Molecular Dissection of Psoriasis: Integrating Genetics and Biology
2009; Elsevier BV; Volume: 130; Issue: 5 Linguagem: Inglês
10.1038/jid.2009.319
ISSN1523-1747
AutoresJames T. Elder, Allen T. Bruce, Jóhann E. Guðjónsson, Andrew Johnston, Philip E. Stuart, Trilokraj Tejasvi, John J. Voorhees, Gonçalo R. Abecasis, Rajan P. Nair,
Tópico(s)Oral Health Pathology and Treatment
ResumoPsoriasis 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. 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. antigen antigen-presenting cell Collaborative Association Study of Psoriasis dendritic cell epidermal differentiation complex genome-wide association study keratinocyte killer immunoglobulin-like receptors late cornified envelope linkage disequilibrium major histocompatibility complex plasmacytoid dendritic cells psoriatic arthritis psoriasis susceptibility-1 single-nucleotide polymorphism Toll-like receptor tumor necrosis factor-α Psoriasis is a common disease, affecting about 2% of Americans at a cost of over 3 billion dollars a year (Sander et al., 1993Sander H.M. Morris L.F. Phillips C.M. Harrison P.E. Menter A. The annual cost of psoriasis.J Am Acad Dermatol. 1993; 28: 422-425Abstract Full Text PDF PubMed Google Scholar). Psoriasis has a major impact on the quality of life (Gupta et al., 1993Gupta M.A. Schork N.J. Gupta A.K. Kirkby S. Ellis C.N. Suicidal ideation in psoriasis.Int J Dermatol. 1993; 32: 188-190Crossref PubMed Google Scholar; Choi and Koo, 2003Choi J. Koo J.Y. Quality of life issues in psoriasis.J Am Acad Dermatol. 2003; 49: S57-S61Abstract Full Text Full Text PDF PubMed Google Scholar), 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 et al., 1999Rapp 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.J Am Acad Dermatol. 1999; 41: 401-407Abstract Full Text Full Text PDF PubMed Scopus (787) Google Scholar). 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 et al., 1984Krueger G.G. Bergstresser P.R. Lowe N.J. Voorhees J.J. Weinstein G.D. Psoriasis.J Am Acad Dermatol. 1984; 11: 937-947Abstract Full Text PDF PubMed Scopus (74) Google Scholar). A total of 10–40% of psoriatics develop psoriatic arthritis (PsA), which is severe and deforming in about 5% of patients (Gladman, 1994Gladman D.D. Natural history of psoriatic arthritis.Baillieres Clin Rheumatol. 1994; 8: 379-394Abstract Full Text PDF PubMed Scopus (114) Google Scholar; Gelfand et al., 2005Gelfand 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.J Am Acad Dermatol. 2005; 53: 573Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar). The clinical and genetic epidemiology of psoriasis and PsA has been reviewed previously, and will be considered only briefly here (Elder et al., 1994Elder J.T. Nair R.P. Guo S.W. Henseler T. Christophers E. Voorhees J.J. The genetics of psoriasis.Arch Dermatol. 1994; 130: 216-224Crossref PubMed Google Scholar; Rahman and Elder, 2005Rahman P. Elder J.T. Genetic epidemiology of psoriasis and psoriatic arthritis.Ann Rheum Dis. 2005; 64 (discussion ii40–ii31): ii37-ii39Crossref PubMed Scopus (110) Google Scholar; Gudjonsson and Elder, 2007bGudjonsson J.E. Elder J.T. Psoriasis: epidemiology.Clin Dermatol. 2007; 25: 535-546Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar). 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 and Christophers, 1985Henseler T. Christophers E. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris.J Am Acad Dermatol. 1985; 13: 450-456Abstract Full Text PDF PubMed Google Scholar; Stuart et al., 2002Stuart 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.Arch Dermatol Res. 2002; 294: 207-213Crossref PubMed Google Scholar). 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 et al., 1999Rahman P. Gladman D.D. Schentag C.T. Petronis A. Excessive paternal transmission in psoriatic arthritis.Arthritis Rheum. 1999; 42: 1228-1231Crossref PubMed Scopus (48) Google Scholar; Karason et al., 2003Karason 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.Am J Hum Genet. 2003; 72: 125-131Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar). 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, 1963Lomholt G. Psoriasis: prevalence, spontaneous course, and genetics.in: Lomholt G. G.E.C. GAD, Copenhagen1963Google Scholar; Watson et al., 1972Watson W. Cann H.M. Farber E.M. Nall M.L. The genetics of psoriasis.Arch Dermatol. 1972; 105: 197-207Crossref PubMed Google Scholar; Gudjonsson and Elder, 2007aGudjonsson J.E. Elder J.T. Psoriasis.in: Wolff K. Goldsmith L.A. Katz S.I. Gilchrest B.A. Paller A.M. Leffell D.J. Fitzpatrick's Dermatology in General Medicine. McGraw-Hill, New York2007: 169-194Google Scholar). Genetic epidemiological studies of PsA indicate that this disorder is even more strongly influenced by genes than is cutaneous psoriasis (Moll et al., 1973Moll J.M. Wright V. O’Neill T. Silman A.J. Familial occurrence of psoriatic arthritis.Ann Rheum Dis. 1973; 32: 181-201Crossref PubMed Google Scholar; Chandran et al., 2007aChandran 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).Arthritis Rheum. 