IL-17-producing T cells, leading to IL-17 release, activates CCL20, CXCL1, CXCL2, and CXCL8/IL-8 synthesis, leading to recruitment of more IL-17-producing T cells and neutrophils into the skin. IL-17 is also a strong inducer for synthesis of AMPs in keratinocytes ( 12 ). Activation of Th22 cells results in increased production of IL-22, which can induce keratinocyte hyperplasia ( 14 ). This causes a switch into an epidermal regenerative growth pathway (with increased synthesis of S100 proteins and other AMPs), and it causes faster growth of keratinocytes, which leads to accelerated loss of surface keratinocytes and elimination of pathogens ( Figure 1b ).

A resident population of DCs in the dermis ( Figure 2a ) also contributes to the ability of skin DCs to activate T cells after encountering antigens. In the late 1980s, dermal immune cells were first characterized using a marker to the clotting factor Factor XIIIa (FXIIIA) ( 18 , 19 ). FXIIIA + cells were large, “fluffy” cells with dendritic morphology scattered throughout the dermis, and they were called dermal DCs or dermal dendrocytes. However, in recent years, newer antibodies identifying these dendritic dermal cell populations have become available, including the α x integrin CD11c, which identifies interstitial DCs ( 20 ). When healthy dermis was stained with CD11c, a different pattern of positive cells was observed in the upper dermis, which contrasted with the FXIIIA + cells scattered throughout the dermis ( 21 ). Two-color immunofluorescence showed that CD11c and FXIIIA indeed identified two distinct populations of cells. Given that CD11c can identify all myeloid cells with varying levels of expression, a more specific cutaneous DC marker was sought. A panel of blood dendritic cell antigen (BDCA) antibodies was developed ( 22 ), with BDCA-1 (CD1c) and BDCA-3 (CD141) identifying distinct circulating myeloid DC subsets. In healthy skin, these two antibodies identify two subpopulations of CD11c + DCs, with the major subpopulation consisting of BDCA-1 + cells ( 21 ). FACS-sorted BDCA-1 + cells from healthy dermis were able to induce minor allogeneic T cell proliferation, but if the DCs were first cultured with DC-maturing cytokines (a cocktail of IL-1β, IL-6, TNF, and PGE 2 ), the T cell proliferation was much more robust. This suggests that BDCA-1 + DCs in steady state are immature, but their responses can be augmented and become more effective when matured. BDCA-3 + cells were increased twofold after acute narrow-band UV radiation (NB-UVB), suggesting they may have a role in acute response to injury ( 23 ). BDCA-3 + cells, the minor CD11c + DC subset in healthy skin, are capable of cross-presentation ( 24 ). Briefly, under normal circumstances, an exogenous antigen (such as bacteria) is taken up by DCs, processed internally, and complexed with MHC class II molecules for presentation with other costimulatory molecules to CD4 + T cells. In contrast, endogenous antigens (such as viral particles) are processed with MHC class I for presentation to CD8 + cytotoxic T cells. During cross-presentation, endogenous antigens are processed for additional CD4 + T cell responses, which may be highly desirable for generating effective and long-lived immune responses ( 25 ). Although initial studies suggested that circulating BDCA-3 + DCs were the most efficient cross-presenting subset of DCs ( 24 ), more recent studies have shown that both BDCA-1 + and BDCA-3 + DCs from human tonsils have this capability ( 26 ). This reinforces the concept that plasticity is a general feature of DCs and that they can behave as the conditions require, rather than having a predefined T cell stimulatory capacity. However, not all investigators use the same DC markers, and it can be quite difficult to interpret and compare studies. The choice of antibody clones to identify cell subsets and methods of obtaining cells from skin for studies may influence results. Some investigators use CD14 and CD1a to identify two subsets of dermal DCs in healthy skin ( 27 – 29 ). CD14 identifies a minor subset of DCs that appear to drive T cell help for B cell and plasma cell responses. However, dermal CD14 + cells may also express BDCA-1 and BDCA-3 ( 30 ). The CD1a + dermal myeloid DC subset is also BDCA-1 + ( 30 ), but as CD1a is also an epidermal LC marker, BDCA-1 may be more suitable for the dermal subset as it shows more selectivity here.

