Psoriasis pathogenesis and the development of novel targeted immune therapies

Psoriasis is caused by a complex interplay between the immune system, psoriasis-associated susceptibility loci, autoantigens, and multiple environmental factors. Over the last 2 decades, research has unequivocally shown that psoriasis represents a bona fide T cell–mediated disease primarily driven by pathogenic T cells that produce high levels of IL-17 in response to IL-23. The discovery of the central role for the IL-23/type 17 T-cell axis in the development of psoriasis has led to a major paradigm shift in the pathogenic model for this condition. The activation and upregulation of IL-17 in prepsoriatic skin produces a “feed forward” inflammatory response in keratinocytes that is self-amplifying and drives the development of mature psoriatic plaques by inducing epidermal hyperplasia, epidermal cell proliferation, and recruitment of leukocyte subsets into the skin. Clinical trial data for mAbs against IL-17 signaling (secukinumab, ixekizumab, and brodalumab) and newer IL-23p19 antagonists (tildrakizumab, guselkumab, and risankizumab) underscore the central role of these cytokines as predominant drivers of psoriatic disease. Currently, we are witnessing a translational revolution in the treatment and management of psoriasis. Emerging bispecific antibodies offer the potential for even better disease control, whereas small-molecule drugs offer future alternatives to the use of biologics and less costly long-term disease management. Psoriasis is caused by a complex interplay between the immune system, psoriasis-associated susceptibility loci, autoantigens, and multiple environmental factors. Over the last 2 decades, research has unequivocally shown that psoriasis represents a bona fide T cell–mediated disease primarily driven by pathogenic T cells that produce high levels of IL-17 in response to IL-23. The discovery of the central role for the IL-23/type 17 T-cell axis in the development of psoriasis has led to a major paradigm shift in the pathogenic model for this condition. The activation and upregulation of IL-17 in prepsoriatic skin produces a “feed forward” inflammatory response in keratinocytes that is self-amplifying and drives the development of mature psoriatic plaques by inducing epidermal hyperplasia, epidermal cell proliferation, and recruitment of leukocyte subsets into the skin. Clinical trial data for mAbs against IL-17 signaling (secukinumab, ixekizumab, and brodalumab) and newer IL-23p19 antagonists (tildrakizumab, guselkumab, and risankizumab) underscore the central role of these cytokines as predominant drivers of psoriatic disease. Currently, we are witnessing a translational revolution in the treatment and management of psoriasis. Emerging bispecific antibodies offer the potential for even better disease control, whereas small-molecule drugs offer future alternatives to the use of biologics and less costly long-term disease management. GlossaryBODY SURFACE AREA (BSA)Typically expressed in meters squared. The Mosteller formula, BSA = √[(W × H)/3600] = 0.016667 × W0.5 × H0.5, and the Du Bois formula, BSA = 0.20247 × height (m)0.725 × weight (kg)0.425, are most commonly used to estimate BSA.CD11aA cell adhesion protein that forms part of lymphocyte function-associated antigen 1, the defective protein in leukocyte adhesion deficiency type I.CUTANEOUS LYMPHOCYTE ANTIGEN (CLA)A homing molecule on T cells that binds to E-selectin on endothelial cells. Its expression is induced by dendritic cells binding to naive T cells in skin-draining lymph nodes.CYTOTOXIC T LYMPHOCYTE–ASSOCIATED ANTIGEN 4 (CTLA-4)An immunoglobulin family transmembrane protein expressed on peripheral T cells after activation. CTLA-4 contains immune tyrosine inhibitory motifs. CTLA-4 inhibits T cells by competing for ligands with CD28 and by associating with Src-homology domain 2–containing protein tyrosine phosphatase 2 and protein phosphatase 2 to affect proximal TCR signaling. CTLA-4 deficiency, an autosomal dominant primary immunodeficiency, results in impaired function of regulatory T cells, leading to autoimmune cytopenias, enteropathy, interstitial lung disease, recurrent infections, and extralymphoid lymphocytic infiltration.DACTYLITISInflammation of an entire digit. When accompanied by soft-tissue swelling, the term “sausage digit” is often applied.ENTHESITISInflammation of the enthesis, the site of attachment of a tendon, ligament, or joint capsule onto bone or cartilage.JANUS KINASE (JAK)A tyrosine kinase family that phosphorylates several cytokine receptors and STATs, which allows