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Molecular Dissection of Psoriasis: Integrating Genetics and Biology

      Psoriasis is a common and debilitating disease of the skin, nails, and joints, with an acknowledged but complex genetic basis. Early genome-wide linkage studies of psoriasis focused on segregation of microsatellite markers in families; however, the only locus consistently identified resided in the major histocompatibility complex. Subsequently, several groups mapped this locus to the vicinity of HLA-C, and two groups have reported HLA-Cw6 itself to be the major susceptibility allele. More recently, the development of millions of single-nucleotide polymorphisms, coupled with the development of high-throughput genotyping platforms and a comprehensive map of human haplotypes, has made possible a genome-wide association approach using cases and controls rather than families. Taking advantage of these developments, we participated in a collaborative genome-wide association study of psoriasis involving thousands of cases and controls. Initial analysis of these data revealed and/or confirmed association between psoriasis and seven genetic loci—HLA-C, IL12B, IL23R, IL23A, IL4/IL13, TNFAIP3, and TNIP1—and ongoing studies are revealing additional loci. Here, we review the epidemiology, immunopathology, and genetics of psoriasis, and present a disease model integrating its genetics and immunology.

      Abbreviations

      Ag
      antigen
      APC
      antigen-presenting cell
      CASP
      Collaborative Association Study of Psoriasis
      DC
      dendritic cell
      EDC
      epidermal differentiation complex
      GWAS
      genome-wide association study
      KC
      keratinocyte
      KIR
      killer immunoglobulin-like receptors
      LCE
      late cornified envelope
      LD
      linkage disequilibrium
      MHC
      major histocompatibility complex
      pDC
      plasmacytoid dendritic cells
      PsA
      psoriatic arthritis
      PSORS1
      psoriasis susceptibility-1
      SNP
      single-nucleotide polymorphism
      TLR
      Toll-like receptor
      TNF-α
      tumor necrosis factor-α

      Epidemiology of Psoriasis: an Overview

      Psoriasis is a common disease, affecting about 2% of Americans at a cost of over 3 billion dollars a year (
      • Sander H.M.
      • Morris L.F.
      • Phillips C.M.
      • Harrison P.E.
      • Menter A.
      The annual cost of psoriasis.
      ). Psoriasis has a major impact on the quality of life (
      • Gupta M.A.
      • Schork N.J.
      • Gupta A.K.
      • Kirkby S.
      • Ellis C.N.
      Suicidal ideation in psoriasis.
      ;
      • Choi J.
      • Koo J.Y.
      Quality of life issues in psoriasis.
      ), leading psoriatics to report a reduction in physical and mental functioning comparable with that seen in cancer, arthritis, hypertension, heart disease, diabetes, and depression (
      • Rapp S.R.
      • Feldman S.R.
      • Exum M.L.
      • Fleischer Jr, A.B.
      • Reboussin D.M.
      Psoriasis causes as much disability as other major medical diseases.
      ). More than 150,000 new diagnoses of psoriasis are made each year in the United States. Most of these are made in persons under 30 years of age, with more than 10,000 being less than 10 years old (
      • Krueger G.G.
      • Bergstresser P.R.
      • Lowe N.J.
      • Voorhees J.J.
      • Weinstein G.D.
      Psoriasis.
      ). A total of 10–40% of psoriatics develop psoriatic arthritis (PsA), which is severe and deforming in about 5% of patients (
      • Gladman D.D.
      Natural history of psoriatic arthritis.
      ;
      • Gelfand J.M.
      • Gladman D.D.
      • Mease P.J.
      • Smith N.
      • Margolis D.J.
      • Nijsten T.
      • et al.
      Epidemiology of psoriatic arthritis in the population of the United States.
      ).
      The clinical and genetic epidemiology of psoriasis and PsA has been reviewed previously, and will be considered only briefly here (
      • Elder J.T.
      • Nair R.P.
      • Guo S.W.
      • Henseler T.
      • Christophers E.
      • Voorhees J.J.
      The genetics of psoriasis.
      ;
      • Rahman P.
      • Elder J.T.
      Genetic epidemiology of psoriasis and psoriatic arthritis.
      ;
      • Gudjonsson J.E.
      • Elder J.T.
      Psoriasis: epidemiology.
      ). Disease onset is most commonly observed in the early twenties. It has been proposed that two forms of psoriasis can be recognized (type I and type II), with type I psoriasis, characterized by onset age ≤40 years, being more likely to be familial, severe, and strongly associated with HLA-Cw6 (
      • Henseler T.
      • Christophers E.
      Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris.
      ;
      • Stuart P.
      • Malick F.
      • Nair R.P.
      • Henseler T.
      • Lim H.
      • Jenisch S.
      • et al.
      Analysis of phenotypic variation in psoriasis as a function of age at onset and family history.
      ). The prevalence of psoriasis is approximately the same in males and females, though PsA has been suggested to be preferentially transmitted from male parents (
      • Rahman P.
      • Gladman D.D.
      • Schentag C.T.
      • Petronis A.
      Excessive paternal transmission in psoriatic arthritis.
      ;
      • Karason A.
      • Gudjonsson J.E.
      • Upmanyu R.
      • Antonsdottir A.A.
      • Hauksson V.B.
      • Runasdottir E.H.
      • et al.
      A susceptibility gene for psoriatic arthritis maps to chromosome 16q: evidence for imprinting.
      ).
      Substantial genetic epidemiological data, including studies of twins, pedigrees, and relatives of unrelated index patients suggest that psoriasis is multifactorial, that is, influenced by multiple genes as well as environmental factors including stress, trauma, and infections, notably Streptococcal pharyngitis (
      • Lomholt G.
      Psoriasis: prevalence, spontaneous course, and genetics.
      ;
      • Watson W.
      • Cann H.M.
      • Farber E.M.
      • Nall M.L.
      The genetics of psoriasis.
      ;
      • Gudjonsson J.E.
      • Elder J.T.
      Psoriasis.
      ). Genetic epidemiological studies of PsA indicate that this disorder is even more strongly influenced by genes than is cutaneous psoriasis (
      • Moll J.M.
      • Wright V.
      • O’Neill T.
      • Silman A.J.
      Familial occurrence of psoriatic arthritis.
      ;
      • Chandran V.
      • Pellett F.J.
      • Shanmugarajah S.
      • Schentag C.T.
      • Brockbank J.
      • Toloza S.
      • et al.
      Recurrence risk of psoriatic arthritis (PsA) and psoriasis (Ps) in relatives of patients with PsA (abstract).
      ).
      Several different forms of cutaneous psoriasis can be observed in the same person, either simultaneously or over time. These include chronic plaque, guttate, inverse, seborrheic, and localized and generalized pustular psoriasis, as well as palmoplantar pustulosis. Of these, chronic plaque disease is the most common. Guttate psoriasis is characterized by the rapid and generalized development of many small papules, which resolve spontaneously in about half the cases, and progress to chronic plaque psoriasis in the rest.
      Psoriatic arthritis typically presents between the ages of 35 and 45 years, usually but not always after onset of skin disease (
      • Gladman D.D.
      • Shuckett R.
      • Russell M.L.
      • Thorne J.C.
      • Schachter R.K.
      Psoriatic arthritis (PSA) – an analysis of 220 patients.
      ). The Moll and Wright classification of PsA has been widely used (
      • Moll J.M.
      • Wright V.
      Psoriatic arthritis.
      ). They defined PsA as a rheumatoid factor-negative inflammatory arthritis involving (a) distal interphalangeal predominant arthritis of hands and feet, (b) symmetric polyarthritis, (c) symmetric oligoarticular arthritis, (d) predominant axial spondylitis, and/or (e) arthritis mutilans. As seen for cutaneous psoriasis, the clinical manifestations of PsA can change considerably over time in any given patient (
      • Jones S.M.
      • Armas J.B.
      • Cohen M.G.
      • Lovell C.R.
      • Evison G.
      • McHugh N.J.
      Psoriatic arthritis: outcome of disease subsets and relationship of joint disease to nail and skin disease.
      ;
      • Marsal S.
      • Armadans-Gil L.
      • Martinez M.
      • Gallardo D.
      • Ribera A.
      • Lience E.
      Clinical, radiographic and HLA associations as markers for different patterns of psoriatic arthritis.
      ). More recently, the CASPAR (ClASsification criteria for Psoriatic ARthritis) criteria have emerged as a sensitive, specific, and reproducible tool for making a diagnosis of PsA (
      • Taylor W.
      • Gladman D.
      • Helliwell P.
      • Marchesoni A.
      • Mease P.
      • Mielants H.
      Classification criteria for psoriatic arthritis: development of new criteria from a large international study.
      ). These criteria are based on both genetic and clinical features, and define PsA as the presence of inflammatory articular disease with at least 3 points from the following items: current psoriasis (2 points), a personal history of psoriasis (1 point, unless current psoriasis is present), a family history of psoriasis (1 point, unless current psoriasis was present or there was a personal history of psoriasis), dactylitis, juxta-articular new bone formation, rheumatoid factor negativity, and nail dystrophy (1 point each). These criteria have been shown to be sensitive and specific, not only in the original study (
      • Taylor W.
      • Gladman D.
      • Helliwell P.
      • Marchesoni A.
      • Mease P.
      • Mielants H.
      Classification criteria for psoriatic arthritis: development of new criteria from a large international study.
      ) but also in early arthritis clinic, in early PsA clinic, and in family medicine clinics (
      • Taylor W.
      • Gladman D.
      • Helliwell P.
      • Marchesoni A.
      • Mease P.
      • Mielants H.
      Classification criteria for psoriatic arthritis: development of new criteria from a large international study.
      ;
      • Chandran V.
      • Schentag C.T.
      • Gladman D.D.
      Sensitivity of the classification of psoriatic arthritis criteria in early psoriatic arthritis.
      ). The presence of enthesitis (inflammation of ligament, tendon, and capsular insertions into bone) has been proposed as a unifying factor in the pathogenesis of PsA (
      • McGonagle D.
      • Conaghan P.G.
      • Emery P.
      Psoriatic arthritis: a unified concept twenty years on.
      ).
      Approximately half of psoriasis patients develop nail changes, including pitting, “oil drop” spotting, and onychodystrophy. Nail changes are strongly associated with PsA (
      • Wright V.
      Psoriatic arthritis: a comparative study of rheumatoid arthritis and arthritis associated with psoriasis.
      ;
      • Baker H.
      • Golding D.N.
      • Thompson M.
      The nails in psoriatic arthritis.
      ;
      • Eastmond C.J.
      • Wright V.
      The nail dystrophy of psoriatic arthritis.
      ;
      • Gladman D.D.
      • Anhorn K.A.
      • Schachter R.K.
      • Mervart H.
      HLA antigens in psoriatic arthritis.
      ;
      • Lavaroni G.
      • Kokelj F.
      • Pauluzzi P.
      • Trevisan G.
      The nails in psoriatic arthritis.
      ;
      • Williamson L.
      • Dalbeth N.
      • Dockerty J.L.
      • Gee B.C.
      • Weatherall R.
      • Wordsworth B.P.
      Extended report: nail disease in psoriatic arthritis – clinically important, potentially treatable and often overlooked.
      ), possibly because of the close proximity of the nail folds to the “entheseal unit” of the distal interphalangeal joint region (
      • Tan A.L.
      • Benjamin M.
      • Toumi H.
      • Grainger A.J.
      • Tanner S.F.
      • Emery P.
      • et al.
      The relationship between the extensor tendon enthesis and the nail in distal interphalangeal joint disease in psoriatic arthritis – a high-resolution MRI and histological study.
      ).