Clinical and Histological Features of Psoriasis Psoriasis is a common skin disease affecting 1–3% of the North American population. Classic psoriasis, called large plaque psoriasis or psoriasis vulgaris, is the most common type. It can be fairly easily diagnosed as characteristic red colored plaques with well-defined borders and silvery-white dry scale, located on elbows, knees, and scalp and in the lumbosacral area ( Figure 3a ), although it can be more extensive ( Figure 3b ). Other less common types of psoriasis also occur, such as guttate, inverse, pustular, erythrodermic, palmo-plantar, and drug-associated psoriasis ( 33 – 35 ). The amount of psoriasis covering the body can be measured roughly as a percentage of body area, using the palm to represent 1% of the body. In approximately one-third of patients, more than 10% of the body is covered, and this is termed moderate to severe psoriasis. Clinical disease can also be assessed by a trained health-care practitioner, using the Psoriasis Activity and Severity Index (PASI) score. This tool ranks severity and area of erythema (redness), induration (thickness), and desquamation (scale) of the plaques in different body sections, with 72 as the maximal score. A baseline PASI score is assigned (for inclusion in clinical trials a PASI of 12 or greater is often required), the score is then reevaluated at various time points, and the improvement is calculated. Most clinical studies consider that an improvement of 75% from baseline is required for the treatment to be considered successful (reported as PASI75 ), although a PASI50 can also be very meaningful for an individual patient. The classic histological features of psoriasis can help explain the clinical appearance, demonstrated by hematoxylin and eosin stain ( Figure 3c ) ( 36 ). The epidermis is greatly thickened (acanthosis) as the keratinocytes move through the epidermis over 4–5 days, a tenfold acceleration. As the normal process of differentiation cannot occur, there is a loss of the normal granular layer, thickened stratum corneum (hyperkeratosis), and retention of nuclei in the upper layers and stratum corneum (parakeratosis). There is increased keratin 16 staining throughout the epidermis ( Figure 2b ), and neutrophils collect in the epidermis and stratum corneum (Kogoj pustules and Munro's microabscesses). In the dermis, there are abundant mononuclear cells, predominantly myeloid cells ( Figure 2b,c ) and T cells ( Figure 3d ). The erythema of psoriasis lesions is due to a greater number of dilated dermal blood vessels.

For many years, there was a debate about whether the primary process in psoriasis involved hyperplastic keratinocytes with secondary immune activation or vice versa. In part, this debate was fueled by a lack of knowledge regarding therapeutic mechanisms of commonly used agents. On the one hand, corticosteroids and some immunosuppressants could be used to treat psoriasis, but on the other hand, systemic agents such as methotrexate were viewed as keratinocyte-directed agents. The first specific indication that the immune system could be playing a more integral role came with the clinical trial targeting T cells with the DAB 389 IL-2 agent, a fusion protein also called denileukin diftitox or Ontak ® , that causes apoptosis in activated T cells expressing functional IL-2 receptors ( 42 ). Table 1 lists this and other immune treatments that have been used in psoriasis. This study showed that specific depletion of activated T cells in psoriasis lesions could cause clinical and histological disease resolution. Hence, this study set up the general hypothesis that psoriasis is a disease mediated by activated T cells that are present in focal skin regions (plaques of disease). This view has been solidified and refined by the availability of a series of immune-targeted drugs that have been tested in psoriasis patients and by the ability to study immune cell subsets and molecular pathways in diseased tissue through biopsies of skin. CTLA-4-Ig (abatacept) was used to block B7-mediated costimulation to T cells ( 43 ). At high doses (above 10 mg/kg), consistent improvements in psoriasis were detected that correlated with a decrease of DC and T cell subsets from diseased skin