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Genetics of Psoriasis: Evidence for Epistatic Interaction between Skin Barrier Abnormalities and Immune Deviation

  • Judith G.M. Bergboer
    Affiliations
    Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
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  • Patrick L.J.M. Zeeuwen
    Affiliations
    Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
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  • Joost Schalkwijk
    Correspondence
    Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, PO Box 9101, Nijmegen 6500 HB, The Netherlands
    Affiliations
    Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands
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      Psoriasis was until recently regarded as a T-cell-driven disease with presumed (auto)immune mechanisms as its primary cause. This view was supported by clinical data and genetic studies that identified risk factors functioning in adaptive and innate immunity, such as HLA-C*06, ERAP1, the IL-23 pathway, and NF-κB signaling. Candidate gene approaches and genome-wide association studies, however, have identified copy number polymorphisms of the β-defensin cluster and deletion of late cornified envelope (LCE) 3B and 3C genes (LCE3C_LCE3B-del) as psoriasis risk factors. As these genes are expressed in epithelial cells and not by the immune system, these findings may cause a change of paradigm for psoriasis, not unlike the reported filaggrin association that has profoundly changed the views on atopic dermatitis. In addition to genetic polymorphisms of the immune system, genetic variations affecting the skin barrier are likely to contribute to psoriasis. Recent studies have shown epistatic interactions involving HLA-C*06, ERAP1, and LCE3C_LCE3B-del, which makes psoriasis a unique model to investigate genetic and biological interactions of associated genes in a complex disease. We present a model for disease initiation and perpetuation, which integrates the available genetic, immunobiological, and clinical data.

      Abbreviations

      CDSN
      corneodesmosin
      CE
      cornified envelope
      CNV
      copy number variation
      GWAS
      genome-wide association study
      LCE
      late cornified envelope
      PAMP
      pathogen-associated molecular pattern
      SNP
      single-nucleotide polymorphism

      Introduction

      Psoriasis: epidermal versus immune pathogenesis

      Psoriasis is a common inflammatory skin disease that has both genetic and environmental factors to its etiology. For an in-depth overview of clinical aspects and immunobiology of psoriasis, we refer to several excellent reviews on this subject (
      • Bowcock A.M.
      • Krueger J.G.
      Getting under the skin: the immunogenetics of psoriasis.
      ;
      • Schon M.P.
      • Boehncke W.H.
      Psoriasis.
      ;
      • Nestle F.O.
      • Kaplan D.H.
      • Barker J.
      Psoriasis.
      . The question whether psoriasis is an epithelial disease or an immune-mediated disease has generated considerable debate over the past decades, but remains essentially unresolved. Until the early 1980s, psoriasis was considered to be a keratinocyte disease, but the advent of cyclosporin A as an effective mechanism-based treatment has changed this (
      • Ellis C.N.
      • Gorsulowsky D.C.
      • Hamilton T.A.
      • et al.
      Cyclosporine improves psoriasis in a double-blind study.
      . For the past three decades, psoriasis was primarily regarded as an immune-mediated disease, although the pendulum has begun to swing back lately (
      • Nickoloff B.J.
      Keratinocytes regain momentum as instigators of cutaneous inflammation.
      . The concept of an (auto)immune basis is supported by the presence of activated T cells and other immunocompetent cells in psoriatic lesions and the efficacy of T-cell-targeted therapeutics, such as cyclosporin A, DAB389IL-2, alefacept, and efaluzimab (
      • Lowes M.A.
      • Bowcock A.M.
      • Krueger J.G.
      Pathogenesis and therapy of psoriasis.
      . Other circumstantial evidence for an immune-based pathogenesis stems from genetic data (discussed below) and antipsoriatic therapies that are thought to target the adaptive immune system rather than the epidermis (corticosteroids, UVB, fumarates;
      • Schwarz T.
      25 years of UV-induced immunosuppression mediated by T cells-from disregarded T suppressor cells to highly respected regulatory T cells.
      . Animal models involving xenograft transplantation provide further evidence for an immune-mediated pathogenesis. In these experiments, grafts of human uninvolved psoriatic skin onto severe combined immunodeficient mice can develop into lesional psoriatic skin by direct injection of activated T cells from the donor (
      • Wrone-Smith T.
      • Nickoloff B.J.
      Dermal injection of immunocytes induces psoriasis.
      . In addition, a psoriatic phenotype can develop by expansion of resident T cells of grafted non-lesional skin (
      • Boyman O.
      • Hefti H.P.
      • Conrad C.
      • et al.
      Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha.
      . Although it is clear that participation of cell types non-intrinsic to the skin is mandatory for the development of psoriatic lesions, none of these animal models excludes a contribution of the epidermal keratinocytes.
      Various studies have documented skin barrier abnormalities in psoriasis, but genes involved in keratinocyte differentiation, with the exception of corneodesmosin (CDSN), have not been considered as genetic risk factors until recently. Here we review data from genetic studies and provide an overview of all currently known risk factors. Copy number variation (CNV) of genes involved in the chemical and physical skin barrier found to be associated with psoriasis are discussed in detail.