      Immunopathogenesis of Psoriasis

      In pathophysiological terms, psoriasis is characterized by markedly increased epidermal growth and altered differentiation, many biochemical, immunological, inflammatory, and vascular abnormalities, and a poorly understood relationship to nervous system function (
      • Gudjonsson J.E.
      • Elder J.T.
      Psoriasis.
      ). There is a large body of literature on the immunopathogenesis of psoriasis, which has been comprehensively reviewed recently (
      • Lowes M.A.
      • Bowcock A.M.
      • Krueger J.G.
      Pathogenesis and therapy of psoriasis.
      ;
      • Nickoloff B.J.
      • Qin J.Z.
      • Nestle F.O.
      Immunopathogenesis of psoriasis.
      ). Many observations suggest that psoriasis is a T-cell-mediated disease driven at least in part by a positive feedback loop from activated T cells to antigen-presenting cells (APCs) that is mediated by IFN-γ, IL-1, and tumor necrosis factor-α (TNF-α). Moreover, there are important contributions of innate immune mechanisms involving the epidermis and macrophages (
      • Buchau A.S.
      • Gallo R.L.
      Innate immunity and antimicrobial defense systems in psoriasis.
      ). In psoriatic lesions, there is a distinct compartmentalization of T cells between the anatomic layers of the skin: CD4+ T cells are found predominantly in the upper dermis, whereas CD8+ T cells mostly localize to the epidermis (
      • Baker B.S.
      • Swain A.F.
      • Fry L.
      • Valdimarsson H.
      Epidermal T lymphocytes and HLA-DR expression in psoriasis.
      ). The functional importance of T cells is emphasized by the high therapeutic efficacy of cyclosporine A, a T-cell-selective immunosuppressant (
      • Ellis C.N.
      • Gorsulowsky D.C.
      • Hamilton T.A.
      • Billings J.K.
      • Brown M.D.
      • Headington J.T.
      • et al.
      Cyclosporine improves psoriasis in a double-blind study.
      ), as well as other T-cell-selective immunomodulators, including anti-CD4 antibodies (
      • Prinz J.
      • Braun-Falco O.
      • Meurer M.
      • Daddona P.
      • Reiter C.
      • Rieber P.
      • et al.
      Chimaeric CD4 monoclonal antibody in treatment of generalised pustular psoriasis [letter].
      ), CTLA4Ig (
      • Abrams J.R.
      • Kelley S.L.
      • Hayes E.
      • Kikuchi T.
      • Brown M.J.
      • Kang S.
      • et al.
      Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells.
      ), alefacept (
      • Sugiyama M.
      • Speight P.M.
      • Prime S.S.
      • Watt F.M.
      Comparison of integrin expression and terminal differentiation capacity in cell lines derived from oral squamous cell carcinomas.
      ), and DAB389IL-2 (
      • Gottlieb S.L.
      • Gilleaudeau P.
      • Johnson R.
      • Estes L.
      • Woodworth T.G.
      • Gottlieb A.B.
      • et al.
      Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis.
      ). The role of hematopoietic cells in psoriasis is further highlighted by cases of psoriasis caused by or cured by bone marrow transplants, depending on whether the donor or recipient had psoriasis (
      • Gardembas-Pain M.
      • Ifrah N.
      • Foussard C.
      • Boasson M.
      • Saint Andre J.P.
      • Verret J.L.
      Psoriasis after allogeneic bone marrow transplantation [letter].
      ;
      • Kanamori H.
      • Tanaka M.
      • Kawaguchi H.
      • Yamaji S.
      • Fujimaki K.
      • Tomita N.
      • et al.
      Resolution of psoriasis following allogeneic bone marrow transplantation for chronic myelogenous leukemia: case report and review of the literature.
      ). Biologics that block TNF-α are also highly effective, reflecting important roles for this multifunctional cytokine in antigen (Ag) presentation, macrophage activation, and leukocyte trafficking (for review, see
      • Gudjonsson J.E.
      • Elder J.T.
      Psoriasis.
      ).
      The recent discovery of a new subset of human T cells expressing IL-17 (
      • Steinman L.
      A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage.
      ) has led to the suggestion that these cells have a major role in psoriasis (
      • Lowes M.A.
      • Kikuchi T.
      • Fuentes-Duculan J.
      • Cardinale I.
      • Zaba L.C.
      • Haider A.S.
      • et al.
      Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells.
      ) as well as other autoimmune epithelial disorders such as Crohn's disease (
      • Neurath M.F.
      IL-23: a master regulator in Crohn disease.
      ). Although the mechanisms involved in the differentiation of IL-17-expressing T cells from naïve precursors remain controversial (
      • Steinman L.
      A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage.
      ), it is clear that the expansion and survival of these cells are driven by IL-23, largely produced by dendritic APC acting on the IL-23 receptor on T cells. We recently showed that IFN-γ causes myeloid APC to produce IL-1 and IL-23 and thereby stimulate the expansion of IL-17+ T cells (
      • Kryczek I.
      • Bruce A.T.
      • Gudjonsson J.E.
      • Johnston A.
      • Vatan L.
      • Szeliga W.
      • et al.
      Induction of memory IL-17+ T cell trafficking and expansion by IFN-gamma: mechanism and pathological relevance.
      ) (Figure 1). In this study, we also found a marked expansion of CD8+ T cells expressing IL-17 in psoriatic epidermis. Nearly all of the epidermal IL-17-producing T cells were CD8+, whereas such cells were essentially absent from normal epidermis (
      • Kryczek I.
      • Bruce A.T.
      • Gudjonsson J.E.
      • Johnston A.
      • Vatan L.
      • Szeliga W.
      • et al.
      Induction of memory IL-17+ T cell trafficking and expansion by IFN-gamma: mechanism and pathological relevance.
      ). More recently, we and others (
      • Nograles K.E.
      • Zaba L.C.
      • Shemer A.
      • Fuentes-Duculan J.
      • Cardinale I.
      • Kikuchi T.
      • et al.
      IL-22-producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells.
      ) have made similar observations for IL-22. Unlike mouse T cells, in which IL-17 and IL-22 are typically co-expressed, we found little overlap between T cells expressing IL-17 and those expressing IL-22 in normal or psoriatic skin (
      • Rubin C.J.
      • Kryczek I.
      • Gudjonsson J.E.
      • Johnston A.
      • Zou W.
      • Elder J.T.
      Psoriasis lesions contain distinct populations of CD4+ and CD8+ T cells producing interferon-gamma, interleukin-17, and interleukin-22 [abstract].
      ). As we will discuss in more detail later, these intriguing cells form an important link in the chain connecting the genetics and immunology of psoriasis.
      Figure thumbnail gr1
      Figure 1Proposed mechanism for Th1-mediated support of IL-17-producing T cells. Th1 cells produce IFN-γ, which stimulates myeloid antigen-presenting cells (APCs) to secrete IL-23. Together with IL-1, IL-23 promotes the survival and expansion of CD4+ and CD8+ T cells expressing IL-17. (The same mechanism expands to a largely non-overlapping population of T cells expressing IL-22, not shown). The entry of IL-17- and IL-22-producing CD8+ T cells into the epidermis promotes epidermal hyperplasia and an innate keratinocyte defense response involving proteins such as human β-defensin 2 (HBD-2), which are highly overexpressed in psoriasis. Obtained with permission from
      • Kryczek I.
      • Bruce A.T.
      • Gudjonsson J.E.
      • Johnston A.
      • Vatan L.
      • Szeliga W.
      • et al.
      Induction of memory IL-17+ T cell trafficking and expansion by IFN-gamma: mechanism and pathological relevance.
      .
      Another key link in this chain is provided by an elegant series of experiments by Nestle and colleagues, making use of a xenograft model in which nonlesional psoriatic skin is grafted onto highly immunocompromised AGR mice. In this model, local activation of human immunity occurs within the graft, possibly as a result of the trauma of grafting. Using this model, they initially showed that local proliferation of human T cells within the grafted skin itself, rather than trafficking of circulating immunocytes into the skin, is sufficient for the development of psoriasis (
      • Boyman O.
      • Hefti H.P.
      • Conrad C.
      • Nickoloff B.J.
      • Suter M.
      • Nestle F.O.
      Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha.
      ). These studies also established a strong correlation between the presence of epidermal T cells and the development of epidermal hyperplasia (
      • Boyman O.
      • Hefti H.P.
      • Conrad C.
      • Nickoloff B.J.
      • Suter M.
      • Nestle F.O.
      Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha.
      ). In subsequent experiments, they used a mAb against very late activation Ag-1 (α1β1 integrin), which is required for T-cell interaction with the epidermal basement membrane and subsequent emigration of T cells into the epidermis, to ask whether this emigration was necessary for lesion development. Indeed, antibody treatment blocked accumulation of T cells within the epidermis, and this blockade inhibited psoriatic lesion development to the same extent as observed after neutralization of TNF-α. The anti--very late activation Ag antibodies were less effective, however, when some T cells were already present in the grafted epidermis, and were ineffective when fully-developed psoriatic lesions were grafted (
      • Conrad C.
      • Boyman O.
      • Tonel G.
      • Tun-Kyi A.
      • Laggner U.
      • de Fougerolles A.
      • et al.
      Alpha1beta1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis.
      ). These studies are highly relevant to the genetics of psoriasis, because most epidermal T cells are CD8+ and are therefore likely to respond to Ags presented in the context of major histocompatibility complex (MHC) Class I molecules, such as HLA-Cw6. Consistent with this notion, many of the clonally expanded epidermal T cells in chronic psoriatic plaques are CD8+ (
      • Chang J.C.
      • Smith L.R.
      • Froning K.J.
      • Schwabe B.J.
      • Laxer J.A.
      • Caralli L.L.
      • et al.
      CD8+ T cells in psoriatic lesions preferentially use T-cell receptor V beta 3 and/or V beta 13.1 genes.
      ).