regions. Hence, this study was the first to show that disease activity could be restrained by a specific T cell antagonist that did not deplete T cells as its primary mechanism of action. Subsequently, two biologics targeted primarily at T cell activation pathways became FDA approved therapeutics for psoriasis. One of these agents was an LFA-3-Ig fusion protein(alefacept), which blocks CD2-mediated T cell activation. With this agent, strong clearing of psoriasis lesions was seen in patients in which the drug induced large decreases in T cells and DC populations in the skin ( 44 ). Effector memory T cells were often depleted in the peripheral circulation of patients treated with alefacept ( 45 ), providing additional evidence for pathogenic actions of activated T cells that infiltrate skin lesions of psoriasis vulgaris. Another T cell–targeted biologic used for psoriasis was a monoclonal antibody to the integrin CD11a (efalizumab), although it is no longer FDA-approved. T cells selectively use the integrin CD11a/CD18 (LFA-1) for migration to peripheral tissues and as a part of T cell costimulation. Efalizumab blocks T cell migration and activation responses in psoriasis patients, again without inducing T cell cytotoxicity as a primary mechanism. Strong improvements in psoriasis lesions were seen in patients that had accompanying reductions in T cell and DC subsets that infiltrate skin lesions ( 46 ). During studies of the mechanism of action of efalizumab, an inflammatory DC population was discovered in psoriasis lesions called TNF- and iNOS-producing dendritic cells, or TIP-DCs ( 46 ), as discussed in more detail in the next section. Subsequently, the role of different T cell subsets in psoriasis, including Th1 (IFN-γ), Th17 (IL-17), and Th22 (IL-22), has been dissected through the testing of a range of cytokine antagonists ( 47 ), listed in Table 1 .

The earliest indication that myeloid DCs may be important in psoriasis were experiments by Nestle et al. ( 55 ) showing that psoriasis lesion-derived dermal DCs stimulated a T cell response with production of IL-2 and IFN-γ. It is now appreciated that myeloid DCs are key proximal cells in the pathogenic psoriatic pathway ( Figure 4b ). CD11c + DC cell counts were increased in psoriasis lesions and reduced with all successful treatments studied (alefacept, efalizumab, etanercept, infliximab, NB-UVB). However, in psoriasis lesions, there were many CD11c + cells that did not costain BDCA-1 + or BDCA-3 + , and were subsequently termed inflammatory myeloid DCs ( 56 ). We consider TIP-DCs ( 46 , 57 ) to be a subset of the inflammatory DCs because not all CD11c + cells express TNF and iNOS. BDCA-1 + DCs expressed markers of DC maturity, such as CD208 (DC-LAMP) and CD205 (DEC-205), in contrast to BDCA-1- DCs, which showed increased CD209 (DC-SIGN) ( Figure 2b ). Interestingly, these two populations of CD11c + myeloid DCs (BDCA-1 + and BDCA-1 − ) could both stimulate T cells robustly in an allogeneic mixed lymphocyte reaction and similarly induce allogeneic T cells to produce IFN-γ and IL-17. To further characterize these cells, the transcriptome of the FACS-sorted cells was determined by comparing gene expression of BDCA-1 + versus BDCA-1 − DCs. Several new markers that define the inflammatory DCs were discovered with this approach, including TRAIL and TLR1 and TLR2 ( 58 ). Myeloid DCs also produce IL-20 in psoriasis lesions ( 59 ), and this could be a driver of epidermal hyperplasia. Myeloid cells expressing 6-sulfo-LacNAc (slan) have also been proposed to be inflammatory DC precursors in psoriasis, driving strong Th17 and Th1 responses ( 60 ). Although the above markers describe inflammatory DCs in psoriasis, a recent paper defined CD11c + HLA-DR hi myeloid subsets in ascites fluid from cancer patients differently, using BDCA-1 to define a subset to inflammatory DCs and CD16 to define inflammatory macrophages ( 61 ). We have previously shown, by two-color immunofluorescence and flow cytometry, that cutaneous DCs are CD16 + ( 32 , 56 ), so CD16 does not appear to define two discrete inflammatory myeloid subsets in the skin. Additional studies are required, and the DCs may have different markers in specific organs or across various disease states.