      Genetics of psoriasis

      A strong genetic basis for psoriasis has been firmly established in many epidemiological and genetic studies for which many excellent reviews are available (
      • Capon F.
      • Trembath R.C.
      • Barker J.N.
      An update on the genetics of psoriasis.
      ,
      • Capon F.
      • Burden A.D.
      • Trembath R.C.
      • et al.
      Psoriasis and other complex trait dermatoses: from Loci to functional pathways.
      ;
      • Bowcock A.M.
      • Krueger J.G.
      Getting under the skin: the immunogenetics of psoriasis.
      ;
      • Gudjonsson J.E.
      • Elder J.T.
      Psoriasis: epidemiology.
      . Twin studies showed a concordance rate of 35–72% in monozygotic twins, and 12–35% in dizygotic twins. About 70% of the patients with childhood psoriasis report a positive family history (
      • Morris A.
      • Rogers M.
      • Fischer G.
      • et al.
      Childhood psoriasis: a clinical review of 1262 cases.
      . In the past decades, several linkage studies (
      • Tomfohrde J.
      • Silverman A.
      • Barnes R.
      • et al.
      Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q.
      ;
      • Nair R.P.
      • Henseler T.
      • Jenisch S.
      • et al.
      Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.
      ;
      • Capon F.
      • Novelli G.
      • Semprini S.
      • et al.
      Searching for psoriasis susceptibility genes in Italy: genome scan and evidence for a new locus on chromosome 1.
      and, more recently, genome-wide association studies (GWASs) have been conducted to find susceptibility loci for psoriasis (
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      ;
      • Capon F.
      • Bijlmakers M.J.
      • Wolf N.
      • et al.
      Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene.
      ;
      • Liu Y.
      • Helms C.
      • Liao W.
      • et al.
      A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci.
      ;
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ;
      • Zhang X.J.
      • Huang W.
      • Yang S.
      • et al.
      Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21.
      ;
      • Ellinghaus E.
      • Ellinghaus D.
      • Stuart P.E.
      • et al.
      Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      ;
      • Stuart P.E.
      • Nair R.P.
      • Ellinghaus E.
      • et al.
      Genome-wide association analysis identifies three psoriasis susceptibility loci.
      ;
      • Sun L.D.
      • Cheng H.
      • Wang Z.X.
      • et al.
      Association analyses identify six new psoriasis susceptibility loci in the Chinese population.
      ;
      • Huffmeier U.
      • Uebe S.
      • Ekici A.B.
      • et al.
      Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis.
      . Linkage analysis has identified at least nine loci and have been designated PSORS1 to PSORS9. GWASs and candidate gene approaches have now identified over 20 psoriasis loci. Several, albeit not all of them, have been confirmed by studies in various populations. All performed GWASs for psoriasis, however, show associations with the PSORS1 region. Furthermore, each scan finds its own new regions, but these are often difficult to validate in an independent data set (
      • Capon F.
      • Trembath R.C.
      • Barker J.N.
      An update on the genetics of psoriasis.
      . For most of these loci, single-nucleotide polymorphisms (SNPs) have been identified in or near candidate genes, but convincing evidence for causative mutations that clearly define a mechanistic basis is largely lacking. Despite these difficulties, genetic studies are a useful source of knowledge and can provide new insights into the pathogenesis of psoriasis, as recently reviewed by
      • Capon F.
      • Burden A.D.
      • Trembath R.C.
      • et al.
      Psoriasis and other complex trait dermatoses: from Loci to functional pathways.
      .
      The strongest and invariably reproduced susceptibility locus, PSORS1, harbors HLA-C*06, which was already known to be associated with psoriasis in the 1970s. This locus contains several genes including CDSN, which encodes a protein expressed in differentiated keratinocytes. However, because of linkage disequilibrium, the tendency of two genes to be inherited together more often than would be predicted by chance, it is difficult to identify the true causative susceptibility gene of the PSORS1 locus. Studies of
      • Orru S.
      • Giuressi E.
      • Carcassi C.
      • et al.
      Mapping of the major psoriasis-susceptibility locus (PSORS1) in a 70-Kb interval around the corneodesmosin gene (CDSN).
      suggest that the CDSN is the susceptibility gene, whereas
      • Nair R.P.
      • Stuart P.E.
      • Nistor I.
      • et al.
      Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.
      reported that HLA-C*06 is the most likely susceptibility gene in the PSORS1 region. Alternatively, it might even be possible that both HLA-C*06 and CDSN contribute to psoriasis susceptibility (
      • Capon F.
      • Trembath R.C.
      • Barker J.N.
      An update on the genetics of psoriasis.
      . Given its role in antigen presentation, the association with HLA-C*06 strongly points at a role of the adaptive immune system in psoriasis. Although the PSORS1 region is the most replicated and best-known susceptibility locus for psoriasis, it accounts for less than 50% of the familial aggregation (estimated population attributable risk: 29%, based on frequency of HLA-C*06 in control population 0.17 and odds ratio of 3.45 (
      • Riveira-Munoz E.
      • He S.M.
      • Escaramis G.
      • et al.
      Meta-analysis confirms the LCE3C_LCE3B deletion as a risk factor for psoriasis in several ethnic groups and finds interaction with HLA-Cw6.
      ). Therefore, other loci must contribute to the pathogenesis of psoriasis. Recent, widely replicated associations comprise SNPs mapped near the IL-12B gene, coding for the p40 subunit of IL-12 and near a subunit of the IL-23 receptor (
      • Tsunemi Y.
      • Saeki H.
      • Nakamura K.
      • et al.
      Interleukin-12 p40 gene (IL12B) 3′-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris.
      ;
      • Capon F.
      • Di M.P.
      • Szaub J.
      • et al.
      Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis.
      ;
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      . In several other large-scale GWASs (
      • Capon F.
      • Bijlmakers M.J.
      • Wolf N.
      • et al.
      Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene.
      ;
      • Liu Y.
      • Helms C.
      • Liao W.
      • et al.
      A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci.
      ;
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ;
      • Zhang X.J.
      • Huang W.
      • Yang S.
      • et al.
      Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21.
      ;
      • Ellinghaus E.
      • Ellinghaus D.
      • Stuart P.E.
      • et al.
      Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      ;
      • Stuart P.E.
      • Nair R.P.
      • Ellinghaus E.
      • et al.
      Genome-wide association analysis identifies three psoriasis susceptibility loci.
      ;
      • Sun L.D.
      • Cheng H.
      • Wang Z.X.
      • et al.
      Association analyses identify six new psoriasis susceptibility loci in the Chinese population.
      ;
      • Huffmeier U.
      • Uebe S.
      • Ekici A.B.
      • et al.
      Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis.
      many of these associations were confirmed, and additionally many new SNPs were reported to be associated with psoriasis. Several of these new SNPs were found in or near genes associated with the adaptive or innate immune system such as IL23A, TNFAIP3 (tumor necrosis factor (TNF)-α induced protein 3), TNIP1 (TNFAIP3-interacting protein 1), IL-4, and IL-13. Table 1 lists the known replicated genetic associations with psoriasis to date.
      Table 1Replicated genetic risk factors for psoriasis
      Putative biological pathwayGene or locusDescriptionLocusExpression in(Putative) FunctionReferences
      Adaptive immunityIL-23RIL-23 receptor subunit1p31.3Macrophages, IL-23-activated dendritic cells (DCs), Th17 cellsMaturation T cells
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      , replicated many times
      Adaptive immunityERAP1Endoplasmic reticulum aminopeptidase 15q15Generally expressedSeveral proposed functions, including trimming of peptide antigens for binding to major histocompatibility complex I
      • Zhang X.J.
      • Huang W.
      • Yang S.
      • et al.
      Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      ;
      • Sun L.D.
      • Cheng H.
      • Wang Z.X.
      • et al.
      Association analyses identify six new psoriasis susceptibility loci in the Chinese population.
      Adaptive immunityIL-12BIL-12/23, subunit p405q31.1-q33.1Th1, Th0, NK, monocyte, DC, and B-cell lines, induced in psoriasis involved skinMaturation T cells
      • Tsunemi Y.
      • Saeki H.
      • Nakamura K.
      • et al.
      Interleukin-12 p40 gene (IL12B) 3′-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris.
      , replicated many times
      Adaptive immunityTNFTumor necrosis factor-α6p21Immune cellsMajor proinflammatory cytokine involved in psoriasis
      • Arias A.I.
      • Giles B.
      • Eiermann T.H.
      • et al.
      Tumor necrosis factor-alpha gene polymorphism in psoriasis.
      ;
      • Hohler T.
      • Kruger A.
      • Schneider P.M.
      • et al.
      A TNF-alpha promoter polymorphism is associated with juvenile onset psoriasis and psoriatic arthritis.
      ;
      • Reich K.
      • Mossner R.
      • Konig I.R.
      • et al.
      Promoter polymorphisms of the genes encoding tumor necrosis factor-alpha and interleukin-1beta are associated with different subtypes of psoriasis characterized by early and late disease onset.
      ;
      • Li C.
      • Wang G.
      • Gao Y.
      • et al.
      TNF-alpha gene promoter -238G>A and -308G>A polymorphisms alter risk of psoriasis vulgaris: a meta-analysis.
      Adaptive immunityTRAF3IP2TRAF3-interacting protein 26q21Generally expressed, induced in psoriasis involved skinSignaling adaptor involved in regulation of adaptive immunity
      • Ellinghaus E.
      • Ellinghaus D.
      • Stuart P.E.
      • et al.
      Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2.
      ;
      • Huffmeier U.
      • Uebe S.
      • Ekici A.B.
      • et al.
      Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      Adaptive immunityIL-4, IL-13IL-4, 135q31.1Th2 cellsModulate humoral immune response mediated by Th2 cells
      • Chang M.
      • Li Y.
      • Yan C.
      • et al.
      Variants in the 5q31 cytokine gene cluster are associated with psoriasis.
      ;
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      ;
      • Sun L.D.
      • Cheng H.
      • Wang Z.X.
      • et al.
      Association analyses identify six new psoriasis susceptibility loci in the Chinese population.
      Adaptive immunityIL-23A/STAT2IL-23, subunit p1912q13.2DCs and monocytes, induced in psoriasis involved skinRegulation T-cell activation
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      ;
      • Chen H.
      • Poon A.
      • Yeung C.
      • et al.
      A genetic risk score combining ten psoriasis risk loci improves disease prediction.
      Adaptive immunityIL-23AIL-23, α-subunit p1912q13.3DCs and phagocytic cellsInvolved in Th17 axis
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      Adaptive immunityZNF313/RNF114Ring-finger protein 11420q13.14Generally expressed, strongest in skin, T-lymphocytes, and DCsUbiquitination, regulation of immune responses
      • Capon F.
      • Bijlmakers M.J.
      • Wolf N.
      • et al.
      Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene.
      ;
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      Adaptive immunityHLA-CMHC gene6p21.33All nucleated cellsPresenting antigens to immune cells
      • Trembath R.C.
      • Clough R.L.
      • Rosbotham J.L.
      • et al.
      Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis.
      , replicated many times
      Barrier function skinLCE3B and LCE3CLate cornified envelope 3B and 3C1q21.3Epithelia and lesional PS skinBarrier function skin
      • de Cid R.
      • Riveira-Munoz E.
      • Zeeuwen P.L.
      • et al.
      Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.
      ;
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ;
      • Zhang X.J.
      • Huang W.
      • Yang S.
      • et al.
      Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21.
      ;
      • Huffmeier U.
      • Bergboer J.G.
      • Becker T.
      • et al.
      Replication of LCE3C-LCE3B CNV as a risk factor for psoriasis and analysis of interaction with other genetic risk factors.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      ;
      • Chen H.
      • Poon A.
      • Yeung C.
      • et al.
      A genetic risk score combining ten psoriasis risk loci improves disease prediction.
      ;
      • Li M.
      • Wu Y.
      • Chen G.
      • et al.
      Deletion of the late cornified envelope genes LCE3C and LCE3B is associated with psoriasis in a chinese population.
      ;
      • Xu L.
      • Li Y.
      • Zhang X.
      • et al.
      Deletion of LCE3C and LCE3B genes is associated with psoriasis in a northern Chinese population.
      Barrier function skinCDSNCorneodesmosin6p21Epidermis, upregulated in psoriasisComponent of the cornified envelope
      • Guerrin M.
      • Vincent C.
      • Simon M.
      • et al.
      Identification of six novel polymorphisms in the human corneodesmosin gene.
      ;
      • Orru S.
      • Giuressi E.
      • Casula M.
      • et al.
      Psoriasis is associated with a SNP haplotype of the corneodesmosin gene (CDSN).
      ,
      • Orru S.
      • Giuressi E.
      • Carcassi C.
      • et al.
      Mapping of the major psoriasis-susceptibility locus (PSORS1) in a 70-Kb interval around the corneodesmosin gene (CDSN).
      ;
      • Capon F.
      • Toal I.K.
      • Evans J.C.
      • et al.
      Haplotype analysis of distantly related populations implicates corneodesmosin in psoriasis susceptibility.
      Barrier function skinDEFB clusterβ-Defensins8p23.1Epithelium and male reproductive systemAntimicrobial and chemotactic functions
      • Hollox E.J.
      • Huffmeier U.
      • Zeeuwen P.L.
      • et al.
      Psoriasis is associated with increased beta-defensin genomic copy number.
      ; Stuart et al. (in press)
      Barrier function skinGJB2Gap junction protein β2, connexin 2613q11-q12Skin, highly upregulated in psoriasisInvolved in gap junction formation
      • Sun L.D.
      • Cheng H.
      • Wang Z.X.
      • et al.
      Association analyses identify six new psoriasis susceptibility loci in the Chinese population.
      Innate immunityIFIH1IFN induced with helicase C domain 1, MDA52q24Generally expressed, induced in psoriasis involved skinRig-like helicase, involved in recognition RNA viruses(
      • Li Y.
      • Liao W.
      • Cargill M.
      • et al.
      Carriers of rare missense variants in IFIH1 are protected from psoriasis.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      Innate immunityRELv-rel reticuloendotheliosis viral oncogene homolog2p13Blood, intestine, larynx, lymph node, thyroid, tracheaTranscription factor, member of the REL/NF-κB family
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      Innate immunityTNIP1TNAIP3-interacting protein 15q32-q33.1Ubiquitously, stronger in blood lymphocytes, spleen, and skeletal muscle, induced in psoriasis involved skinRegulation of NF-κB signaling
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      ;
      • Sun L.D.
      • Cheng H.
      • Wang Z.X.
      • et al.
      Association analyses identify six new psoriasis susceptibility loci in the Chinese population.
      ;
      • Chen H.
      • Poon A.
      • Yeung C.
      • et al.
      A genetic risk score combining ten psoriasis risk loci improves disease prediction.
      Innate immunityTNFAIP3Tumor necrosis factor-α-induced protein 3/A206q23.3Epithelia and lymphoid tissuesTNFα inducible zinc-finger protein that temporarily limits immune response by inhibiting NF-κB signaling
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      ;
      • Sun L.D.
      • Cheng H.
      • Wang Z.X.
      • et al.
      Association analyses identify six new psoriasis susceptibility loci in the Chinese population.
      Innate immunityIL-28RAIL-29 receptor subunit1p36.11Lymph, lymph nodeReceptor for IL-28A, IL-28B, and IL-29
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      Innate immunityNFKBIANF of kappa light polypeptide gene enhancer in B cells inhibitor, alpha14q13.2Generally expressedInhibiting NF-κB signaling
      • Ellinghaus E.
      • Ellinghaus D.
      • Stuart P.E.
      • et al.
      Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      ;
      • Stuart P.E.
      • Nair R.P.
      • Ellinghaus E.
      • et al.
      Genome-wide association analysis identifies three psoriasis susceptibility loci.
      Innate immunityFBXL19F-box and leucine-rich repeat protein 1916p11.2Epithelia, brain, eye, lymph, bone, induced in psoriasis involved skinPutative inhibitor of demethylase activity to activate NF-κB
      • Stuart P.E.
      • Nair R.P.
      • Ellinghaus E.
      • et al.
      Genome-wide association analysis identifies three psoriasis susceptibility loci.
      Innate immunityNOS2Nitric oxide synthase 2, inducible17q11.1Immune system, cardiovascular systemCytokine inducible enzymes that catalyze the production of nitric oxide for immune defense against pathogens
      • Stuart P.E.
      • Nair R.P.
      • Ellinghaus E.
      • et al.
      Genome-wide association analysis identifies three psoriasis susceptibility loci.
      Innate immunityTYK2Tyrosine kinase 219p13.2Generally expressedTyrosine kinase, associates with cytoplasmic domains of type I and type II cytokine receptors
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      Not determinedSLC12A8Solute carrier family 12, member 83q21Generally expressedCation/chloride cotransporter, putatively involved in keratinocyte differentiation
      • Hewett D.
      • Samuelsson L.
      • Polding J.
      • et al.
      Identification of a psoriasis susceptibility candidate gene by linkage disequilibrium mapping with a localized single nucleotide polymorphism map.
      ;
      • Huffmeier U.
      • Lascorz J.
      • Traupe H.
      • et al.
      Systematic linkage disequilibrium analysis of SLC12A8 at PSORS5 confirms a role in susceptibility to psoriasis vulgaris.
      ;
      • Oudot T.
      • Lesueur F.
      • Guedj M.
      • et al.
      An association study of 22 candidate genes in psoriasis families reveals shared genetic factors with other autoimmune and skin disorders.
      Not determinedPTTG1Pituitary tumor transforming gene5q35.1Generally expressed, not in skin and tissues from gastrointestinal tractMultiple functions, roles in control of mitosis, cell transformation, DNA repair, and gene regulation
      • Sun L.D.
      • Cheng H.
      • Wang Z.X.
      • et al.
      Association analyses identify six new psoriasis susceptibility loci in the Chinese population.
      Not determinedCSMD1CUB and Sushi multiple domains 18p23.2Areas of regenerative growth, such as skin and epithelial cellsTumor repressor gene
      • Sun L.D.
      • Cheng H.
      • Wang Z.X.
      • et al.
      Association analyses identify six new psoriasis susceptibility loci in the Chinese population.
      Not determinedADAM33A disintegrin and metalloproteases metallopeptidase domain 3320p13Mesenchymal cellsMetalloprotease, linked to angiogenesis and remodeling
      • Lesueur F.
      • Oudot T.
      • Heath S.
      • et al.
      ADAM33, a new candidate for psoriasis susceptibility.
      ;
      • Siroux V.
      • Bouzigon E.
      • Dizier M.H.
      • et al.
      Replication of association between ADAM33 polymorphisms and psoriasis.
      ;
      • Li Y.
      • Liao W.
      • Chang M.
      • et al.
      Further genetic evidence for three psoriasis-risk genes: ADAM33, CDKAL1, and PTPN22.
      Not determinedSERPINB8Serpin peptidase inhibitor clade B member 818q21.3Skin, vascular tissue, connective tissue, upregulated in psoriasisSerine proteinase inhibitor, regulate wide range of functions
      • Sun L.D.
      • Cheng H.
      • Wang Z.X.
      • et al.
      Association analyses identify six new psoriasis susceptibility loci in the Chinese population.
      Not determinedZNF816AZinc-finger protein 816A19q13.41Generally expressedRegulatory function, belongs to same family as ZNF313
      • Sun L.D.
      • Cheng H.
      • Wang Z.X.
      • et al.
      Association analyses identify six new psoriasis susceptibility loci in the Chinese population.
      Although most of the available genetic and clinical data at this point supported a role of T-cell-driven processes, epidermis-expressed genes could not be completely ruled out. For example, cell biological studies suggest that keratinocytes of psoriatic patients, and also from atopic dermatitis patients, are intrinsically different from control keratinocytes. Cultured keratinocytes from patients react differently to stimuli such as cytokines, most likely because of genetically programmed differences (
      • Giustizieri M.L.
      • Mascia F.
      • Frezzolini A.
      • et al.
      Keratinocytes from patients with atopic dermatitis and psoriasis show a distinct chemokine production profile in response to T cell-derived cytokines.
      ;
      • Zeeuwen P.L.
      • de Jongh G.J.
      • Rodijk-Olthuis D.
      • et al.
      Genetically programmed differences in epidermal host defense between psoriasis and atopic dermatitis patients.
      . The recent finding that filaggrin is a major gene in atopic dermatitis, a disease thought to be primarily driven by the immune system, provided a shift of paradigm, indicating that we should consider similar mechanisms in psoriasis as well. Two studies have recently identified regions in the human genome that are subject to CNV and are associated with psoriasis. CNV of a genomic segment on chromosome 8p23.1 harboring a cluster of DEFB genes, encoding the β-defensins, and a CNV in the PSORS4 region on chromosome 1q21, specifically the deletion of late cornified envelope (LCE)3B and LCE3C, were found to be associated with psoriasis. Remarkably, these newly associated genes are expressed in the epidermis and not in immunocytes (see Figures 1 and 2), as will be discussed below.
      Figure thumbnail gr1
      Figure 1DEFB4 and LCE genes are mainly expressed in skin. Relative mRNA expression levels of DEFB4, LCE2B, and LCE3A in normal and psoriasis skin, several immune-associated tissues, and oral human tissues. Expression of target genes was normalized to that of RPLP0. For graphic representation, per gene values are expressed relative to expression in tongue, which was set at unity, to enable comparison of expression between tissues (see
      • Livak K.J.
      • Schmittgen T.D.
      Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method.
      ).
      LCE data reprinted from
      • Bergboer J.G.
      • Tjabringa G.S.
      • Kamsteeg M.
      • et al.
      Psoriasis risk genes of the late cornified envelope-3 group are distinctly expressed compared with genes of other LCE groups.
      , with permission from Elsevier.DEFB4 data reprinted from
      • Jansen P.A.
      • Rodijk-Olthuis D.
      • Hollox E.J.
      • et al.
      Beta-defensin-2 protein is a serum biomarker for disease activity in psoriasis and reaches biologically relevant concentrations in lesional skin.
      .
      Figure thumbnail gr2
      Figure 2hBD-2 and LCE2 protein expression in skin. (a) hBD-2 protein expression in normal skin (left) and in involved psoriasis skin (right). In normal skin hBD-2 is not expressed, and in involved psoriasis skin hBD-2 expression is heavily induced, bar=100μm. (b) LCE2 protein expression in normal skin assessed by immunoelectron microscopy. Arrows indicate gold-labeled LCE2 antibodies that stain the cornified envelope structure in normal skin, bar=200nm.