      Genetic Linkage Studies of Psoriasis

      Psoriasis is one of the most common and most heritable of the common diseases that display familial aggregation (
      • Vyse T.J.
      • Todd J.A.
      Genetic analysis of autoimmune disease.
      ). The epidemiological rationale for considering psoriasis to be a multifactorial (polygenic and environmentally influenced) genodermatosis was discussed earlier. However, these studies did not identify the specific genes involved. In 1990, Risch showed that polygenic disorders could be studied for allele sharing in a practical number (hundreds) of chosen families, as long as λ1 (the overall excess risk of disease in a first-degree relative of an affected person) was at least 4, and as long as at least one of these loci was of major effect (that is, as long as the excess risk was not more or less evenly divided between hundreds of genes) (
      • Risch N.
      Linkage strategies for genetically complex traits. II. The power of affected relative pairs.
      ). As λ1 has been estimated to be in the range of 3–6 (
      • Elder J.T.
      • Nair R.P.
      • Guo S.W.
      • Henseler T.
      • Christophers E.
      • Voorhees J.J.
      The genetics of psoriasis.
      ) and as high as 10 for juvenile-onset psoriasis (
      • Elder J.T.
      • Nair R.P.
      • Henseler T.
      • Jenisch S.
      • Stuart P.
      • Chia N.
      • et al.
      The genetics of psoriasis 2001: the odyssey continues.
      ), and with the emergence of microsatellites as practical genetic markers, in the 1990s, several groups embarked on a search for genetic determinants of psoriasis (
      • Matthews D.
      • Fry L.
      • Powles A.
      • Weber J.
      • McCarthy M.
      • Fisher E.
      • et al.
      Evidence that a locus for familial psoriasis maps to chromosome 4q.
      ;
      • Nair R.P.
      • Henseler T.
      • Jenisch S.
      • Stuart P.
      • Bichakjian C.K.
      • Lenk W.
      • et al.
      Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan.
      ;
      • Trembath R.C.
      • Clough R.L.
      • Rosbotham J.L.
      • Jones A.B.
      • Camp R.D.R.
      • Frodsham A.
      • 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.
      ;
      • Samuelsson L.
      • Enlund F.
      • Torinsson A.
      • Yhr M.
      • Inerot A.
      • Enerback C.
      • et al.
      A genome-wide search for genes predisposing to familial psoriasis by using a stratification approach.
      ;
      • Capon F.
      • Semprini S.
      • Dallapiccola B.
      • Novelli G.
      Evidence for interaction between psoriasis-susceptibility loci on chromosomes 6p21 and 1q21 [letter].
      ;
      • Karason A.
      • Kong A.
      • Frigge A.
      • Snorradottir S.
      • Nahimas J.
      • Olafsdotir E.
      • et al.
      A search for psoriasis genes in the Icelandic population [abstract].
      ;
      • Lee Y.A.
      • Ruschendorf F.
      • Windemuth C.
      • Schmitt-Egenolf M.
      • Stadelmann A.
      • Nurnberg G.
      • et al.
      Genomewide scan in German families reveals evidence for a novel psoriasis-susceptibility locus on chromosome 19p13.
      ;
      • Fischer J.
      ;
      • Lesueur F.
      • Lefevre C.
      • Has C.
      • Guilloud-Bataille M.
      • Oudot T.
      • Mahe E.
      • et al.
      Confirmation of psoriasis susceptibility loci on chromosome 6p21 and 20p13 in French families.
      ). These studies relied on genetic linkage techniques (that is, either consistent co-segregation of a particular genetic marker with disease or sharing of alleles in affected sibling pairs). However, with the exception of the psoriasis susceptibility-1 (PSORS1) locus, these studies yielded no consistent evidence for linkage to specific non-MHC loci that could be robustly replicated (reviewed in
      • Capon F.
      • Trembath R.C.
      • Barker J.N.
      An update on the genetics of psoriasis.
      ). The same problem has been encountered in a variety of other complex genetic disorders (
      • Altmuller J.
      • Palmer L.J.
      • Fischer G.
      • Scherb H.
      • Wjst M.
      Genomewide scans of complex human diseases: true linkage is hard to find.
      ). We now appreciate that this was due to the high population frequency of disease alleles in many complex genetic disorders (
      • Risch N.
      • Merikangas K.
      The future of genetic studies of complex human diseases.
      ).

      Psoriasis Genetics and the MHC

      Human leukocyte antigen associations with psoriasis have been known for over 35 years (
      • Russell T.J.
      • Schultes L.M.
      • Kuban D.J.
      Histocompatibility (HLA) antigens associated with psoriasis.
      ), and earlier studies had localized the disease determinant to the Class I end of the MHC (
      • Schmitt-Egenolf M.
      • Eiermann T.H.
      • Boehncke W.H.
      • Ständer M.
      • Sterry W.
      Familial juvenile onset psoriasis is associated with the human leukocyte antigen (HLA) class I side of the extended haplotype Cw6- B57-DRB1*0701-DQA1*0201-DQB1*0303: a population- and family-based study.
      ;
      • Jenisch S.
      • Henseler T.
      • Nair R.P.
      • Guo S.-W.
      • Westphal E.
      • Stuart P.
      • et al.
      Linkage analysis of HLA markers in familial psoriasis: strong disequilibrium effects provide evidence for a major determinant in the HLA-B/-C region.
      ). More recently, several groups reached the conclusion that PSORS1 was in the vicinity of HLA-C, but other nearby genes could not be excluded (for review, see
      • Capon F.
      • Trembath R.C.
      • Barker J.N.
      An update on the genetics of psoriasis.
      ). Despite the somewhat disappointing results of genome-wide linkage studies, the many psoriasis families we and others chose proved to be very useful for detailed mapping of PSORS1. As the defined genetic relationships between family members make it possible to determine the phases of the microsatellite genotypes (that is, to determine which marker alleles were on which chromosome), it is possible to infer recombinant ancestral haplotypes (that is, to infer meiotic crossover events that occurred many generations ago). We initially carried out an analysis of MHC haplotypes using 62 microsatellite markers (
      • Nair R.P.
      • Stuart P.
      • Henseler T.
      • Jenisch S.
      • Chia N.V.
      • Westphal E.
      • et al.
      Localization of psoriasis-susceptibility locus PSORS1 to a 60-kb interval telomeric to HLA-C.
      ), which mapped PSORS1 to the proximal MHC Class I region in the vicinity of HLA-C, and similar results were reported by Trembath and colleagues (
      • Veal C.D.
      • Capon F.
      • Allen M.H.
      • Heath E.K.
      • Evans J.C.
      • Jones A.
      • et al.
      Family-based analysis using a dense single-nucleotide polymorphism-based map defines genetic variation at PSORS1, the major psoriasis-susceptibility locus.
      ). In 2006, we reported a more detailed recombinant ancestral haplotype mapping of the region in 678 families, along with DNA sequencing of the critical interval in two disease and five normal chromosomes. This analysis strongly implicated HLA-C rather than any of the 10 other nearby genes, and identified HLA-Cw6 as very likely to be the disease allele at PSORS1 (
      • Nair R.P.
      • Stuart P.E.
      • Nistor I.
      • Hiremagalore R.
      • Chia N.V.
      • Jenisch S.
      • et al.
      Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.
      ). Our conclusions were recently confirmed by a large study of Han Chinese psoriatics, many of whom do not carry the same extended haplotypes found in psoriatics of Northern European descent (
      • Fan X.
      • Yang S.
      • Huang W.
      • Wang Z.M.
      • Sun L.D.
      • Liang Y.H.
      • et al.
      Fine mapping of the psoriasis susceptibility locus PSORS1 supports HLA-C as the susceptibility gene in the Han Chinese population.
      ).

      Genome-wide Association Studies of Psoriasis

      Unlike many Mendelian disorders in which the disease alleles are rare and of catastrophic effect, the alleles underlying complex genetic disorders are relatively common and make only modest individual contributions to disease risk, rendering them difficult to identify by linkage (
      • Botstein D.
      • Risch N.
      Discovering genotypes underlying human phenotypes: past successes for Mendelian disease, future approaches for complex disease.
      ). In this setting, tests of association are much more powerful than tests of linkage, provided causal variants or proxies for them can be genotyped (
      • Risch N.
      • Merikangas K.
      The future of genetic studies of complex human diseases.
      ). However, in contrast to linkage studies, association studies require at least 100,000 genetic markers to comprehensively survey the genome (
      • Kruglyak L.
      Prospects for whole-genome linkage disequilibrium mapping of common disease genes.
      ;
      • International HapMap Consortium
      The International HapMap Project.
      ). For this reason, genome-wide association studies (GWAS) were not feasible in the 1990s, and genetic association studies were limited to candidate genes or regions. In this decade, however, the HapMap has provided millions of genetic markers in the form of single-nucleotide polymorphisms (SNPs) (
      • Altshuler D.
      • Brooks L.D.
      • Chakravarti A.
      • Collins F.S.
      • Daly M.J.
      • Donnelly P.
      A haplotype map of the human genome.
      ). Concurrently, technologies were developed for high-throughput genotyping, allowing 100,000–1,000,000 SNPs to be typed in thousands of individuals at a reasonable cost. Anticipating these developments, we decided to focus our collection efforts on unrelated cases and controls, instead of families. This made it much easier to enroll subjects through dermatology clinics, allowing a rapid increase in sample size. In 2006, we initiated a multicenter collaboration with Dr Anne Bowcock at the Washington University of St Louis and Dr Gerald Krueger of the University of Utah to carry out a GWAS of psoriasis, which we named the Collaborative Association Study of Psoriasis (CASP). Our initial results were published recently (
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • Ding J.
      • Stuart P.E.
      • Goldgar D.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ).
      After quality control filtering of the data, we analyzed 438,670 SNPs typed for 1,359 cases and 1,400 controls. As shown in Figure 2, the discovery GWAS revealed strong associations not only at the established susceptibility loci HLA-C, IL12B, and IL23R (
      • Tsunemi Y.
      • Saeki H.
      • Nakamura K.
      • Sekiya T.
      • Hirai K.
      • Fujita H.
      • et al.
      Interleukin-12 p40 gene (IL12B) 3′-untranslated region polymorphism is associated with susceptibility to atopic dermatitis and psoriasis vulgaris.
      ;
      • Capon F.
      • Di Meglio P.
      • Szaub J.
      • Prescott N.J.
      • Dunster C.
      • Baumber L.
      • 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.
      • Garcia V.E.
      • Brandon R.
      • Callis K.P.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      ;
      • Nair R.P.
      • Ruether A.
      • Stuart P.E.
      • Jenisch S.
      • Tejasvi T.
      • Hiremagalore R.
      • et al.
      Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.
      ) but also showed promising association signals that fell short of genome-wide significance at numerous other loci. With additional colleagues from Canada, Germany, and France, we carried out a replication analysis of the GWAS results, genotyping 21 SNPs representing 19 independent loci in 6 independent samples of European origin, numbering 5,048 cases and 5,051 controls. We confirmed association at seven loci (with P<10−3 in the replication study and P<5 × 10−8 overall). In addition to the three loci previously associated with psoriasis, namely, HLA-C, IL12B, and IL23R, we identified novel genetic signals located near four plausible psoriasis candidate genes: IL23A, IL4/IL13, TNFAIP3, and TNIP1. These will be discussed in more detail below.
      Figure thumbnail gr2
      Figure 2Results of the discovery phase of the Collaborative Association Study of Psoriasis genome-wide association study. The upper panel is a “Manhattan plot” summarizing the association results obtained for 438,670 genotyped single-nucleotide polymorphisms (SNPs), plotted against chromosomal position. Seven of the 19 regions that were followed up yielded convincing evidence of association in the replication study, as indicated by green coloration. The lower panel presents a quantile–quantile plot comparing observed versus expected P-values obtained for the 438,670 genotyped SNPs. Red symbols represents all SNPs, orange symbols represent the results after excluding major histocompatibility complex (MHC) SNPs, and blue symbols represent the results after excluding SNPs at all replicated loci. The gray area represents the 90% confidence interval expected under a null distribution of P-values. Note that all panels are truncated at a -log10(P-value) of 20; markers near HLA-C exceed this threshold considerably (P≈10−53). Adapted from
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • Ding J.
      • Stuart P.E.
      • Goldgar D.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      , with permission.
      Four other GWAS of psoriasis have been reported (
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • Garcia V.E.
      • Brandon R.
      • Callis K.P.
      • 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.
      • Quaranta M.
      • Huffmeier U.
      • Allen M.
      • et al.
      Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene.
      ;
      • Liu Y.
      • Helms C.
      • Liao W.
      • Zaba L.C.
      • Duan S.
      • Gardner J.
      • et al.
      A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci.
      ;
      • Zhang X.J.
      • Huang W.
      • Yang S.
      • Sun L.D.
      • Zhang F.Y.
      • Zhu Q.X.
      • et al.
      Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21.
      ). All of them detected strong associations in the vicinity of HLA-Cw6, and additional signals in genes whose products are components of the IL-23 ligand–receptor complex. One of them detected a very strong association to the vicinity of the late cornified envelope (LCE) genes located in the epidermal differentiation complex (
      • Zhang X.J.
      • Huang W.
      • Yang S.
      • Sun L.D.
      • Zhang F.Y.
      • Zhu Q.X.
      • et al.
      Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21.
      ). This finding was simultaneously reported in a study focusing on copy number variation in psoriasis, which showed that increased risk of psoriasis is associated with deletion of the LCE3B and LCE3C genes (
      • de Cid R.
      • Riveira-Munoz E.
      • Zeeuwen P.L.
      • Robarge J.
      • Liao W.
      • Dannhauser E.N.
      • et al.
      Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.
      ). This interesting family of genes, which we initially identified in 1997 by positional cloning (
      • Zhao X.P.
      • Elder J.T.
      Positional cloning of skin-specific genes from the human epidermal differentiation complex.
      ), is involved in the terminal stages of epidermal maturation (
      • Jackson B.
      • Tilli C.L.
      • Hardman M.
      • Avilion A.
      • Macleod M.
      • Ashcroft G.
      • et al.
      Late cornified envelope family in differentiating epithelia – response to calcium and ultraviolet irradiation.
      ). Although LCE3B and LCE3C are not expressed in normal skin, they are highly expressed in psoriasis and after epidermal injury produced by tape stripping (
      • de Cid R.
      • Riveira-Munoz E.
      • Zeeuwen P.L.
      • Robarge J.
      • Liao W.
      • Dannhauser E.N.
      • et al.
      Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.
      ). Another locus identified in one of these GWAS maps to chromosome 20q13 near the ZNF313 gene. ZNF313 is strongly expressed in the skin and, similar to TNFAIP3 and TNIP1 (see below), encodes a ubiquitin ligase (
      • Capon F.
      • Bijlmakers M.J.
      • Wolf N.
      • Quaranta M.
      • Huffmeier U.
      • Allen M.
      • et al.
      Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene.
      ). Recently, we were able to confirm this association in a sample of 2,140 cases and 1,922 controls (OR=1.19, P=8.9 × 10−5) (
      • Nair R.
      • Stuart P.
      • Tejasvi T.
      • Christophers E.
      • Voorhees J.J.
      • Elder J.T.
      Replication of association of ZNF313 locus on chromosome 20q13 with psoriasis [abstract].
      ). Other genetic signals for which replication has been claimed include SNPs in the vicinity of PTPN22 other than the R620W mutation known to increase risk in several other autoimmune diseases (
      • Chung S.A.
      • Criswell L.A.
      PTPN22: its role in SLE and autoimmunity.
      ), and several SNPs in the CDKAL1 region. We find confirmatory associations with SNPs in the CDKAL1 region in the CASP primary GWAS data set (P=0.0001), but not with SNPs in the PTPN22 region (data not shown).
      An interesting feature of the GWAS results obtained thus far in psoriasis and other complex genetic disorders is that the risk allele is often the most common allele in the population. There are several possible explanations for this. The disease allele may be ancestral, as is the case for lactose intolerance. Alternatively, the “disease” allele may be beneficial in certain contexts (that is, defense against pathogens), as is the case for hemoglobinopathies increasing resistance to malaria, or at least be selectively neutral with respect to reproduction. It is also possible that the rare variant may actually encode a protective function. Finally, the actual functional variant may be rare, but carried on a common haplotype tagged by the observed variant. Fine mapping and functional studies of disease-associated variants are in their early stages in psoriasis and in many other complex genetic disorders. With time, the outcome of these studies should allow us to distinguish between these possibilities.