Natural killer (NK) cells are a specialized subset of CD56 + CD16 + cells with the ability to kill cancer and virally infected cells in a non-MHC-dependent manner ( 82 ). However, NK cells may play a role in psoriasis by releasing cytokines such as IFN-γ, TNF, and IL-22. NKT cells are a heterogeneous group of innate cells that share some features of both NK cells and T cells ( 83 ). There are three subsets, and they may also play a role in psoriasis by releasing cytokines such as IFN-γ. CD1d, an invariant stimulator of NKT cells, is abundantly expressed in psoriatic epidermis ( 84 ). In general, however, the roles of these immune cell subsets in psoriasis are not fully understood.

Investigators have long appreciated the genetic nature of psoriasis. The concordance rate of psoriasis is approximately 70% in monogenic twins and 20% in dizygotic twins, depending on the study and the population ( 99 ). Approximately three billion base pairs exist in the human genome, and only 3–5% of these sequences code for proteins. A disease-causing mutation is usually quite rare (<1%) and is commonly found in a coding or regulatory region. Psoriasis is a complex disease with over 30 single nucleotide polymorphisms (SNPs) contributing to disease risk, but two gene mutations have recently been found that can independently induce psoriasis ( IL36RN and CARD14 ), and these genes have an effect on both the skin and the immune system. CARD14 Mutations Eighteen years ago, PSORS2 was identified on chromosome 17q in a large family with typical large plaque psoriasis. Recently, through NexGen sequencing of patients with familial psoriasis, a gain-of-function mutation in the Caspase Recruitment Domain-Containing Protein 14 (CARD14) gene was found at this site, which segregated with psoriasis ( 100 , 101 ). A de novo mutation in CARD14 was concurrently discovered in a pediatric patient with a severe clinical presentation of psoriasis, without a family history. The CARD14 gene region was resequenced in many patients and controls (>6,000 cases and >4,000 controls), and numerous additional CARD14 missense mutations were found ( 100 ). CARD14 mRNA was found to be elevated 2.7-fold in the psoriasis transcriptome ( 101 ), and a CARD14 SNP was also recently discovered ( 102 ). CARD14 protein was expressed in the epidermis and dermis of psoriasis plaques of a patient with this mutation as well as in classic psoriasis. How might CARD14 mutations cause psoriasis? CARD proteins are involved in scaffold formation for inflammasome activation, and wild-type CARD14 activates Bcl10 and NF-κB. Mutations in the CARD14 gene lead to altered CARD14 protein and in association with an inflammatory trigger may induce increased activation of NF-κB, leading to transcription of many genes including key chemokines upregulated in psoriasis such as CCL20, CXCL8/IL-8, and IL-36γ/IL-1F9. These chemokines recruit additional cells such as neutrophils, DCs, and T cells that then produce their own inflammatory mediators. All of these events contribute to the vicious cycle of inflammation and acanthosis seen in psoriasis.

The human genome is inherited in blocks, with linkage disequilibrium of genes in close proximity being inherited together. At least 12 major psoriasis susceptibility ( PSORS ) loci have now been identified, originally by linkage disequilibrium in family-based studies. Often, several candidate genes at each PSORS locus may be contributing to the disease. In the future, the gene at each locus will ultimately be identified by deep sequencing at each chromosomal position. The first psoriasis-associated susceptibility locus ( PSORS1 ) at chromosomal position 6p21.3 was identified by genome-wide linkage scans on the background of the serological association between psoriasis and HLA-Cw6 ( 99 , 105 ). The PSORS1 locus has the highest odds ratio (OR) of any PSORS loci, of approximately 3.0. In fact, this region has the greatest impact on psoriasis heritability, a major association upheld even when 10 susceptibility loci were considered as a group ( 106 ). The exact identity of the PSORS1 gene is controversial due to extensive disequilibrium across the region, with approximately 10 genes in the 300 kb candidate region that are genetically inseparable. PSORS1 lies within the class I region of the MHC, and there is consensus that HLA-C is the most likely PSORS1 gene ( 105 ). The exact functional implications of alleles at this locus are not yet fully known, although there appear to be allele-specific differences in HLA-C expression and regulation by cytokines in psoriasis ( 107 ). Given our understanding that HLA class I molecules are important for antigen presentation to CD8 + T cells, this locus links the genetics of psoriasis with the immunological basis of the disease.