2007; 56: S798Google Scholar). 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 et al., 1987Gladman D.D. Shuckett R. Russell M.L. Thorne J.C. Schachter R.K. Psoriatic arthritis (PSA) – an analysis of 220 patients.Q J Med. 1987; 62: 127-141PubMed Google Scholar). The Moll and Wright classification of PsA has been widely used (Moll and Wright, 1973Moll J.M. Wright V. Psoriatic arthritis.Semin Arthritis Rheum. 1973; 3: 55-78Abstract Full Text PDF PubMed Scopus (854) Google Scholar). 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 et al., 1994Jones 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.Br J Rheumatol. 1994; 33: 834-839Crossref PubMed Google Scholar; Marsal et al., 1999Marsal 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.Rheumatology (Oxford). 1999; 38: 332-337Crossref PubMed Scopus (102) Google Scholar). 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 et al., 2006Taylor 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.Arthritis Rheum. 2006; 54: 2665-2673Crossref PubMed Scopus (946) Google Scholar). 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 et al., 2006Taylor 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.Arthritis Rheum. 2006; 54: 2665-2673Crossref PubMed Scopus (946) Google Scholar) but also in early arthritis clinic, in early PsA clinic, and in family medicine clinics (Taylor et al., 2006Taylor 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.Arthritis Rheum. 2006; 54: 2665-2673Crossref PubMed Scopus (946) Google Scholar; Chandran et al., 2007bChandran V. Schentag C.T. Gladman D.D. Sensitivity of the classification of psoriatic arthritis criteria in early psoriatic arthritis.Arthritis Rheum. 2007; 57: 1560-1563Crossref PubMed Scopus (81) Google Scholar). 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 et al., 1999McGonagle D. Conaghan P.G. Emery P. Psoriatic arthritis: a unified concept twenty years on.Arthritis Rheum. 1999; 42: 1080-1086Crossref PubMed Scopus (229) Google Scholar). Approximately half of psoriasis patients develop nail changes, including pitting, “oil drop” spotting, and onychodystrophy. Nail changes are strongly associated with PsA (Wright, 1959Wright V. Psoriatic arthritis: a comparative study of rheumatoid arthritis and arthritis associated with psoriasis.Arch Dermatol. 1959; 80: 27-37Crossref Google Scholar; Baker et al., 1964Baker H. Golding D.N. Thompson M. The nails in psoriatic arthritis.Br J Dermatol. 1964; 76: 549-554Crossref PubMed Google Scholar; Eastmond and Wright, 1979Eastmond C.J. Wright V. The nail dystrophy of psoriatic arthritis.Ann Rheum Dis. 1979; 38: 226-228Crossref PubMed Google Scholar; Gladman et al., 1986Gladman D.D. Anhorn K.A. Schachter R.K. Mervart H. HLA antigens in psoriatic arthritis.J Rheumatol. 1986; 13: 586-592PubMed Google Scholar; Lavaroni et al., 1994Lavaroni G. Kokelj F. Pauluzzi P. Trevisan G. The nails in psoriatic arthritis.Acta Derm Venereol Suppl (Stockh). 1994; 186: 113PubMed Google Scholar; Williamson et al., 2004Williamson 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.Rheumatology (Oxford). 2004; 43: 790-794Crossref PubMed Scopus (90) Google Scholar), possibly because of the close proximity of the nail folds to the “entheseal unit” of the distal interphalangeal joint region (Tan et al., 2007Tan 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.Rheumatology (Oxford). 2007; 46: 253-256Crossref PubMed Scopus (99) Google Scholar). 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 and Elder, 2007aGudjonsson J.E. Elder J.T. Psoriasis.in: Wolff K. Goldsmith L.A. Katz S.I. Gilchrest B.A. Paller A.M. Leffell D.J. Fitzpatrick's Dermatology in General Medicine. McGraw-Hill, New York2007: 169-194Google Scholar). There is a large body of literature on the immunopathogenesis of psoriasis, which has been comprehensively reviewed recently (Lowes et al., 2007Lowes M.A. Bowcock A.M. Krueger J.G. Pathogenesis and therapy of psoriasis.Nature. 2007; 445: 866-873Crossref PubMed Scopus (736) Google Scholar; Nickoloff et al., 2007Nickoloff B.J. Qin J.Z. Nestle F.O. Immunopathogenesis of psoriasis.Clin Rev Allergy Immunol. 2007; 33: 45-56Crossref PubMed Scopus (86) Google Scholar). 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 and Gallo, 2007Buchau A.S. Gallo R.L. Innate immunity and antimicrobial defense systems in psoriasis.Clin Dermatol. 2007; 25: 616-624Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). 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 et al., 1984Baker B.S. Swain A.F. Fry L. Valdimarsson H. Epidermal T lymphocytes and HLA-DR expression in psoriasis.Br J Dermatol. 1984; 110: 555-564Crossref PubMed Google Scholar). The functional importance of T cells is emphasized by the high therapeutic efficacy of cyclosporine A, a T-cell-selective immunosuppressant (Ellis et al., 1986Ellis 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.JAMA. 1986; 256: 3110-3116Crossref PubMed Google Scholar), as well as other T-cell-selective immunomodulators, including anti-CD4 antibodies (Prinz et al., 1991Prinz 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].Lancet. 