      Integrating the Genetics and Immunology of Psoriasis

      With the likely exception of HLA-Cw6 (
      • Nair R.P.
      • Stuart P.E.
      • Nistor I.
      • Hiremagalore R.
      • Chia N.V.
      • Jenisch S.
      • et al.
      Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.
      ), the disease-predisposing variants responsible for the genetic signals we and others have observed in psoriasis remain to be identified. Nevertheless, our results suggest roles for several key immunological pathways in disease susceptibility. Here, we present a model integrating the genetics and immunology of psoriasis emphasizing the functional relationships between the genetic loci that have been implicated to date. Some aspects of this model have been presented previously (
      • Elder J.T.
      Genome-wide association scan yields new insights into the immunopathogenesis of psoriasis.
      ;
      • Nair R.P.
      • Ding J.
      • Duffin K.C.
      • Helms C.
      • Voorhees J.J.
      • Krueger G.G.
      • et al.
      Psoriasis bench to bedside: genetics meets immunology.
      ).

      HLA-Cw6

      As expected from our earlier work (
      • Nair R.P.
      • Stuart P.E.
      • Nistor I.
      • Hiremagalore R.
      • Chia N.V.
      • Jenisch S.
      • et al.
      Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene.
      ), the MHC yielded by far the strongest association signals in the CASP study (Figure 2). The SNP that yielded the strongest association with psoriasis (rs12191877, ORreplication=2.64, Pcombined<<10−100) was in strong linkage disequilibrium (LD) with HLA-Cw6 (r2=0.63). In cases and controls for which HLA-Cw6 typing was available, HLA-Cw6 was much more highly associated with psoriasis than any single SNP. However, neither rs12191877 (
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • Ding J.
      • Stuart P.E.
      • Goldgar D.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ) nor HLA-Cw6 itself (
      • Feng B.J.
      • Soltani-Arabsahi R.
      • Bowcock A.M.
      • Nair R.
      • Elder J.T.
      • Schrodi S.J.
      • et al.
      Multiple loci within the major histocompatibility complex confer risk of psoriasis [abstract].
      ) could fully account for the MHC association signals. To search for additional disease-associated variants, we carried out a forward selection procedure, yielding a model with three imputed SNPs. Two of these were in strong LD with HLA-Cw6 and are likely to be surrogates for it. However, the third SNP (rs2022544, P-value=10−7) maps between the MHC Class III region and the HLA-DR gene cluster and exhibits only weak LD with HLA-Cw6 (r2=0.01). These results confirm the predominance of HLA-Cw6 in terms of the magnitude of its genetic effect, but suggest that at least one additional psoriasis susceptibility determinant remains to be identified in the MHC.
      Guttate psoriasis is very strongly associated with HLA-Cw6, and in one study, this allele was present in 100% of guttate psoriasis cases (
      • Mallon E.
      • Bunce M.
      • Savoie H.
      • Rowe A.
      • Newson R.
      • Gotch F.
      • et al.
      HLA-C and guttate psoriasis.
      ). Guttate psoriasis is frequently preceded by Streptococcal pharyngitis (
      • Gudjonsson J.E.
      • Elder J.T.
      Psoriasis.
      ), and this is the only infection that has been shown to trigger psoriasis in a prospective cohort study (
      • Gudjonsson J.E.
      • Thorarinsson A.M.
      • Sigurgeirsson B.
      • Kristinsson K.G.
      • Valdimarsson H.
      Streptococcal throat infections and exacerbation of chronic plaque psoriasis: a prospective study.
      ). Further suggestive of a critical role for the tonsils, other streptococcal infections of the skin, such as impetigo or erysipelas, do not have the same propensity to trigger psoriasis. Tonsillar T cells recognize activated skin capillary endothelium (
      • Akagi Y.
      • Kimura T.
      • Kunimoto M.
      • Kuki K.
      • Tabata T.
      A role of tonsillar lymphocyte for focal infection. With special reference to lymphocyte adhesion to vessels in dermis.
      ) and express the skin-specific homing molecule CLA (cutaneous lymphocyte antigen). During an episode of Streptococcal pharyngitis, we envision that Streptococcal Ags are presented in the context of HLA-Cw6 to naïve T cells in the tonsils, causing them to proliferate, differentiate into an effector/memory phenotype, and acquire skin-homing capacity. In addition, innate immune mechanisms may serve to polyclonally activate existing skin-homing memory T cells during the initial infection. On the basis of the observation of peptidoglycan-containing macrophages in the papillary and perivascular infiltrates of guttate and chronic plaque psoriasis, it has been suggested that peptidoglycan, a major constituent of the Streptococcal cell wall, may function to activate T cells in psoriasis through a Toll-like receptor (TLR)-mediated and cytokine-dependent mechanism (
      • Baker B.S.
      • Laman J.D.
      • Powles A.
      • van der Fits L.
      • Voerman J.S.
      • Melief M.J.
      • et al.
      Peptidoglycan and peptidoglycan-specific Th1 cells in psoriatic skin lesions.
      ).
      After homing to the skin, polyclonally activated T cells may provoke the initial development of the small but widespread lesions that are characteristic of guttate psoriasis. In one study, a lack of clonal TCR gene rearrangement coupled with skewing of TCR Vβ chain usage was observed in acute flares of guttate psoriasis, suggesting that superantigens might be involved in the development of guttate flares (
      • Leung D.Y.
      • Travers J.B.
      • Giorno R.
      • Norris D.A.
      • Skinner R.
      • Aelion J.
      • et al.
      Evidence for a streptococcal superantigen-driven process in acute guttate psoriasis.
      ). In contrast, studies of chronic plaque psoriasis have identified oligoclonal TCR rearrangements, suggesting the involvement of nominal Ags rather than superantigens (
      • Chang J.C.
      • Smith L.R.
      • Froning K.J.
      • Schwabe B.J.
      • Laxer J.A.
      • Caralli L.L.
      • et al.
      CD8+ T cells in psoriatic lesions preferentially use T-cell receptor V beta 3 and/or V beta 13.1 genes.
      ;
      • Prinz J.C.
      • Vollmer S.
      • Boehncke W.H.
      • Menssen A.
      • Laisney I.
      • Trommler P.
      Selection of conserved TCR VDJ rearrangements in chronic psoriatic plaques indicates a common antigen in psoriasis vulgaris.
      ;
      • Lin W.J.
      • Norris D.A.
      • Achziger M.
      • Kotzin B.L.
      • Tomkinson B.
      Oligoclonal expansion of intraepidermal T cells in psoriasis skin lesions.
      ;
      • Vollmer S.
      • Menssen A.
      • Prinz J.C.
      Dominant lesional T cell receptor rearrangements persist in relapsing psoriasis but are absent from nonlesional skin: evidence for a stable antigen-specific pathogenic T cell response in psoriasis vulgaris.
      ;
      • Diluvio L.
      • Vollmer S.
      • Besgen P.
      • Ellwart J.W.
      • Chimenti S.
      • Prinz J.C.
      Identical TCR beta-chain rearrangements in streptococcal angina and skin lesions of patients with psoriasis vulgaris.
      ). Importantly, the same clonal expansions of skin-homing T cells are found in the tonsils and in lesional skin of psoriatic patients (
      • Diluvio L.
      • Vollmer S.
      • Besgen P.
      • Ellwart J.W.
      • Chimenti S.
      • Prinz J.C.
      Identical TCR beta-chain rearrangements in streptococcal angina and skin lesions of patients with psoriasis vulgaris.
      ). These findings suggest that over time, a relatively small number of Streptococcus-specific, skin-homing T cells begin to recognize self-Ags, leading to the development of chronic plaque psoriasis (
      • Gudjonsson J.E.
      • Johnston A.
      • Sigmundsdottir H.
      • Valdimarsson H.
      Immunopathogenic mechanisms in psoriasis.
      ). Consistent with an ongoing role for HLA-Cw6 in the chronic phase of the process, both chronic plaque and generalized pustular psoriasis are also strongly associated with HLA-Cw6 (
      • Ozawa A.
      • Miyahara M.
      • Sugai J.
      • Iizuka M.
      • Kawakubo Y.
      • Matsuo I.
      • et al.
      HLA class I and II alleles and susceptibility to generalized pustular psoriasis: significant associations with HLA-Cw1 and HLA-DQB1*0303.
      ).
      In at least half of guttate psoriasis cases, the disease resolves spontaneously and recurs only rarely if at all. What determines which patients will progress to chronic plaque disease? Presumably, with the resolution of active infection, pathogen-derived innate immune stimulants such as peptidoglycan are cleared. However, for a response to self-Ags to develop leading to chronic plaque disease, there must be a prolonged loss of immunological tolerance. One genetic determinant of tolerance could be that certain self-Ags might be presented in the context of HLA-Cw6 in such a way as to overcome or bypass normal tolerance. However, the precise nature of the Ag(s) involved has remained elusive. One study found that HLA-Cw6 preferentially presented peptides common to Streptococcal M protein and the hyperproliferative keratin K17 to skin-homing CD8+ T cells (
      • Johnston A.
      • Gudjonsson J.E.
      • Sigmundsdottir H.
      • Love T.J.
      • Valdimarsson H.