To learn the potential functional implications of the SNPs uncovered in this meta-GWAS ( 102 ), we evaluated whether positional candidate genes around each SNP had altered gene expression in psoriasis. Many studies have examined the transcriptome of psoriasis, which is defined as differentially expressed genes (DEGs) between lesional and nonlesional skin. Recently, our group conducted a meta-analysis-derived (MAD) transcriptome of all the published studies using HGU133 Plus 2.0 chips, called MAD3 transcriptome, defining a robust list of psoriasis DEGs ( 110 ). Figure 5 shows a Manhattan-type plot depicting the gene expression fold change on the MAD3 transcriptome ordered by their position on the genome (in gray shades). Genes located +/− 500 kb around each of 36 psoriasis SNPs identified in the meta-GWAS ( 102 ) are highlighted in colors (by chromosome). The subset of these positional genes that were DEGs in the MAD3 transcriptome are represented as dots of darker shades and listed on the right-hand side (colored by chromosome). The notable genes IL23R, IL12B, IL23A, and IL4 were added because there were SNPs in these genes, and although they were not detected by microarray, they were determined by RT-PCR or FACS to be differentially regulated ( 90 , 111 ). Thus, many genetic susceptibility loci also contain genes with strong upregulation of mRNA products. It is interesting and logical that the Th2 cytokine IL-4 is the only gene downregulated [log 2 (FCH) = −1.45, p = 0.034]. It thus seems that many of the genetic risk loci for psoriasis map to immune pathways that become activated in the disease and are likely drivers of the psoriasis phenotype. For example, as discussed above, IL-23R, IL-12B, and IL-23A are components of the IL-23-IL-17 axis. REL is part of the NF-κB complex, which may be important as a TNF- and IL-17-dependent transcription factor in psoriasis ( 112 ), and STAT3 is required for Th17 differentiation ( 113 ). SOCS1 is a member of the suppressor of cytokine signaling family of proteins, with a role in T17 differentiation. MICB encodes the MHC class I chain–related gene B, which further supports the potential importance of genes at the PSORS1 locus. There were a number of IFN-related genes, including ( a ) DDX58 , the RIG-I innate antiviral receptor that recognizes double-stranded RNA and regulates IFN production ( 102 ); ( b ) IFIH1 , which encodes the interferon-induced helicase c domain-containing protein; and ( c ) IRF1 , the IFN-regulatory factor 1. Several SNP-DEGs are involved in keratinization, such as FLG2, LCE3D, and CDSN, supporting the potential for genetic influence in epidermal processes during psoriatic inflammation as well.