      β-Defensins and psoriasis

      β-Defensins are small antimicrobial peptides that possess a broad spectrum of antimicrobial activity against both Gram-positive and Gram-negative bacteria, as well as fungi and viruses (
      • Schroder J.M.
      • Harder J.
      Human beta-defensin-2.
      ;
      • Ganz T.
      Defensins: antimicrobial peptides of innate immunity.
      . Because of their antimicrobial activity, the β-defensins, together with other antimicrobial peptides, are likely to be responsible for the chemical barrier and innate immunity of the skin. This idea is supported by observations in inflammatory skin diseases such as psoriasis and atopic dermatitis. Atopic dermatitis is associated with a high prevalence of skin infections, whereas infections are rare in psoriasis (
      • Christophers E.
      • Henseler T.
      Contrasting disease patterns in psoriasis and atopic dermatitis.
      . This could be explained by reduced mRNA and protein levels of antimicrobial proteins (e.g., hBD-2, hBD-3, elafin, and LL-37) in atopic dermatitis as compared with psoriasis (
      • Ong P.Y.
      • Ohtake T.
      • Brandt C.
      • et al.
      Endogenous antimicrobial peptides and skin infections in atopic dermatitis.
      ;
      • de Jongh G.J.
      • Zeeuwen P.L.
      • Kucharekova M.
      • et al.
      High expression levels of keratinocyte antimicrobial proteins in psoriasis compared with atopic dermatitis.
      . When comparing the expression of hBD-1, 2, and 3 in normal skin and in psoriasis and atopic dermatitis patients, it was shown that hBD-2 is by far the most upregulated β-defensin in lesional psoriatic skin and can be used as a serum biomarker for disease activity (Figure 1 panel DEFB4, Figure 2a
      • Jansen P.A.
      • Rodijk-Olthuis D.
      • Hollox E.J.
      • et al.
      Beta-defensin-2 protein is a serum biomarker for disease activity in psoriasis and reaches biologically relevant concentrations in lesional skin.
      .
      Besides antimicrobial activity, β-defensins also exhibit proinflammatory properties as chemoattractants for immune cells, such as immature dendritic cells, memory T cells, TNF-α-treated neutrophils, and mast cells (
      • Yang D.
      • Chertov O.
      • Bykovskaia S.N.
      • et al.
      Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6.
      ,
      • Yang D.
      • Biragyn A.
      • Kwak L.W.
      • et al.
      Mammalian defensins in immunity: more than just microbicidal.
      ;
      • Niyonsaba F.
      • Iwabuchi K.
      • Matsuda H.
      • et al.
      Epithelial cell-derived human beta-defensin-2 acts as a chemotaxin for mast cells through a pertussis toxin-sensitive and phospholipase C-dependent pathway.
      ,
      • Niyonsaba F.
      • Ogawa H.
      • Nagaoka I.
      Human beta-defensin-2 functions as a chemotactic agent for tumour necrosis factor-alpha-treated human neutrophils.
      . Because of these properties, β-defensins provide a link between the innate and adaptive immune system.
      The genes coding for the β-defensins are located on chromosome 8p23.1 of the human genome. In this region, seven β-defensin genes are located. Six of these genes, including DEFB4 (encoding hBD-2) and DEFB103 (encoding hBD-3), are localized on a very large repeat unit that can vary in copy number. DEFB1 (encoding the protein hBD-1) is not localized on this repeat and therefore not subject to CNV (
      • Hollox E.J.
      • Armour J.A.
      • Barber J.C.
      Extensive normal copy number variation of a beta-defensin antimicrobial-gene cluster.
      . In humans, up to 12 copies of this repeat have been found, with a mode of four copies per diploid genome (
      • Hollox E.J.
      • Huffmeier U.
      • Zeeuwen P.L.
      • et al.
      Psoriasis is associated with increased beta-defensin genomic copy number.
      . On the basis of the functional data on β-defensins (particularly hBD-2) and psoriasis, we hypothesized that the CNV of the β-defensin cluster on 8p23.1 could be associated with psoriasis. Analysis of the β-defensin cluster in a Dutch and German case–control cohort showed indeed a significant association between higher genomic copy number and the risk of psoriasis (
      • Hollox E.J.
      • Huffmeier U.
      • Zeeuwen P.L.
      • et al.
      Psoriasis is associated with increased beta-defensin genomic copy number.
      . This finding has recently been replicated in a large independent cohort, although the association was weaker than that of the initial study (

      Stuart PE, Huffmeier U, Nair RP et al. Association of beta-defensin copy number and psoriasis in three cohorts of European origin. J Invest Dermatol (in press)

      . As six β-defensin genes are part of the repeat region and show the same CNV, we were not able to distinguish whether one gene or a combination of all β-defensins is responsible for the association with psoriasis. Altogether, these data indicate that the β-defensins, produced in keratinocytes, could have a role in the pathophysiology of psoriasis.
      The mechanism, however, by which increased defensin genomic copy number predisposes to psoriasis is currently unknown. We presume that a high copy number of the β-defensin cluster on 8p23.1 provides increased β-defensin protein production. In a recent study, we could demonstrate that there is indeed a significant, albeit moderate, correlation between genomic copy number and serum hBD-2 levels in healthy controls (
      • Jansen P.A.
      • Rodijk-Olthuis D.
      • Hollox E.J.
      • et al.
      Beta-defensin-2 protein is a serum biomarker for disease activity in psoriasis and reaches biologically relevant concentrations in lesional skin.
      . Speculatively, increased cutaneous β-defensin production could provide increased protection against infection upon skin barrier disruption. This evolutionary benefit may have promoted the frequency of chromosomes carrying higher β-defensin copy numbers. As the defensins are also chemotactic for inflammatory cells, high copy numbers may also increase the propensity to mount a vigorous inflammatory response to minor stimuli. These properties of β-defensins may be two sides of the same coin, leading to an evolutionary advantage for carriers of high defensin copy numbers at the expense of an increased risk for psoriasis.