      Peripheral blood T cell responses to keratin peptides that share sequences with streptococcal M proteins are largely restricted to skin-homing CD8(+) T cells.
      ). This mechanism has been suggested to explain the preferential reactivity of these cells for peptides with structural homology between Streptococcal M protein and the hyperproliferative keratins, K16 and K17 (
      • Johnston A.
      • Gudjonsson J.E.
      • Sigmundsdottir H.
      • Love T.J.
      • Valdimarsson H.
      Peripheral blood T cell responses to keratin peptides that share sequences with streptococcal M proteins are largely restricted to skin-homing CD8(+) T cells.
      ). Another study attempted to identify psoriasis Ags by expression cloning of RNA derived from psoriatic skin (
      • Jones D.A.
      • Yawalkar N.
      • Suh K.Y.
      • Sadat S.
      • Rich B.
      • Kupper T.S.
      Identification of autoantigens in psoriatic plaques using expression cloning.
      ). However, at variance with expectation, T cells from the blood of normal controls were as strongly reactive as T cells derived from the blood of psoriatic patients. Although our model focuses on HLA-Cw6 as the key MHC determinant of immunological self-tolerance in psoriasis, considerable evidence supports the notion that HLA-B alleles that are not in LD with HLA-Cw6 are also associated with psoriasis and PsA, notably with HLA-B27, HLA-B38, HLA-B39 (
      • Espinoza L.R.
      • Vasey F.B.
      • Gaylord S.W.
      • Dietz C.
      • Bergen L.
      • Bridgeford P.
      • et al.
      Histocompatibility typing in the seronegative spondyloarthropathies: a survey.
      ), and HLA-B46 (
      • Choonhakarn C.
      • Romphruk A.
      • Puapairoj C.
      • Jirarattanapochai K.
      • Leelayuwat C.
      Haplotype associations of the major histocompatibility complex with psoriasis in Northeastern Thais.
      ;
      • Nair R.P.
      • Stuart P.E.
      • Hiremagalore R.
      • Kullavanijaya P.
      • Tejasvi T.
      • Voorhees J.J.
      • et al.
      Analysis of the HLA-Cw1-B46 psoriasis risk haplotype reveals allelic heterogeneity with HLA-Cw6 [abstract].
      ). It is possible that these additional associations could reflect loss-of-tolerance events similar to those we envision for Streptococcus pyogenes and HLA-Cw6, except that different microorganisms provide the initial Ags.
      Loss of tolerance could also involve the sudden appearance of proteins that are strongly expressed in psoriasis but not in normal skin. When processed, peptides derived from such proteins could serve as neoantigens. In addition to the keratins K16 and K17 discussed above, other proteins that are strongly upregulated in psoriasis include human β-defensin-2 (encoded by DEFB4), psoriasin (S100A7), calgranulin (S100A8 and S100A9), small proline-rich region proteins (SPRR), and LCE proteins. Interestingly, many of these proteins are encoded by genes located in the epidermal differentiation complex located on human chromosome 1q21.3, in which genetic linkage and association to psoriasis have been reported (
      • Bhalerao J.
      • Bowcock A.M.
      The genetics of psoriasis: a complex disorder of the skin and immune system.
      ;
      • Capon F.
      • Novelli G.
      • Semprini S.
      • Clementi M.
      • Nudo M.
      • Vultaggio P.
      • et al.
      Searching for psoriasis susceptibility genes in Italy: genome scan and evidence for a new locus on chromosome 1.
      ,
      • Capon F.
      • Semprini S.
      • Chimenti S.
      • Fabrizi G.
      • Zambruno G.
      • Murgia S.
      • et al.
      Fine mapping of the PSORS4 psoriasis susceptibility region on chromosome 1q21.
      ;
      • de Cid R.
      • Riveira-Munoz E.
      • Zeeuwen P.L.
      • Robarge J.
      • Liao W.
      • Dannhauser E.N.
      • et al.
      Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis.
      ;
      • Zhang X.J.
      • Huang W.
      • Yang S.
      • Sun L.D.
      • Zhang F.Y.
      • Zhu Q.X.
      • et al.
      Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21.
      ).
      Psoriatic lesions manifest a complex and highly active proteolytic environment, particularly in the more differentiated layers in which proteins encoded in the epidermal differentiation complex are most highly expressed (
      • Zeeuwen P.L.
      • Cheng T.
      • Schalkwijk J.
      The biology of cystatin M/E and its cognate target proteases.
      ). It is possible that this aberrant proteolytic environment might also contribute to the development of neoantigenic peptides. Alternatively, proteases could be involved in the generation of innate defense peptides with altered antimicrobial and/or inflammatory properties, as has been observed for cathelicidins in rosacea (
      • Yamasaki K.
      • Di Nardo A.
      • Bardan A.
      • Murakami M.
      • Ohtake T.
      • Coda A.
      • et al.
      Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea.
      ).
      Many of these potentially neoantigenic proteins are intracellular components of keratinocytes (KCs) and yet must be presented on the surface of dendritic APC for effective Ag presentation, suggesting a requirement for cross-presentation (
      • Heath W.R.
      • Belz G.T.
      • Behrens G.M.
      • Smith C.M.
      • Forehan S.P.
      • Parish I.A.
      • et al.
      Cross-presentation, dendritic cell subsets, and the generation of immunity to cellular antigens.
      ). The fact that cross-presentation is dependent on CD4+ T cell might explain the observed dependence of psoriasis on CD4+ T cells in the severe combined immunodeficient mouse xenograft model (
      • Nickoloff B.J.
      • Wrone-Smith T.
      Injection of pre-psoriatic skin with CD4+ T cells induces psoriasis.
      ). However, it remains possible that Ag-driven CD4+ T cells have a more direct role, as many of the observed TCR rearrangements observed in psoriatic dermis arise in CD4+ cells (
      • Chang J.C.
      • Smith L.R.
      • Froning K.J.
      • Schwabe B.J.
      • Laxer J.A.
      • Caralli L.L.
      • et al.
      CD8+ T cells in psoriatic lesions preferentially use T-cell receptor V beta 3 and/or V beta 13.1 genes.
      ). Moreover, Streptococcus-specific CD4+ T-cell lines from psoriatic patients responded in an HLA-DR-restricted fashion, ruling out mitogenic or superantigenic stimulation (
      • Baker B.S.
      • Laman J.D.
      • Powles A.
      • van der Fits L.
      • Voerman J.S.
      • Melief M.J.
      • et al.
      Peptidoglycan and peptidoglycan-specific Th1 cells in psoriatic skin lesions.
      ). It has been suggested that Streptococcal peptidoglycan may function both as an Ag and as a stimulus for innate immunity by TLR activation (
      • Baker B.S.
      • Laman J.D.
      • Powles A.
      • van der Fits L.
      • Voerman J.S.
      • Melief M.J.
      • et al.
      Peptidoglycan and peptidoglycan-specific Th1 cells in psoriatic skin lesions.
      ). In any event, it is important to note that the vast majority of T cells in psoriatic skin are not clonally expanded, indicating that additional, non-Ag-specific mechanisms are involved in maintaining the psoriatic infiltrate.
      HLA-C also serves as a ligand for killer immunoglobulin-like receptors (KIRs), which can either inhibit or stimulate natural killer cells. Interestingly, the KIR locus has been reported to be associated with PsA (
      • Nelson G.W.
      • Martin M.P.
      • Gladman D.
      • Wade J.
      • Trowsdale J.
      • Carrington M.
      Cutting edge: heterozygote advantage in autoimmune disease: hierarchy of protection/susceptibility conferred by HLA and killer Ig-like receptor combinations in psoriatic arthritis.
      ;
      • Williams F.
      • Meenagh A.
      • Sleator C.
      • Cook D.
      • Fernandez-Vina M.
      • Bowcock A.M.
      • et al.
      Activating killer cell immunoglobulin-like receptor gene kir2ds1 is associated with psoriatic arthritis.
      ). Natural killer cells are major producers of IFNs and serve as a bridge between innate and acquired immunity. Inhibitory KIRs negatively regulate natural killer cell activation by interacting with a dimorphic allotype (Asn80/Lys80) of HLA-C (
      • Long E.O.
      • Rajagopalan S.
      HLA class I recognition by killer cell Ig-like receptors.
      ). HLA-Cw6 is one of several “group 2” alleles carrying Lys at position 80. Thus, if this mechanism were responsible for the observed association of HLA-Cw6 with psoriasis, it would be expected that a combination of all “group 2” alleles would provide a stronger association signal in individuals carrying the cognate inhibitory KIR genotype than does HLA-Cw6, but this was not the case in PsA (
      • Nelson G.W.
      • Martin M.P.
      • Gladman D.
      • Wade J.
      • Trowsdale J.
      • Carrington M.
      Cutting edge: heterozygote advantage in autoimmune disease: hierarchy of protection/susceptibility conferred by HLA and killer Ig-like receptor combinations in psoriatic arthritis.
      ). Further increasing complexity, because the KIR locus has an evolutionary history of expansion and contraction, for some inhibitory receptors, an individual may encode receptor only, ligand only, both receptor and ligand, or neither one. Thus, the role of HLA-Cw6 as a genetic regulator of natural killer cell activity in psoriasis remains to be clarified.