Over the past decades, murine models of psoriasis have been developed as tools for understanding the pathogenesis of this disease and also as preclinical models. In 2007, Gudjonsson et al. ( 121 ) reviewed the current mouse models, classifying them as xenografts, allografts, transgenics, targeted mutations, and spontaneous models, and ranked features of human psoriasis in each model. Wagner et al. ( 122 ) provided a comprehensive update in 2010, covering 27 models. Transcriptomic profiling of five of the most representative models (K14-amphiregulin, K5-Stat3C, K5-Tie2, K5-TGF-β1, and Imiquimod) were compared to each other and to human psoriasis ( 123 ). At a global level, there were strong and statistically significant similarities between gene expression patterns in human psoriasis and each of these mouse models, in particular gene expression patterns associated with epidermal development and keratinization. However, marked differences also existed in immune-associated gene expression across the models. The dermal injection of IL-23 into mice is a novel murine model of psoriasis ( 124 , 125 ), although transcriptional profiling of this model has not yet been published. (See Note Added in Proof.) None of the mouse models fully represents the set of cellular changes and molecular features of psoriasis, but they contain sub-elements of this disease that differ across the various strategies used to create a murine inflammatory or hyperplastic epidermal phenotype. To visualize how psoriasis-related cytokine-response pathways are reflected in different mouse models, a graphic representation of cytokine pathway expression is shown in Figure 7 . In this figure, normalized enrichment scores (NES) from Gene Set Enrichment Analysis ( 126 ) have been created for gene sets that are induced in cultured human cells or reconstructed human epidermis by the cytokines IL-17, IL-22, IFN-γ, IFN-α, TNF, IL-1, IL-4, and IL-13, either alone or in combinations that produced additive or synergistic effects in psoriasis lesions ( 12 , 90 , 127 – 129 ). High expression of that pathway in a target tissue produces a NES of greater than 2, whereas low expression of that pathway would be a NES of 1 or less. Results are also coded for level of significance by color, with dark red being most significant [false discovery rate (FDR) < 0.0001]. The actual representations of the cytokine pathways in lesions of psoriasis vulgaris are shown in columns a and b using the MAD3 transcriptome (lesional versus nonlesional skin; Figure 7a ) ( 110 ) and lesional versus normal skin ( Figure 7b ) ( 130 ) as the reference data sets. This shows that psoriasis vulgaris has a high enrichment of gene sets related to TNF, IL-1, IL-17, IL-22, and IFNs but a poor signal of genes induced by Th2 cytokines (IL-4, IL-13). Data generated from gene-array analysis of murine psoriasis-related models are shown in columns c-h . Overall, the highest overlap of cytokine pathways with psoriasis vulgaris is seen in the model in which amphiregulin is overexpressed by a transgene. In particular, the representation of IL-17 and TNF pathways is particularly strong, but the NES is still lower than in the human disease. The STAT3, Tie2, and TGF-β transgene models, along with the imiquimod treatment model, represent models with expression of some inflammatory pathways that are present in psoriasis vulgaris, but with decreasing fidelity to the range of pathways that are expressed in the human disease. Note that STAT3, Tie2, and TGF-β models all have higher expression of IL-13 and/or IL-4 pathways than is seen in psoriasis vulgaris. These might therefore be better models for cytokine expression in intrinsic atopic dermatitis, where IL-17 is expressed in skin lesions along with Th2 cytokines ( 131 ). The most interesting aspect of this range of inflammatory models is that direct, high-level activation of keratinocytes via an autocrine growth factor (amphiregulin) ( 132 ) has the ability to induce cytokine-related gene circuits that most closely resemble psoriasis vulgaris. Hence, these data cement the concept that activated keratinocytes, whether via transgenes, endogenous mutations ( CARD14 ), damage/injury, or exposure to specific T cell–produced cytokines, can induce and sustain a chronic inflammatory response that is highly aligned with psoriasis. Overall, the transgenic models provide interesting insights into means by which inflammatory skin disease phenotypes might be induced or regulated. However, fixed overexpression of transgenes is not well suited to preclinical testing of therapeutics that act through collapsing complex inducible/repressible pathways. One interesting model that meets nearly all human psoriasis features is the xenotransplantation of nonlesional skin onto AGR mice (that lack B and T cells and IFN-γ receptors) ( 133 , 134 ). In this model, there is spontaneous conversion of grafted nonlesional skin to lesional skin over weeks. The lesions are characterized b

In a recent publication by our group, the IL-23-induced mouse transcriptome showed the greatest fidelity overall to human psoriasis. This close relationship was seen when ( a ) cytokine gene sets were analyzed in a manner similar to Figure 7 in this review and ( b ) the IL-23-induced murine upregulated genes were compared to the human psoriasis transcriptome ( 136 ).