      Structural epidermal proteins and psoriasis: the deletion of LCE3B and LCE3C

      Lesional psoriatic skin is characterized by premature keratinocyte differentiation and defective keratinization, including altered formation of the cornified envelope (CE). In psoriatic skin, the components of the CE are differentially expressed as compared with normal skin. Expression of the early differentiation markers such as involucrin, CDSN, the small proline-rich proteins, cystatin A, and transglutaminase 1 is increased, whereas the expression of the late differentiation markers such as loricrin and filaggrin is decreased (
      • Ishida-Yamamoto A.
      • Takahashi H.
      • Iizuka H.
      Immunoelectron microscopy links molecules and morphology in the studies of keratinization.
      ;
      • Iizuka H.
      • Takahashi H.
      • Honma M.
      • et al.
      Unique keratinization process in psoriasis: late differentiation markers are abolished because of the premature cell death.
      . The aberrant formation of the CE affects the barrier capacity of the skin in psoriasis. Several independent studies showed that transepidermal water loss of lesional psoriatic skin is higher than the transepidermal water loss of normal and uninvolved psoriatic skin. Moreover, the level of the transepidermal water loss is related to the clinical severity of the lesion, suggesting that the barrier function of lesional psoriatic skin is weaker than in normal skin (
      • Grice K.
      • Sattar H.
      • Baker H.
      • et al.
      The relationship of transepidermal water loss to skin temperature in psoriasis and eczema.
      ;
      • Motta S.
      • Monti M.
      • Sesana S.
      • et al.
      Abnormality of water barrier function in psoriasis. Role of ceramide fractions.
      . The Koebner phenomenon, i.e., the appearance of psoriatic lesions in uninvolved skin of psoriatic patients as a consequence of superficial trauma, is another indication for the involvement of the physical barrier function of the skin (
      • Powles A.V.
      • Baker B.S.
      • Rutman A.J.
      • et al.
      Epidermal rupture is the initiating factor for the Koebner response in psoriasis.
      . Although the underlying molecular mechanism is not clear yet, the keratinocytes may have a role in this phenomenon, either by compromised barrier function or secretion of cytokines (
      • Wood L.C.
      • Elias P.M.
      • Calhoun C.
      • et al.
      Barrier disruption stimulates interleukin-1 alpha expression and release from a pre-formed pool in murine epidermis.
      .
      In atopic dermatitis, until recently regarded as an immune-mediated disease, the disrupted barrier function of the skin is now considered a major cause of the disease. Loss-of-function mutations in FLG (encoding the epidermis-specific protein filaggrin) were shown to be associated with atopic dermatitis in several populations (
      • Palmer C.N.
      • Irvine A.D.
      • Terron-Kwiatkowski A.
      • et al.
      Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.
      ;
      • Rodriguez E.
      • Baurecht H.
      • Herberich E.
      • et al.
      Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease.
      . As the FLG gene is located in or near PSORS4, FLG mutations were also studied in psoriasis patients, but no associations were found (
      • Huffmeier U.
      • Traupe H.
      • Oji V.
      • et al.
      Loss-of-function variants of the filaggrin gene are not major susceptibility factors for psoriasis vulgaris or psoriatic arthritis in German patients.
      ;
      • Thyssen J.
      • Johansen J.
      • Carlsen B.
      • et al.
      The filaggrin null genotypes R501X and 2282del4 seem not to be associated with psoriasis: results from general population study and meta-analysis.
      . The PSORS4 locus is positioned on chromosome 1q21 in a region called the epidermal differentiation complex (
      • Mischke D.
      • Korge B.P.
      • Marenholz I.
      • et al.
      Genes encoding structural proteins of epidermal cornification and S100 calcium-binding proteins form a gene complex (“epidermal differentiation complex”) on human chromosome 1q21.
      . The epidermal differentiation complex is enriched for genes expressed during epidermal differentiation, including loricrin (LOR), involucrin (IVL), filaggrin (FLG), the small proline-rich protein (SPRR) genes, and the LCE genes (
      • Zhao X.P.
      • Elder J.T.
      Positional cloning of novel skin-specific genes from the human epidermal differentiation complex.
      ;
      • Jackson B.
      • Tilli C.M.
      • Hardman M.J.
      • et al.
      Late cornified envelope family in differentiating epithelia—response to calcium and ultraviolet irradiation.
      . This last cluster, with a total of 18 members, is divided into six groups, LCE1-6, based on related amino-acid sequences, genomic organization, and expression patterns (
      • Jackson B.
      • Tilli C.M.
      • Hardman M.J.
      • et al.
      Late cornified envelope family in differentiating epithelia—response to calcium and ultraviolet irradiation.
      .
      A study by
      • de Cid R.
      • Riveira-Munoz E.
      • Zeeuwen P.L.
      • et al.
      Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.
      using array-comparative genomic hybridization reported four regions on the human genome subject to CNV that were potentially associated with psoriasis in a Spanish cohort. Further investigations of one of these regions demonstrated an association of a CNV in the LCE cluster. A common deletion comprising the LCE3B and LCE3C genes (LCE3C_LCE3B-del) was found with higher frequency in patients compared with the controls. In this study, a population attributable risk of 23% was found, indicating that the deletion explains a sizable proportion of the genetic contribution. The association with LCE3C_LCE3B-del has been replicated in several cohorts with different ethnic backgrounds (
      • Huffmeier U.
      • Bergboer J.G.
      • Becker T.
      • et al.
      Replication of LCE3C-LCE3B CNV as a risk factor for psoriasis and analysis of interaction with other genetic risk factors.
      ;
      • Li M.
      • Wu Y.
      • Chen G.
      • et al.
      Deletion of the late cornified envelope genes LCE3C and LCE3B is associated with psoriasis in a chinese population.
      ;
      • Riveira-Munoz E.
      • He S.M.
      • Escaramis G.
      • et al.
      Meta-analysis confirms the LCE3C_LCE3B deletion as a risk factor for psoriasis in several ethnic groups and finds interaction with HLA-Cw6.
      ;
      • Xu L.
      • Li Y.
      • Zhang X.
      • et al.
      Deletion of LCE3C and LCE3B genes is associated with psoriasis in a northern Chinese population.
      . In addition, in an independent GWAS of a large Chinese cohort, SNPs in strong linkage disequilibrium with LCE3C_LCE3B-del were identified as risk factors for psoriasis (
      • Zhang X.J.
      • Huang W.
      • Yang S.
      • et al.
      Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21.
      . In the Dutch, American, and Chinese psoriasis cohorts, a genetic interaction (epistasis) of LCE3C_LCE3B-del and HLA-C*06 was found (
      • de Cid R.
      • Riveira-Munoz E.
      • Zeeuwen P.L.
      • et al.
      Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.
      ;
      • Riveira-Munoz E.
      • He S.M.
      • Escaramis G.
      • et al.
      Meta-analysis confirms the LCE3C_LCE3B deletion as a risk factor for psoriasis in several ethnic groups and finds interaction with HLA-Cw6.
      ;
      • Zheng H.F.
      • Zuo X.B.
      • Lu W.S.
      • et al.
      Variants in MHC, LCE and IL12B have epistatic effects on psoriasis risk in Chinese population.
      . A similar interaction between PSORS1 and PSORS4 was described previously by
      • Capon F.
      • Semprini S.
      • Dallapiccola B.
      • et al.
      Evidence for interaction between psoriasis-susceptibility loci on chromosomes 6p21 and 1q21.
      in an Italian cohort. Epistasis was less evident in other cohorts studied (
      • de Cid R.
      • Riveira-Munoz E.
      • Zeeuwen P.L.
      • et al.
      Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.
      ;
      • Riveira-Munoz E.
      • He S.M.
      • Escaramis G.
      • et al.
      Meta-analysis confirms the LCE3C_LCE3B deletion as a risk factor for psoriasis in several ethnic groups and finds interaction with HLA-Cw6.
      , which might be due to heterogeneity between populations. Until now, LCE3C_LCE3B-del was found to be associated with psoriasis, psoriatic arthritis, and rheumatoid arthritis in several populations (
      • Bowes J.
      • Flynn E.
      • Ho P.