      NF-κB signaling

      A20 and ABIN1 are the products of the TNFAIP3 and TNIP1 genes, respectively. These proteins interact with each other and participate in the ubiquitin-mediated destruction of IKKγ/NEMO, thereby regulating a key nexus of NF-κB signaling (
      • Mauro C.
      • Pacifico F.
      • Lavorgna A.
      • Mellone S.
      • Iannetti A.
      • Acquaviva R.
      • et al.
      ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-kappaB.
      ). The degradation of several other components of the TNF signaling pathway is also regulated by A20 (
      • Mauro C.
      • Pacifico F.
      • Lavorgna A.
      • Mellone S.
      • Iannetti A.
      • Acquaviva R.
      • et al.
      ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-kappaB.
      ). TNF-α blockade markedly improves psoriasis-like pathology in a mouse model of psoriasis induced by injection of IL-23 (
      • Chan J.R.
      • Blumenschein W.
      • Murphy E.
      • Diveu C.
      • Wiekowski M.
      • Abbondanzo S.
      • et al.
      IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis.
      ), and a region of mouse chromosome 10 containing Tnfaip3 promotes psoriasis in a TNF-α-dependent manner in another mouse model (
      • Wang H.
      • Kess D.
      • Lindqvist A.K.
      • Peters T.
      • Sindrilaru A.
      • Wlaschek M.
      • et al.
      A 9-centimorgan interval of chromosome 10 controls the T cell-dependent psoriasiform skin disease and arthritis in a murine psoriasis model.
      ). Given that atherosclerosis is a major co-morbidity of psoriasis (
      • Gelfand J.M.
      • Neimann A.L.
      • Shin D.B.
      • Wang X.
      • Margolis D.J.
      • Troxel A.B.
      Risk of myocardial infarction in patients with psoriasis.
      ), it is notable that susceptibility to atherosclerosis has also been associated with the same region of mouse chromosome 10 (
      • Idel S.
      • Dansky H.M.
      • Breslow J.L.
      A20, a regulator of NFkappaB, maps to an atherosclerosis locus and differs between parental sensitive C57BL/6J and resistant FVB/N strains.
      ). Moreover, SNPs near TNFAIP3 yield genome-wide significant associations with rheumatoid arthritis (
      • Plenge R.M.
      • Cotsapas C.
      • Davies L.
      • Price A.L.
      • de Bakker P.I.
      • Maller J.
      • et al.
      Two independent alleles at 6q23 associated with risk of rheumatoid arthritis.
      ;
      • Thomson W.
      • Barton A.
      • Ke X.
      • Eyre S.
      • Hinks A.
      • Bowes J.
      • et al.
      Rheumatoid arthritis association at 6q23.
      ) and systemic lupus erythematosus (
      • Graham R.R.
      • Cotsapas C.
      • Davies L.
      • Hackett R.
      • Lessard C.J.
      • Leon J.M.
      • et al.
      Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus.
      ;
      • Musone S.L.
      • Taylor K.E.
      • Lu T.T.
      • Nititham J.
      • Ferreira R.C.
      • Ortmann W.
      • et al.
      Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus.
      ). These polymorphisms were not associated with psoriasis in the CASP study (all P>0.30) and are not in LD with the psoriasis-associated alleles (r2<0.03), suggesting that different alleles of TNFAIP3 increase susceptibility to systemic lupus erythematosus, rheumatoid arthritis, and psoriasis. Given that each of these diseases can be associated with arthritis, it is interesting that the NF-κB inhibitor parthenolide abrogated IL-23-mediated stimulation of receptor activator of NF-κB (RANK) ligand on CD4+ T cells in an arthritogenic mouse model (
      • Ju J.H.
      • Cho M.L.
      • Moon Y.M.
      • Oh H.J.
      • Park J.S.
      • Jhun J.Y.
      • et al.
      IL-23 induces receptor activator of NF-kappaB ligand expression on CD4+ T cells and promotes osteoclastogenesis in an autoimmune arthritis model.
      ).
      Tissue macrophages also have an important role in mouse models of psoriasis, even in the absence of T cells (
      • Stratis A.
      • Pasparakis M.
      • Rupec R.A.
      • Markur D.
      • Hartmann K.
      • Scharffetter-Kochanek K.
      • et al.
      Pathogenic role for skin macrophages in a mouse model of keratinocyte-induced psoriasis-like skin inflammation.
      ;
      • Wang H.
      • Peters T.
      • Kess D.
      • Sindrilaru A.
      • Oreshkova T.
      • Van Rooijen N.
      • et al.
      Activated macrophages are essential in a murine model for T cell-mediated chronic psoriasiform skin inflammation.
      ). As many events in macrophage and dendritic cell (DC) activation and function are NF-κB dependent, genetic variation in TNFAIP3 and TNIP1 could influence the balance between a self-limited response in which tolerance is eventually restored, and a self-sustaining one in which it is not. Clonal expansion of T cells requires the active participation of APC, especially DCs, which are intimately involved in the regulation of immunological tolerance at least in part through the Ag-specific stimulation of regulatory T cells (
      • Yamazaki S.
      • Steinman R.M.
      Dendritic cells as controllers of antigen-specific Foxp3+ regulatory T cells.
      ). As discussed below, an increasingly complex network of resident and inflammatory DCs with tolerogenic as well as immunostimulatory capacities is emerging in psoriasis and other inflammatory skin disorders.

      IL-23 signaling

      Three psoriasis-associated genetic signals map to components of the IL-23 ligand–receptor complex (
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • Ding J.
      • Stuart P.E.
      • Goldgar D.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ). One is found near IL12B (which encodes the p40 subunit common to IL-23 and IL-12), another is located near IL23A (which encodes the p19 subunit of IL-23), and a third resides near IL23R (which encodes a subunit of the IL-23 receptor). This was the first study to implicate genetic variants near IL23A as conferring susceptibility to any human autoimmune disorder. IL-23 signaling promotes cellular immune responses by promoting the survival and expansion of a recently identified subset of T cells expressing IL-17 that protects epithelia against microbial pathogens (
      • Bettelli E.
      • Oukka M.
      • Kuchroo V.K.
      T(H)-17 cells in the circle of immunity and autoimmunity.
      ). These results lead us to speculate that aberrant IL-23 signaling renders certain individuals susceptible to inappropriate immune responses targeting epithelial cells, thus contributing to the chronic and relatively skin-specific inflammation seen in psoriasis. This speculation is supported by the excellent antipsoriatic efficacy of biologics targeting the p40 subunit (
      • Krueger G.G.
      • Langley R.G.
      • Leonardi C.
      • Yeilding N.
      • Guzzo C.
      • Wang Y.
      • et al.
      A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis.
      ), coupled with the fact that IL12B and IL23A are markedly overexpressed in psoriatic lesions, whereas IL12A is not (
      • Lee E.
      • Trepicchio W.L.
      • Oestreicher J.L.
      • Pittman D.
      • Wang F.
      • Chamian F.
      • et al.
      Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris.
      ).
      Given that the epithelial linings of the skin and the gut are somewhat similar, it is notable that one of the same genetic variations in the IL23R gene that increases risk for psoriasis also confers risk for Crohn's disease (
      • Duerr R.H.
      • Taylor K.D.
      • Brant S.R.
      • Rioux J.D.
      • Silverberg M.S.
      • Daly M.J.
      • et al.
      A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.
      ), a condition that is strongly associated with psoriasis clinically (
      • Najarian D.J.
      • Gottlieb A.B.
      Connections between psoriasis and Crohn's disease.
      ). We also showed genome-wide significant associations between PsA and IL12B (
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • Ding J.
      • Stuart P.E.
      • Goldgar D.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ), and we and others have reported strong associations between PsA and IL23A and/or IL23R (
      • Liu Y.
      • Helms C.
      • Liao W.
      • Zaba L.C.
      • Duan S.
      • Gardner J.
      • et al.
      A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci.
      ;
      • Huffmeier U.
      • Lascorz J.
      • Bohm B.
      • Lohmann J.
      • Wendler J.
      • Mossner R.
      • et al.
      Genetic variants of the IL-23R pathway: association with psoriatic arthritis and psoriasis vulgaris, but no specific risk factor for arthritis.
      ;
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • Ding J.
      • Stuart P.E.
      • Goldgar D.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.
      ). Given that PsA is a highly destructive form of arthritis associated with increased RANK-positive myeloid osteoclast precursors (
      • Ritchlin C.T.
      • Haas-Smith S.A.
      • Li P.
      • Hicks D.G.
      • Schwarz E.M.
      Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis.
      ), it is notable that IL-23 promotes osteoclast formation by upregulation of RANK in myeloid precursor cells (
      • Chen L.
      • Wei X.Q.
      • Evans B.
      • Jiang W.
      • Aeschlimann D.
      IL-23 promotes osteoclast formation by up-regulation of receptor activator of NF-kappaB (RANK) expression in myeloid precursor cells.
      ), while inducing expression of RANK ligand on CD4+ T cells (
      • Ju J.H.
      • Cho M.L.
      • Moon Y.M.
      • Oh H.J.
      • Park J.S.
      • Jhun J.Y.
      • et al.
      IL-23 induces receptor activator of NF-kappaB ligand expression on CD4+ T cells and promotes osteoclastogenesis in an autoimmune arthritis model.
      ).

      Th1–Th2–Th17 balance

      One of the genetic signals we identified contains the IL13, IL4, IL-5, and RAD50 genes in a region of strong LD. Although the most highly significant signals reside closer to IL4 and IL13, a locus control region that regulates the transcription of IL13, IL4, and IL5 resides in the RAD50 gene (
      • Lee G.R.
      • Fields P.E.
      • Griffin T.J.
      • Flavell R.A.
      Regulation of the Th2 cytokine locus by a locus control region.
      ). Thus, it is possible that the functional variant may influence the expression of IL4, IL5, and/or IL13. These cytokines act at several levels to regulate allergic responses and defense against extracellular pathogens. In addition to biasing the T-cell repertoire toward Th2 differentiation, IL-4 and IL-13 inhibit the development of Th17 cells from naïve T cells (
      • Harrington L.E.
      • Hatton R.D.
      • Mangan P.R.
      • Turner H.
      • Murphy T.L.
      • Murphy K.M.
      • et al.
      Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.
      ;
      • Newcomb D.C.
      • Zhou W.
      • Moore M.L.
      • Goleniewska K.
      • Hershey G.K.
      • Kolls J.K.
      • et al.
      A functional IL-13 receptor is expressed on polarized murine CD4+ Th17 cells and IL-13 signaling attenuates Th17 cytokine production.
      ). Furthermore, IL-4 was shown to instruct DCs to produce IL-12 and promote Th1 development when present during the initial activation of DCs by infectious agents (
      • Biedermann T.
      • Zimmermann S.
      • Himmelrich H.
      • Gumy A.
      • Egeter O.
      • Sakrauski A.K.
      • et al.
      IL-4 instructs TH1 responses and resistance to Leishmania major in susceptible BALB/c mice.
      ). This unexpected result may be explained by the more recent observation that the levels of IL-4 present during DC differentiation regulate their polarizing effects on T-cell differentiation, with low levels promoting Th2 and higher levels promoting Th1 (
      • Guenova E.
      • Volz T.
      • Sauer K.
      • Kaesler S.
      • Muller M.R.
      • Wolbing F.
      • et al.
      IL-4-mediated fine tuning of IL-12p70 production by human DC.
      ). IL-4 and IL-13 are markedly overexpressed in atopic dermatitis skin relative to normal skin, but not in psoriasis (
      • Van der Ploeg I.
      • Jeddi Tehrani M.
      • Matuseviciene G.
      • Wahlgren C.F.
      • Fransson J.
      • Scheynius A.
      IL-13 over-expression in skin is not confined to IgE-mediated skin inflammation.
      ;
      • Nomura I.
      • Goleva E.
      • Howell M.D.
      • Hamid Q.A.
      • Ong P.Y.
      • Hall C.F.
      • et al.
      Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes.
      ). Treatment of psoriasis with IL-4 results in significant clinical improvement (
      • Ghoreschi K.
      • Thomas P.
      • Breit S.
      • Dugas M.
      • Mailhammer R.
      • van Eden W.
      • et al.
      Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease.
      ), which has recently been shown to be accompanied by reduced expression of IL-23 and reduced numbers of Th17 cells (
      • Guenova E.
      • Ghoreschi K.
      • Hotzenecker W.
      • Weindl G.
      • Sauer K.
      • Schaker K.
      • et al.
      Efficient IL-4 therapy of psoriasis selectively abrogates IL-23 and T17 responses in psoriasis [abstract].
      ). The fact that we observe genetic signals at both ends of this polarizing spectrum (IL-23 on the one hand, and IL-4/IL13 on the other) suggests that Th1–Th2–Th17 balance is likely to be a key functional and genetic determinant of psoriasis.