1991; 338: 320-321Abstract PubMed Google Scholar), CTLA4Ig (Abrams et al., 2000Abrams 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.J Exp Med. 2000; 192: 681-694Crossref PubMed Scopus (256) Google Scholar), alefacept (Sugiyama et al., 1993Sugiyama 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.Carcinogenesis. 1993; 14: 2171-2176Crossref PubMed Google Scholar), and DAB389IL-2 (Gottlieb et al., 1995Gottlieb 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.Nat Med. 1995; 1: 442-447Crossref PubMed Google Scholar). 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 et al., 1990Gardembas-Pain M. Ifrah N. Foussard C. Boasson M. Saint Andre J.P. Verret J.L. Psoriasis after allogeneic bone marrow transplantation [letter].Arch Dermatol. 1990; 126: 1523Crossref PubMed Google Scholar; Kanamori et al., 2002Kanamori 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.Am J Hematol. 2002; 71: 41-44Crossref PubMed Scopus (39) Google Scholar). 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 and Elder, 2007aGudjonsson J.E. Elder J.T. Psoriasis.in: Wolff K. Goldsmith L.A. Katz S.I. Gilchrest B.A. Paller A.M. Leffell D.J. Fitzpatrick's Dermatology in General Medicine. McGraw-Hill, New York2007: 169-194Google Scholar). The recent discovery of a new subset of human T cells expressing IL-17 (Steinman, 2007Steinman 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.Nat Med. 2007; 13: 139-145Crossref PubMed Scopus (790) Google Scholar) has led to the suggestion that these cells have a major role in psoriasis (Lowes et al., 2008Lowes 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.J Invest Dermatol. 2008; 128: 1207-1211Crossref PubMed Scopus (445) Google Scholar) as well as other autoimmune epithelial disorders such as Crohn's disease (Neurath, 2007Neurath M.F. IL-23: a master regulator in Crohn disease.Nat Med. 2007; 13: 26-28Crossref PubMed Scopus (130) Google Scholar). Although the mechanisms involved in the differentiation of IL-17-expressing T cells from naïve precursors remain controversial (Steinman, 2007Steinman 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.Nat Med. 2007; 13: 139-145Crossref PubMed Scopus (790) Google Scholar), 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 et al., 2008Kryczek 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.J Immunol. 2008; 181: 4733-4741Crossref PubMed Google Scholar) (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 et al., 2008Kryczek 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.J Immunol. 2008; 181: 4733-4741Crossref PubMed Google Scholar). More recently, we and others (Nograles et al., 2009Nograles 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.J Allergy Clin Immunol. 2009; 123 (e1242): 1244-1252Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar) 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 et al., 2009Rubin 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].J Invest Dermatol. 2009; 129: S117Google Scholar). 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. 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 et al., 2004Boyman 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.J Exp Med. 2004; 199: 731-736Crossref PubMed Scopus (252) Google Scholar). These studies also established a strong correlation between the presence of epidermal T cells and the development of epidermal hyperplasia (Boyman et al., 2004Boyman 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.J Exp Med. 2004; 199: 731-736Crossref PubMed Scopus (252) Google Scholar). 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 et al., 2007Conrad 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.Nat Med. 2007; 13: 836-842Crossref PubMed Scopus (113) Google Scholar). 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 et al., 1994Chang 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.Proc Natl Acad Sci USA. 1994; 91: 9282-9286Crossref PubMed Google Scholar). Psoriasis is one of the most common and most heritable of the common diseases that display familial aggregation (Vyse and Todd, 1996Vyse T.J. Todd J.A. Genetic analysis of autoimmune disease.Cell. 1996; 85: 311-318Abstract Full Text Full Text PDF PubMed Scopus (565) Google Scholar). 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, 1990Risch N. Linkage strategies for genetically complex traits. II. The power of affected relative pairs.Am J Hum Genet. 1990; 46: 229-241PubMed Google Scholar). As λ1 has been estimated to be in the range of 3–6 (Elder et al., 1994Elder J.T. Nair R.P. Guo S.W. Henseler T. Christophers E. Voorhees J.J. The genetics of psoriasis.Arch Dermatol. 1994; 130: 216-224Crossref PubMed Google Scholar) and as high as 10 for juvenile-onset psoriasis (Elder et al., 2001Elder J.T. Nair R.P. Henseler T. Jenisch S. Stuart P. 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