      • et al.
      Variants in linkage disequilibrium with the late cornified envelope gene cluster deletion are associated with susceptibility to psoriatic arthritis.
      ;
      • Docampo E.
      • Rabionet R.
      • Riveira-Munoz E.
      • et al.
      Deletion of the late cornified envelope genes, LCE3C and LCE3B, is associated with rheumatoid arthritis.
      ,
      • Docampo E.
      • Giardina E.
      • Riveira-Munoz E.
      • et al.
      Deletion of LCE3C and LCE3B is a susceptibility factor for psoriatic arthritis: a study in Spanish and Italian populations and meta-analysis.
      ;
      • Lu X.
      • Guo J.
      • Zhou X.
      • et al.
      Deletion of LCE3C_LCE3B is associated with rheumatoid arthritis and systemic lupus erythematosus in the Chinese Han population.
      ;
      • Bergboer J.G.
      • Umicevic-Mirkov M.
      • Fransen J.
      • et al.
      A replication study of the association between rheumatoid arthritis and deletion of the late cornified envelope genes LCE3B and LCE3C.
      , whereas no association was found for atopic dermatitis (
      • Bergboer J.G.
      • Zeeuwen P.L.
      • Irvine A.D.
      • et al.
      Deletion of late cornified envelope 3B and 3C genes is not associated with atopic dermatitis.
      . In addition, in one study an association with systemic lupus erythematosus was found (
      • Lu X.
      • Guo J.
      • Zhou X.
      • et al.
      Deletion of LCE3C_LCE3B is associated with rheumatoid arthritis and systemic lupus erythematosus in the Chinese Han population.
      , and in another study an association with allergic contact dermatitis was detected (
      • Molin S.
      • Vollmer S.
      • Weiss E.H.
      • et al.
      Deletion of the late cornified envelope genes LCE3B and LCE3C may promote chronic hand eczema with allergic contact dermatitis.
      , implying that LCE3C_LCE3B-del may be a common risk factor for inflammatory diseases.
      To evaluate the possible function of the LCE3B and LCE3C genes in psoriasis,
      • de Cid R.
      • Riveira-Munoz E.
      • Zeeuwen P.L.
      • et al.
      Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.
      and
      • Bergboer J.G.
      • Tjabringa G.S.
      • Kamsteeg M.
      • et al.
      Psoriasis risk genes of the late cornified envelope-3 group are distinctly expressed compared with genes of other LCE groups.
      investigated the expression of almost all human LCE genes. In a large tissue screen, moderate to high LCE expression was largely confined to skin and a few oropharyngeal tissues (see Figure 1 panels LCE2B and LCE3A, and Figure 2b).
      • Jackson B.
      • Tilli C.M.
      • Hardman M.J.
      • et al.
      Late cornified envelope family in differentiating epithelia—response to calcium and ultraviolet irradiation.
      showed that LCE1 and LCE2 group members are mainly expressed in skin, and they are hardly expressed in internal epithelia. The LCE3 group members are absent or variably expressed at low levels in internal and external epithelia, and they show variable expression between tissue types. LCE4 and LCE5 expression was barely detected in the investigated tissues. The authors discovered heterogeneity between individuals with respect to the expression of the different LCE genes. Studies in cultured keratinocytes showed that the LCE2 expression is induced by calcium, and that UV induces the expression of the LCE1 and LCE2 groups and of LCE3E.
      The expression of LCE3 genes was hardly detectable in normal and uninvolved psoriatic skin. In lesional psoriatic skin, however, expression of the LCE3 genes (when present) was highly induced (
      • de Cid R.
      • Riveira-Munoz E.
      • Zeeuwen P.L.
      • et al.
      Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.
      . In contrast, expression of the members of other LCE groups was downregulated under these conditions. To investigate whether skin barrier disruption might be a pathophysiological stimulus for LCE3 expression, their expression was examined in healthy individuals following minor skin injury by tape stripping. Indeed, in normal skin, LCE3 gene expression was induced upon tape stripping, whereas the genes of other LCE groups were downregulated (
      • Bergboer J.G.
      • Tjabringa G.S.
      • Kamsteeg M.
      • et al.
      Psoriasis risk genes of the late cornified envelope-3 group are distinctly expressed compared with genes of other LCE groups.
      . These results indicate a role for the LCE3 genes in psoriasis. The 32.4-kb deleted region harbors, next to the LCE3B and LCE3C genes, also a conserved noncoding element that functions as a epidermal-specific enhancer (
      • de Guzman Strong C.
      • Conlan S.
      • Deming C.B.
      • et al.
      A milieu of regulatory elements in the epidermal differentiation complex syntenic block: implications for atopic dermatitis and psoriasis.
      . The loss of this enhancer in individuals harboring LCE3C_LCE3B-del may function as a contributing factor in psoriasis by affecting global transcription of the epidermal differentiation complex genes.
      The role of the LCE proteins in the formation of the CE has not been extensively studied. In mice,
      • Marshall D.
      • Hardman M.J.
      • Nield K.M.
      • et al.
      Differentially expressed late constituents of the epidermal cornified envelope.
      found that members of the Lce protein family are expressed rather late in epithelia, where they are cross-linked by transglutaminases. By using immunoelectoron microscopy, they demonstrated that an Lce1 member is a structural CE component.
      • Steinert P.M.
      • Parry D.A.
      • Marekov L.N.
      Trichohyalin mechanically strengthens the hair follicle: multiple cross-bridging roles in the inner root shealth.
      found that an LEP (now known as LCE) is indeed cross-linked to involucrin and trichohyalin in murine CEs. In humans, LCE2 protein expression was restricted to the uppermost granular layer and the stratum corneum, as shown by immunohistochemistry and immunoelectron microscopy (
      • Bergboer J.G.
      • Tjabringa G.S.
      • Kamsteeg M.
      • et al.
      Psoriasis risk genes of the late cornified envelope-3 group are distinctly expressed compared with genes of other LCE groups.
      . In murine development, the expression of the Lce genes starts after the expression of the Sprr genes, and is delayed until just before initial formation of the barrier (
      • Marshall D.
      • Hardman M.J.
      • Byrne C.
      SPRR1 gene induction and barrier formation occur as coordinated moving fronts in terminally differentiating epithelia.
      .
      We can only speculate on the role of the deletion of LCE3B and LCE3C in the development of psoriasis. The frequency of the deletion is also high in the general population (about 60–70%), and is in fact more prevalent than the undeleted allele. As the intact LCE3B and LCE3C genes are ancestral and the deletion is a derived state, there might be a possible evolutionary pressure to lose these genes. As LCE3B and LCE3C are not normally expressed at significant levels in skin, the situation is different from FLG and atopic dermatitis. With respect to atopic dermatitis, it has been suggested that a slightly leaky skin barrier could allow penetration of microbial antigens and would favor natural vaccination, thereby protecting against pathogens. In the case of LCE3B and LCE3C, expression is only induced after barrier disruption. Speculatively, incomplete barrier repair after minor injury might lead to antigen penetration and natural immunization against pathogens. The downside would be that penetration of proinflammatory environmental stimuli (e.g., Toll-like receptor ligands) would be favored as well, which could trigger an inflammatory process that leads to psoriasis. Such a scenario could also offer an explanation for the Koebner phenomenon, which is observed in ∼25% of all psoriasis patients (
      • Weiss G.
      • Shemer A.
      • Trau H.
      The Koebner phenomenon: review of the literature.
      . In a recent study, however, we did not find an association between LCE3C_LCE3B-del and Koebner phenomenon in a Dutch cohort of psoriasis patients (
      • Bergboer J.G.
      • Oostveen A.M.
      • de Jager M.E.
      • et al.
      Koebner phenomenon in psoriasis is not associated with deletion of late cornified envelope genes LCE3B and LCE3C.
      . When comparing the reported population attributable risks for LCE3C_LCE3B-del and psoriasis (23%) and FLG-null alleles and atopic dermatitis (13%), it could be argued that skin barrier abnormalities are as important (if not more) in psoriasis as they are for atopic dermatitis.