      Putting it all together: from initiation of lesions to generation of the epidermal response

      Recently, plasmacytoid DCs (pDCs) have been implicated in the initiation of psoriasis lesions (
      • Nestle F.O.
      • Conrad C.
      • Tun-Kyi A.
      • Homey B.
      • Gombert M.
      • Boyman O.
      • et al.
      Plasmacytoid predendritic cells initiate psoriasis through interferon-{alpha} production.
      ). pDCs are a specialized subset of DCs that are increased in number in psoriatic lesions and characterized by the production of large amounts of IFN-α (
      • Wollenberg A.
      • Wagner M.
      • Gunther S.
      • Towarowski A.
      • Tuma E.
      • Moderer M.
      • et al.
      Plasmacytoid dendritic cells: a new cutaneous dendritic cell subset with distinct role in inflammatory skin diseases.
      ). IFN-α had been suspected to have a role in psoriasis based on reports of exacerbations in psoriatic patients receiving intravenous IFN-α (
      • Quesada J.R.
      • Gutterman J.U.
      Psoriasis and alpha-interferon.
      ) and patients treated with the topical TLR7 agonist imiquimod (
      • Gilliet M.
      • Conrad C.
      • Geiges M.
      • Cozzio A.
      • Thurlimann W.
      • Burg G.
      • et al.
      Psoriasis triggered by toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors.
      ). IFN-α has multiple pro-inflammatory biological functions including upregulation of MHC class I expression (
      • Hermann P.
      • Rubio M.
      • Nakajima T.
      • Delespesse G.
      • Sarfati M.
      IFN-alpha priming of human monocytes differentially regulates gram-positive and gram-negative bacteria-induced IL-10 release and selectively enhances IL-12p70, CD80, and MHC class I expression.
      ), inducing cross-presentation of self-Ags to CD8+ T cells (
      • Le Bon A.
      • Etchart N.
      • Rossmann C.
      • Ashton M.
      • Hou S.
      • Gewert D.
      • et al.
      Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon.
      ), and activation of T cells (
      • Nestle F.O.
      • Conrad C.
      • Tun-Kyi A.
      • Homey B.
      • Gombert M.
      • Boyman O.
      • et al.
      Plasmacytoid predendritic cells initiate psoriasis through interferon-{alpha} production.
      ). Activation of these cells can occur through binding of the antimicrobial peptide LL-37 in complexes with host DNA, with intracellularly expressed TLR9 (
      • Lande R.
      • Gregorio J.
      • Facchinetti V.
      • Chatterjee B.
      • Wang Y.H.
      • Homey B.
      • et al.
      Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide.
      ). LL-37 is a secreted peptide that is abundantly expressed in established psoriatic lesions (
      • Frohm M.
      • Agerberth B.
      • Ahangari G.
      • Stahle-Backdahl M.
      • Liden S.
      • Wigzell H.
      • et al.
      The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders.
      ), providing a plausible mechanism for pDC activation. TLR7 signaling occurs in part through the NF-κB pathway (
      • Tamura T.
      • Yanai H.
      • Savitsky D.
      • Taniguchi T.
      The IRF family transcription factors in immunity and oncogenesis.
      ) and this could be one of the means by which the psoriasis risk variants in TNFAIP3 and TNIP1 influence psoriasis risk.
      In addition to pDC, there is a very complex population of myeloid DCs in psoriatic skin, including epidermal Langerhans cells, inflammatory dendritic epidermal cells, as well as resident and inflammatory dermal DCs (
      • Nickoloff B.J.
      • Qin J.Z.
      • Nestle F.O.
      Immunopathogenesis of psoriasis.
      ;
      • Zaba L.C.
      • Krueger J.G.
      • Lowes M.A.
      Resident and “inflammatory” dendritic cells in human skin.
      ). The myeloid DC population is expanded and activated in psoriasis (
      • Baadsgaard O.
      • Gupta A.K.
      • Taylor R.S.
      • Ellis C.N.
      • Voorhees J.J.
      • Cooper K.D.
      Psoriatic epidermal cells demonstrate increased numbers and function of non-Langerhans antigen-presenting cells.
      ;
      • Nestle F.O.
      • Turka L.A.
      • Nickoloff B.J.
      Characterization of dermal dendritic cells in psoriasis. Autostimulation of T lymphocytes and induction of Th1 type cytokines.
      ), with a marked increase in the numbers of immature DCs producing inflammatory cytokines and capable of stimulating T cells producing IL-17 and IFN-γ (
      • Kryczek I.
      • Bruce A.T.
      • Gudjonsson J.E.
      • Johnston A.
      • Vatan L.
      • Szeliga W.
      • et al.
      Induction of memory IL-17+ T cell trafficking and expansion by IFN-gamma: mechanism and pathological relevance.
      ;
      • Zaba L.C.
      • Fuentes-Duculan J.
      • Eungdamrong N.J.
      • Abello M.V.
      • Novitskaya I.
      • Pierson K.C.
      • et al.
      Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell-polarizing myeloid dendritic cells.
      ). Experiments undertaken in the uninvolved skin xenograft model suggest that the induction of myeloid DC maturation and/or activation is a key intermediary through which IFN-α produced by pDCs leads to T-cell activation by myeloid DC (
      • Nestle F.O.
      • Conrad C.
      • Tun-Kyi A.
      • Homey B.
      • Gombert M.
      • Boyman O.
      • et al.
      Plasmacytoid predendritic cells initiate psoriasis through interferon-{alpha} production.
      ). Again, variants in the IL12B, IL23A, IL23R, TNFAIP3, and/or TNP1 genes could all have plausible role(s) in this process.
      As T cells respond clonally to Ags (self-derived or foreign) in the context of HLA-Cw6, and/or more broadly to cytokines produced by activated DC and/or macrophages, they will differentiate, expand, and activate their effector functions. Some of these will be naïve T cells being stimulated to develop into different lineages, such as Th1, Th2, or the progenitor(s) of T cells expressing IL-17 and/or IL-22 (
      • Mills K.H.
      Induction, function and regulation of IL-17-producing T cells.
      ), whereas others will be skin-homing memory T cells (
      • Clark R.A.
      • Chong B.
      • Mirchandani N.
      • Brinster N.K.
      • Yamanaka K.
      • Dowgiert R.K.
      • et al.
      The vast majority of CLA+ T cells are resident in normal skin.
      ) or regulatory T cells (
      • Sakaguchi S.
      Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses.
      ). Subsets of memory CD4+ and CD8+ T cells will expand locally in the dermis in response to IL-23 and IL-1, which in turn are produced by DC in response to stimuli such as IFN-γ (
      • Kryczek I.
      • Bruce A.T.
      • Gudjonsson J.E.
      • Johnston A.
      • Vatan L.
      • Szeliga W.
      • et al.
      Induction of memory IL-17+ T cell trafficking and expansion by IFN-gamma: mechanism and pathological relevance.
      ) (Figure 1). Genetically mediated hyperfunction of IL-23 itself (through variants of IL12B and IL23A) and/or of its receptor (through IL23R) could enhance the expansion of T cells expressing IL-17 and/or IL-22. Whether through direct effects on T cells or altered DC programming, genetically mediated abnormalities in the expression or function of IL-4 and/or IL-13 could lead to development of Th1 bias, leading to increased expression of IFN-γ and DC-mediated expansion of T cells producing IL-17 and/or IL-22 (Figure 3).
      Figure thumbnail gr3
      Figure 3Model integrating the genetics and immunology of psoriasis. Genes identified as psoriasis-associated by the Collaborative Association Study of Psoriasis genome-wide association study are italicized. The majority of dermal T cells are CD4+ (purple); most of these are Th1, but ∼5% of them produce IL-17 (Th17, yellow halo). Most epidermal T cells are CD8+ (green circles) and about 5% of them express IL-17 (Tc17, yellow halo). Upper right panelHLA-Cw6 may increase susceptibility to psoriasis by presenting antigens to CD8+ T cells from the surface of dendritic cells (DCs, blue), and/or by presenting keratinocyte antigens to activated CD8+ T cells. As indicated by the partial yellow halo, some of these T cells may express IL-17. Lower right panelmacrophages (Mφs, orange) and DCs express TNF receptors and Toll-like receptors (TLRs) that signal through IKK-γ to promote translocation of NF-κB to the nucleus. The proteins encoded by TNFAIP3 (A20) and TNIP1 (ABIN1) are capable of binding to each other, and cooperatively block this signaling by altering patterns of protein ubiquitylation. Lower left panel—IL23A and IL12B encode the subunits of IL-23. IL23R encodes one subunit of the receptor for IL-23. IL4 and IL13 may participate in psoriasis by directly skewing the differentiation of CD4+ T cells toward Th2, or by altering the cytokine profile of DCs in such a way as to favor Th1 differentiation. As shown in , Th1 cells stimulate the production of IL-23 by DCs. In turn, IL-23 stimulates the production of IL-17 and/or IL-22 by Th17 cells. Upper left panelIL-17 and IL-22 upregulate keratinocyte innate immune defense mechanisms, including defensins, psoriasin (S100A7), and other proteins that are highly expressed in psoriasis lesions. In addition, IL-22 may promote keratinocyte proliferation and/or alter keratinocyte differentiation. Reproduced from
      • Nair R.P.
      • Ding J.
      • Duffin K.C.
      • Helms C.
      • Voorhees J.J.
      • Krueger G.G.
      • et al.
      Psoriasis bench to bedside: genetics meets immunology.
      , with permission.
      Intraepidermal CD8+ T cells producing IL-17 and/or IL-22 can be predicted to have a particularly important role in promoting the psoriatic epidermal response, as there would be no need for IL-17 and IL-22 produced by these cells to diffuse from the dermis into the epidermis. IL-17 and IL-22 strongly upregulate KC-derived effectors of innate defense known to be highly overexpressed in psoriasis, including the defensins hBD-2 and hBD-3, CCL20, S100A7, S100A8, and S100A9 (
      • Boniface K.
      • Bernard F.X.
      • Garcia M.
      • Gurney A.L.
      • Lecron J.C.
      • Morel F.
      IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes.
      ;
      • Wilson N.J.
      • Boniface K.
      • Chan J.R.
      • McKenzie B.S.
      • Blumenschein W.M.
      • Mattson J.D.
      • et al.
      Development, cytokine profile and function of human interleukin 17-producing helper T cells.
      ;
      • Zheng Y.
      • Danilenko D.M.
      • Valdez P.
      • Kasman I.
      • Eastham-Anderson J.
      • Wu J.
      • et al.
      Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis.
      ;
      • Guttman-Yassky E.
      • Lowes M.A.
      • Fuentes-Duculan J.
      • Zaba L.C.
      • Cardinale I.
      • Nograles K.E.
      • et al.
      Low expression of the IL-23/Th17 pathway in atopic dermatitis compared to psoriasis.
      ;
      • Kryczek I.
      • Bruce A.T.
      • Gudjonsson J.E.
      • Johnston A.
      • Vatan L.
      • Szeliga W.
      • et al.
      Induction of memory IL-17+ T cell trafficking and expansion by IFN-gamma: mechanism and pathological relevance.
      ;
      • Ma H.L.
      • Liang S.
      • Li J.
      • Napierata L.
      • Brown T.
      • Benoit S.
      • et al.
      IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation.