      Genetic interactions in psoriasis

      Genetic polymorphisms that are considered as “disease-causing” do not have the same effects in all individuals. For example, HLA-C*06 is a very strong risk factor for psoriasis (odds ratio 3–34, depending on the population (
      • Riveira-Munoz E.
      • He S.M.
      • Escaramis G.
      • et al.
      Meta-analysis confirms the LCE3C_LCE3B deletion as a risk factor for psoriasis in several ethnic groups and finds interaction with HLA-Cw6.
      ), but the majority of HLA-C*06 carriers do not have psoriasis. Additional causes for developing the disease are environmental influences, epigenetic variation, and genetic background. The dependence of a disease-associated mutation or polymorphism on genetic background is defined as “genetic interaction” or epistasis (
      • Lehner B.
      Molecular mechanisms of epistasis within and between genes.
      . When considering two loci that are associated with a disease, a deviation from the additive effects of the two (either negative or positive) is regarded as genetic interaction. The molecular or cellular mechanism by which these two factors exert their effect is then called “biological interaction”. Complex diseases are often regarded as interplay of many interacting genetic factors and environmental stimuli. There are, however, not many examples of genes that show proof of epistasis in common complex disorders. Psoriasis is unique in that sense, as recent publications have provided evidence for genetic interaction between HLA-C*06 and LCE3C_LCE3B-del, and between HLA-C*06 and ERAP1 (
      • de Cid R.
      • Riveira-Munoz E.
      • Zeeuwen P.L.
      • et al.
      Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.
      ;
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      ;
      • Riveira-Munoz E.
      • He S.M.
      • Escaramis G.
      • et al.
      Meta-analysis confirms the LCE3C_LCE3B deletion as a risk factor for psoriasis in several ethnic groups and finds interaction with HLA-Cw6.
      ;
      • Zheng H.F.
      • Zuo X.B.
      • Lu W.S.
      • et al.
      Variants in MHC, LCE and IL12B have epistatic effects on psoriasis risk in Chinese population.
      . In one study, genetic interaction was observed between three loci, HLA-C, CSTA, and D12346 (
      • Vasilopoulos Y.
      • Sagoo G.S.
      • Cork M.J.
      • et al.
      HLA-C, CSTA and DS12346 susceptibility alleles confer over 100-fold increased risk of developing psoriasis: evidence of gene interaction.
      . The interaction between HLA-C*06 and LCE3C_LCE3B-del was first discovered in our Dutch psoriasis case–control cohort but has now been documented for a number of populations (see meta-analysis by
      • Riveira-Munoz E.
      • He S.M.
      • Escaramis G.
      • et al.
      Meta-analysis confirms the LCE3C_LCE3B deletion as a risk factor for psoriasis in several ethnic groups and finds interaction with HLA-Cw6.
      ). Remarkably, this interaction was not found in a few other populations with similar ethnic background. Whether this reflects technical issues (genotyping by tagging SNP or HLA-C*06 itself) or genetic heterogeneity remains to be investigated. Previous studies have indicated substantial differences in allele frequencies of LCE3C_LCE3B-del in controls of European descent, which may have a role (
      • Riveira-Munoz E.
      • He S.M.
      • Escaramis G.
      • et al.
      Meta-analysis confirms the LCE3C_LCE3B deletion as a risk factor for psoriasis in several ethnic groups and finds interaction with HLA-Cw6.
      . Similarly, FLG mutations associated with atopic dermatitis, although widely replicated in European and Asian populations, were not found in an Italian cohort. The genetic interaction that we observed in our Dutch cohort was particularly strong, as HLA-C*06 was only a risk factor in the group that carried at least one deleted LCE3C_LCE3B allele. Taken together, the combination of HLA-C*06 positivity and a deleted LCE3C_LCE3B allele yielded an odds ratio of 9.8 compared with HLA-C*06/LCE3C_LCE3B-del-negative individuals as a reference category.
      Interestingly, in a recent GWAS, the ERAP1 gene was found to be a risk factor for psoriasis (
      • Strange A.
      • Capon F.
      • Spencer C.C.
      • et al.
      A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1.
      . ERAP1 encodes a protease that has an important role in major histocompatibility complex class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele.
      On the basis of these genetic findings, it is a major challenge to translate these data into meaningful biological experiments, and to explain the observed epistasis in molecular or cellular terms. In the next paragraph, we will discuss the possible biological interactions that underlie the observed genetic interactions between HLA-C*06 and its interacting genes.

      A model for the pathogenesis of psoriasis

      Any model that tries to explain a disease should take clinical, pharmacological, cell biological, and genetic data into account. On the basis of genetic data, we propose that candidate genes with a presumed or proven role in the adaptive immune system are important. Table 1 lists all genes with a presumed function in the adaptive immune system that were found to be associated with psoriasis. The most prominent genes from this list are HLA-C*06 and genes of the IL-23 pathway, as these are the most widely replicated genes. A second group of genetic risk factors listed in Table 1 are genes associated with innate immunity, such as the β-defensins and genes associated with TNF-α and NF-κB-regulated pathways such as TNIP1 and TNFAIP3. A third functional category would be genes involved in physical skin barrier maintenance, such as the LCE3B and LCE3C genes. In Figure 3 we have tried to put these genetic factors into place, in relation to biology and clinical data.
      Figure thumbnail gr3
      Figure 3Tentative model of psoriasis based on genetic and cell biological data. Polymorphisms of genes involved in skin barrier and immune function will cooperatively determine the exposure, handling, and response to environmental stimuli (pathogen-associated molecular patterns, antigens). Depending on the host genotype, this may lead to increased penetration of antigens, low-grade inflammation caused by keratinocyte activation, and chemotaxis of immunocompetent cells. Ultimately, this could lead to activation of adaptive immunity in genetically predisposed individuals who respond to hitherto unidentified external antigens or autoantigens through molecular mimicry. The ensuing (HLA-Cw6-restricted) immune response, which includes secretion of Th1 and Th17 cytokines, will in turn cause activation of keratinocytes, resulting in a vicious cycle and chronicity of inflammation.
      Reprinted from
      • Bergboer J.G.
      • Tjabringa G.S.
      • Kamsteeg M.
      • et al.
      Psoriasis risk genes of the late cornified envelope-3 group are distinctly expressed compared with genes of other LCE groups.
      , with permission from Elsevier.
      The epidermis is continuously exposed to mechanical trauma and subclinical infections. Therefore, environmental antigens and microbial components collectively named pathogen-associated molecular patterns (PAMPs) will enter the epidermis. These PAMPs can be derived from resident commensal microorganisms, or from sources elsewhere in the body (throat, gut, lungs). PAMPs can activate keratinocytes and immunocompetent cells via pattern recognition receptors such as the Toll-like receptors, NOD-like receptors, C-type lectin receptors, and RIGI-like helicases (
      • Medzhitov R.
      Recognition of microorganisms and activation of the immune response.
      ;
      • De Koning H.D.
      • Rodijk-Olthuis D.
      • van Vlijmen-Willems I.M.
      • et al.
      A comprehensive analysis of pattern recognition receptors in normal and inflamed human epidermis: upregulation of dectin-1 in psoriasis.
      . These PAMPs activate the epidermal innate immune system and drive expression and secretion of antimicrobial proteins (defensins, SLPI, S100 proteins and LL-37) and chemokines/cytokines such as IL-8, CXCL10, IL-1β, and TNF-α (
      • De Koning H.D.
      • Kamsteeg M.
      • Rodijk-Olthuis D.
      • et al.
      Epidermal expression of host response genes upon skin barrier disruption in normal skin and uninvolved skin of psoriasis and atopic dermatitis patients.
      . Minor disturbances of the skin barrier will also initiate a repair response, which includes upregulation of regular skin barrier proteins (involucrin, transglutaminase-1) but will also induce de novo expression of structural proteins putatively involved in repair, regeneration, and temporal barrier recovery (e.g., keratins 6 and 17, SPRRs, SKALP/elafin, and members of the LCE3 group). Under normal steady-state conditions, superficial skin injury and exposure to PAMPs will quickly lead to keratinocyte activation, elimination of infectious agents, barrier repair, and restoration of homeostasis. In genetically predisposed individuals, minor injury and exposure to PAMPs and cytokines could lead to enhanced inflammatory responses (
      • Zeeuwen P.L.
      • de Jongh G.J.
      • Rodijk-Olthuis D.
      • et al.
      Genetically programmed differences in epidermal host defense between psoriasis and atopic dermatitis patients.
      , increased production of β-defensins in individuals with high copy numbers (
      • Jansen P.A.
      • Rodijk-Olthuis D.
      • Hollox E.J.
      • et al.
      Beta-defensin-2 protein is a serum biomarker for disease activity in psoriasis and reaches biologically relevant concentrations in lesional skin.
      , and insufficient or delayed skin barrier repair in individuals who are heterozygous or homozygous for LCE3C_LCE3B-del (
      • de Cid R.
      • Riveira-Munoz E.
      • Zeeuwen P.L.
      • et al.
      Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.
      ;
      • Bergboer J.G.
      • Tjabringa G.S.
      • Kamsteeg M.
      • et al.
      Psoriasis risk genes of the late cornified envelope-3 group are distinctly expressed compared with genes of other LCE groups.
      . This will affect the innate and adaptive immune system in several ways. First, the secretion of mediators such as IL-8, CXCL10, and β-defensins will attract neutrophils, T cells, and dendritic cells to the epidermal compartment. Second, incomplete barrier repair will allow sustained penetration of PAMPs or even larger (protein) antigens that will be taken up by Langerhans cells and dendritic cells and presented to T cells. At this point, T-cell activation will be initiated, which could be facilitated by genetic predispositions such as HLA-C*06 or polymorphisms in genes of the IL-23 pathway and other factors mentioned above. The observed epistatic interaction between LCE3C_LCE3B-del and HLA-C*06 could be explained in the context of such a mechanism. Sustained penetration of protein antigens with HLA-Cw6-restricted immunodominant epitopes could cause antigen-specific activation of CD8+ T cells, leading to secretion of TNF-α and IFN-γ. This is compatible with the TNF-α and IFN-γ keratinocyte gene expression signature found in psoriatic epidermis. In a similar way, the observed epistasis of HLA-C*06 and ERAP1 can be explained by preferred trimming of immunogenic HLA-Cw6-restricted peptides from relevant antigens by the ERAP1 protease. So far, no T cells specific for a defined HLA-Cw6-restricted peptide have ever been identified in psoriasis. It is therefore not clear whether a regular adaptive immune response to foreign proteins is relevant in this disease. Similarly, no convincing evidence for an autoreactive response has been obtained so far. Assuming that HLA-C*06 is the true causative gene of PSORS1, it remains to be proven whether HLA-Cw6 is a classical major histocompatibility complex allele involved in presentation of self-peptides, or crosspresentation of nonself peptides, leading to (cross)priming of T cells. Similarly, a role of HLA-Cw6 in the interaction with natural killer cells via killer Ig receptors cannot be ruled out.
      Whatever the mechanism of T-cell activation may be, either antigen-driven or not, large numbers of activated CD4+ and CD8+ cells are present in the lesion. CD8+ cells in particular also invade the epidermis and are in close contact with keratinocytes and Langerhans cells. These activated T cells will secrete Th1 and Th17 cytokines (IFN-γ, TNF-α IL-17, IL-23, IL-22), which will further activate the keratinocytes. IFN-γ and Th17 cytokines will also synergize with IL-1 and TNF-α, e.g., derived from keratinocytes, to further enhance expression of antimicrobial proteins and chemokines by keratinocytes. This scenario creates a vicious circle: activated keratinocytes produce chemokines and antimicrobial proteins that attract immunocompetent cells. Keratinocytes will continue to proliferate, and differentiate incompletely, thereby expressing genes that make a provisional skin barrier, which may be inferior in individuals carrying heterozygous or homozygous deletions of the LCE3B and LCE3C genes. At the same time, the expression of some genes involved in normal cornification (e.g., filaggrin and loricrin) is suppressed. The resulting incomplete barrier of lesional psoriatic skin will continuously allow PAMPs and protein antigens to enter the skin and activate immunocompetent cells. As there is no negative feedback in the process once initiated (depicted in Figure 3), this could explain the chronicity of a lesion.
      From the scheme in Figure 3 it is also evident that the vicious circle can be interrupted at any point, using the appropriate medication. T-cell-directed therapies will suppress secretion of Th1 and Th17 cytokines, resulting in a decrease of keratinocyte activation and a concomitant suppression of keratinocyte-derived chemokine secretion. Anti-TNF will act on secreted or membrane-bound TNF, either from keratinocytes or from immunocytes, and has indeed proven to be an effective therapy (
      • Lowes M.A.
      • Bowcock A.M.
      • Krueger J.G.
      Pathogenesis and therapy of psoriasis.
      . Retinoids suppress cytokine-induced keratinocyte activation and will decrease defensin and cytokine secretion (
      • Tjabringa G.
      • Bergers M.
      • van Rens D.
      • et al.
      Development and validation of human psoriatic skin equivalents.
      . Vitamin D3 derivatives will inhibit keratinocyte proliferation (
      • Gniadecki R.
      Effects of 1,25-dihydroxyvitamin D3 and its 20-epi analogues (MC 1288, MC 1301, KH 1060), on clonal keratinocyte growth: evidence for differentiation of keratinocyte stem cells and analysis of the modulatory effects of cytokines.
      and thereby normalize epidermal differentiation, promoting skin barrier restoration. In addition, both retinoids and vitamin D3 derivatives may also act on the immune system by stimulating the expansion of regulatory T cells or suppressing Th17 function (
      • Mucida D.
      • Park Y.
      • Kim G.
      • et al.
      Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid.
      ;
      • Ghoreishi M.
      • Bach P.
      • Obst J.
      • et al.
      Expansion of antigen-specific regulatory T cells with the topical vitamin d analog calcipotriol.
      . Various other successful antipsoriatic therapies such as corticosteroids, dithranol, and methotrexate may act on many points in the vicious circle, as they are found to be immunosuppressive but can also affect keratinocyte proliferation and differentiation (
      • Gottlieb A.B.
      • Khandke L.
      • Krane J.F.
      • et al.
      Anthralin decreases keratinocyte TGF-alpha expression and EGF-receptor binding in vitro.
      ;
      • Schwartz P.M.
      • Barnett S.K.
      • Atillasoy E.S.
      • et al.
      Methotrexate induces differentiation of human keratinocytes.
      . Even the observed moderately beneficial effects of skin occlusion as a monotherapy could be explained by decreasing the exposure to exogenous stimuli using an artificial skin barrier (
      • Gottlieb A.B.
      • Staiano-Coico L.
      • Cohen S.R.
      • et al.
      Occlusive hydrocolloid dressings decrease keratinocyte population growth fraction and clinical scale and skin thickness in active psoriatic plaques.
      .

      Concluding Remarks

      In summary, there are now more than 25 psoriasis risk genes known, and two of them (HLA-C*06 and LCE3C_LCE3B-del) contribute a significant proportion of the population attributable risk. At least three different biological pathways (adaptive immunity, innate immunity, and skin barrier) are known to be involved, and their potential mode of genetic and biological interaction is illustrated in Figure 3. We believe that this model generates testable hypotheses, which may uncover the pathobiological mechanisms of psoriasis, and could contribute to prevention and therapy for psoriasis.

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