      ). Interestingly, all these molecules have been shown to have chemotactic as well as antimicrobial activity, and are all induced in response to epidermal insult (
      • Schauber J.
      • Gallo R.L.
      Expanding the roles of antimicrobial peptides in skin: alarming and arming keratinocytes.
      ). This could explain the well-known tendency of psoriasis to flare at sites of skin injury (the Koebner phenomenon). Thus, it would appear that T-cell-derived cytokines have a key role not only in stimulating the antimicrobial activities of KCs but also in their ability to promote the influx of inflammatory cells. We have recently shown that this response is activated more often in uninvolved psoriatic skin than it is in site-matched skin from normal individuals, in concert with a decrease in expression of genes involved in lipid biosynthesis (
      • Gudjonsson J.E.
      • Ding J.
      • Li X.
      • Nair R.P.
      • Tejasvi T.
      • Qin Z.S.
      • et al.
      Global gene expression analysis reveals evidence for decreased lipid biosynthesis and increased innate immunity in uninvolved psoriatic skin.
      ). We speculate that this subtle but highly coordinated response might represent the incipient epidermal response to T cells whose normal task is skin immunosurveillance.
      Despite decades of study, the mechanism(s) by which cutaneous inflammation provokes epidermal hyperplasia in psoriasis have remained enigmatic. Early studies suggested that psoriatic KCs are refractory to cAMP-dependent growth regulatory signals (
      • Voorhees J.J.
      • Duell E.A.
      Psoriasis as a possible defect of the adenyl cyclase-cyclic AMP cascade. A defective chalone mechanism?.
      ) or that KCs are more responsive to psoriatic fibroblasts than to normal fibroblasts (
      • Saiag P.
      • Coulomb B.
      • Lebreton C.
      • Bell E.
      • Dubertret L.
      Psoriatic fibroblasts induce hyperproliferation of normal keratinocytes in a skin equivalent model in vitro.
      ). Once it became clear that the T-cell-specific immunosuppressant cyclosporine rapidly and markedly reduced psoriatic epidermal hyperplasia (
      • Ellis C.N.
      • Gorsulowsky D.C.
      • Hamilton T.A.
      • Billings J.K.
      • Brown M.D.
      • Headington J.T.
      • et al.
      Cyclosporine improves psoriasis in a double-blind study.
      ) and cytokine expression (
      • Elder J.T.
      • Hammerberg C.
      • Cooper K.D.
      • Kojima T.
      • Nair R.P.
      • Ellis C.N.
      • et al.
      Cyclosporin A rapidly inhibits epidermal cytokine expression in psoriasis lesions, but not in cytokine-stimulated cultured keratinocytes.
      ;
      • Kojima T.
      • Cromie M.A.
      • Fisher G.J.
      • Voorhees J.J.
      • Elder J.T.
      Gro-alpha mRNA is selectively overexpressed in psoriatic epidermis and is reduced by cyclosporin A in vivo, but not in cultured keratinocytes.
      ), and that several other T-cell-selective immunomodulators were clinically effective (
      • Prinz J.
      • Braun-Falco O.
      • Meurer M.
      • Daddona P.
      • Reiter C.
      • Rieber P.
      • et al.
      Chimaeric CD4 monoclonal antibody in treatment of generalised pustular psoriasis [letter].
      ;
      • Sugiyama M.
      • Speight P.M.
      • Prime S.S.
      • Watt F.M.
      Comparison of integrin expression and terminal differentiation capacity in cell lines derived from oral squamous cell carcinomas.
      ;
      • Gottlieb S.L.
      • Gilleaudeau P.
      • Johnson R.
      • Estes L.
      • Woodworth T.G.
      • Gottlieb A.B.
      • et al.
      Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis.
      ;
      • Abrams J.R.
      • Kelley S.L.
      • Hayes E.
      • Kikuchi T.
      • Brown M.J.
      • Kang S.
      • et al.
      Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells.
      ), the focus shifted to T cells. These clinical observations prompted the use of in vitro and animal models of psoriasis, which further supported a critical role for T cells. Making use of short-term cultures of human monolayer KCs, it was reported that T-cell clones could produce soluble factors that were mitogenic for KCs (
      • Prinz J.C.
      • Gross B.
      • Vollmer S.
      • Trommler P.
      • Strobel I.
      • Meurer M.
      • et al.
      T cell clones from psoriasis skin lesions can promote keratinocyte proliferation in vitro via secreted products.
      ), and that psoriatic KCs are hyperresponsive to the effects of T-cell-derived cytokines, at least one of which was IFN-γ (
      • Bata-Csorgo Z.
      • Hammerberg C.
      • Voorhees J.J.
      • Cooper K.D.
      Kinetics and regulation of human keratinocyte stem cell growth in short-term primary ex vivo culture. Cooperative growth factors from psoriatic lesional T lymphocytes stimulate proliferation among psoriatic uninvolved, but not normal, stem keratinocytes.
      ). However, it is difficult to extrapolate from monolayer KC cultures to the in vivo situation, because KCs rapidly become hyperproliferative in culture. This experimental problem was overcome when it was shown that injection of T cells can provoke epidermal hyperplasia in pre-psoriatic skin grafted onto severe combined immunodeficient mice (
      • Nickoloff B.J.
      • Wrone-Smith T.
      Injection of pre-psoriatic skin with CD4+ T cells induces psoriasis.
      ) and that the entry of T cells into the epidermis is necessary for spontaneous development of the epidermal hyperplasia in the AGR xenograft model (
      • Conrad C.
      • Boyman O.
      • Tonel G.
      • Tun-Kyi A.
      • Laggner U.
      • de Fougerolles A.
      • et al.
      Alpha1beta1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis.
      ). Another approach has been the use of skin equivalent models. However, despite their ability to stratify, these models retain an innate immune gene expression response very similar to psoriasis (
      • McFarland K.L.
      • Klingenberg J.M.
      • Boyce S.T.
      • Supp D.M.
      Expression of genes encoding antimicrobial proteins and members of the toll-like receptor/nuclear factor-kappaB pathways in engineered human skin.
      ), and do not fully recapitulate the distinctive cellular milieu of psoriatic lesions. Despite these limitations, IL-22 has been shown to promote epidermal thickening and altered KC differentiation, along with marked upregulation of the innate defense response, in three independent studies (
      • Boniface K.
      • Bernard F.X.
      • Garcia M.
      • Gurney A.L.
      • Lecron J.C.
      • Morel F.
      IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes.
      ;
      • Sa S.M.
      • Valdez P.A.
      • Wu J.
      • Jung K.
      • Zhong F.
      • Hall L.
      • et al.
      The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis.
      ;
      • Nograles K.E.
      • Zaba L.C.
      • Guttman-Yassky E.
      • Fuentes-Duculan J.
      • Suarez-Farinas M.
      • Cardinale I.
      • et al.
      Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways.
      ). However, actual KC hyperproliferation was seen in only one of these studies (
      • Sa S.M.
      • Valdez P.A.
      • Wu J.
      • Jung K.
      • Zhong F.
      • Hall L.
      • et al.
      The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis.
      ). Interestingly, in this study it was necessary to block the EGFR to observe the hyperproliferative effect of IL-22 (
      • Sa S.M.
      • Valdez P.A.
      • Wu J.
      • Jung K.
      • Zhong F.
      • Hall L.
      • et al.
      The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis.
      ).
      In addition to these cytokine-driven mechanisms, CD8+ T cells might also promote epidermal hyperplasia by inflicting cytotoxic injury on KCs. Epidermal CD8+ T cells in psoriasis express perforin, and therefore could directly damage KCs in the traditional cytotoxic manner (
      • Kastelan M.
      • Prpic Massari L.
      • Gruber F.
      • Zamolo G.
      • Zauhar G.
      • Coklo M.
      • et al.
      Perforin expression is upregulated in the epidermis of psoriatic lesions.
      ;
      • Prpic Massari L.
      • Kastelan M.
      • Laskarin G.
      • Zamolo G.
      • Massari D.
      • Rukavina D.
      Analysis of perforin expression in peripheral blood and lesions in severe and mild psoriasis.
      ). This damage might be sublethal in nature, as frank cytolysis of KCs is not a prominent feature of psoriasis. It has been suggested that psoriatic KCs are relatively resistant to apoptotic damage because they exhibit exaggerated features of senescence (
      • Nickoloff B.J.
      Creation of psoriatic plaques: the ultimate tumor suppressor pathway. A new model for an ancient T-cell-mediated skin disease. Viewpoint.
      ). KCs are known to respond to Fas ligand-mediated apoptotic insult by elaborating the epidermal growth factor-like growth factor, amphiregulin, thereby encouraging the proliferation and survival of their neighbors despite their own demise (
      • Iordanov M.S.
      • Sundholm A.J.
      • Simpson E.L.
      • Hanifin J.M.
      • Ryabinina O.P.
      • Choi R.J.
      • et al.
      Cell death-induced activation of epidermal growth factor receptor in keratinocytes: implications for restricting epidermal damage in dermatitis.
      ). These findings leave open the long-suggested possibility that autocrine EGFR activation may have an important role in the elicitation of psoriatic epidermal hyperplasia (
      • Elder J.T.
      • Fisher G.J.
      • Lindquist P.B.
      • Bennett G.L.
      • Pittelkow M.R.
      • Coffey Jr, R.
      • et al.
      Overexpression of transforming growth factor alpha in psoriatic epidermis.
      ). Of course, CD8+ T cells could also trigger KCs to release a variety of other soluble factors, including cytokines such as TNF-α, chemokines such as IL-8 and CCL20, eicosanoids, and/or growth factors, which could further increase local inflammation and stimulate KC proliferation.
      Despite the evident experimental complexities presented by the psoriatic tissue response, we now have the beginnings of a genetic “Rosetta stone” pointing us toward molecular pathways that will help us finally understand why such a distinctive pattern of cutaneous inflammation develops in psoriasis, and how this inflammation provokes its equally distinctive epidermal response. Although this stone requires further extensive polishing (that is, the identification of additional genetic signals and the elucidation of causative genetic variants outside the MHC), it should be valuable for years to come.

      Conflict of Interest

      The authors state no conflict of interest.

      ACKNOWLEDGMENTS

      We gratefully acknowledge the important contributions of Dr Ilona Kryczek, Dr Weiping Zou, and Mr Jun Ding to the research presented in this review. Research by the authors was supported by awards from the National Institute of Arthritis, Musculoskeletal, and Skin Diseases, the National Institutes of Health, the Ann Arbor VA Hospital, the Dudley and Dawn Holmes Fund, the Babcock Memorial Trust, the National Psoriasis Foundation, the Dermatology Foundation, the American Skin Association, and by an award (M01 RR00042) from the National Center for Research Resources, National Institutes of Health, to the University of Michigan General Clinical Research Center.

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