STAT binding and subsequent STAT activation. JAK3 deficiency causes T−B+ severe combined immunodeficiency. The 4 JAK family members are JAK1, JAK2, JAK3, and TYK2.PLASMACYTOID DENDRITIC CELLA type of dendritic cell with a distinct histologic morphology that can produce high levels of type I interferon. Plasmacytoid dendritic cells are thought to play special roles in antiviral host defense and autoimmunity.RETINOIC ACID RECEPTOR-RELATED ORPHAN RECEPTOR γT (RORγt)A characteristic transcription factor for TH17 development. Its production is induced by TGF-β, IL-6, and IL-1. RORγt is encoded by RORC but represents a truncated version of the RORγ protein. RORC mutations are associated with susceptibility to mycobacterial disease and candidiasis.The editors wish to acknowledge Daniel Searing, MD, for preparing this glossary. Typically expressed in meters squared. The Mosteller formula, BSA = √[(W × H)/3600] = 0.016667 × W0.5 × H0.5, and the Du Bois formula, BSA = 0.20247 × height (m)0.725 × weight (kg)0.425, are most commonly used to estimate BSA. A cell adhesion protein that forms part of lymphocyte function-associated antigen 1, the defective protein in leukocyte adhesion deficiency type I. A homing molecule on T cells that binds to E-selectin on endothelial cells. Its expression is induced by dendritic cells binding to naive T cells in skin-draining lymph nodes. An immunoglobulin family transmembrane protein expressed on peripheral T cells after activation. CTLA-4 contains immune tyrosine inhibitory motifs. CTLA-4 inhibits T cells by competing for ligands with CD28 and by associating with Src-homology domain 2–containing protein tyrosine phosphatase 2 and protein phosphatase 2 to affect proximal TCR signaling. CTLA-4 deficiency, an autosomal dominant primary immunodeficiency, results in impaired function of regulatory T cells, leading to autoimmune cytopenias, enteropathy, interstitial lung disease, recurrent infections, and extralymphoid lymphocytic infiltration. Inflammation of an entire digit. When accompanied by soft-tissue swelling, the term “sausage digit” is often applied. Inflammation of the enthesis, the site of attachment of a tendon, ligament, or joint capsule onto bone or cartilage. A tyrosine kinase family that phosphorylates several cytokine receptors and STATs, which allows STAT binding and subsequent STAT activation. JAK3 deficiency causes T−B+ severe combined immunodeficiency. The 4 JAK family members are JAK1, JAK2, JAK3, and TYK2. A type of dendritic cell with a distinct histologic morphology that can produce high levels of type I interferon. Plasmacytoid dendritic cells are thought to play special roles in antiviral host defense and autoimmunity. A characteristic transcription factor for TH17 development. Its production is induced by TGF-β, IL-6, and IL-1. RORγt is encoded by RORC but represents a truncated version of the RORγ protein. RORC mutations are associated with susceptibility to mycobacterial disease and candidiasis. The editors wish to acknowledge Daniel Searing, MD, for preparing this glossary. Psoriasis vulgaris is a common chronic inflammatory skin condition that affects 2% to 3% of persons in the United States.1Rachakonda T.D. Schupp C.W. Armstrong A.W. Psoriasis prevalence among adults in the United States.J Am Acad Dermatol. 2014; 70: 512-516Abstract Full Text Full Text PDF PubMed Scopus (577) Google Scholar Plaque psoriasis, the most common disease variant, which is seen in approximately 85% of cases, commonly manifests as erythematous plaques with thick scaling on the extensor surfaces, trunk, and scalp.2Nestle F.O. Kaplan D.H. Barker J. Psoriasis.N Engl J Med. 2009; 361: 496-509Crossref PubMed Scopus (2172) Google Scholar The severity of psoriasis ranges from mild disease with a limited number of localized inflammatory skin lesions to more severe disease involving widespread plaques that cover more than 10% of the body surface area. Approximately one third of patients with chronic disease go on to develop psoriatic arthritis, an inflammatory arthritis characterized by asymmetric oligoarthritis, nail disease, enthesitis, and/or dactylitis.3Gladman D.D. Clinical features and diagnostic considerations in psoriatic arthritis.Rheum Dis Clin North Am. 2015; 41: 569-579Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar Other less common psoriasis subtypes include erythrodermic, pustular, guttate, inverse, and palmoplantar psoriasis. The economic burden associated with the care of patients affected by psoriasis is significant and accounts for billions of dollars spent annually in the United States alone.4Brezinski E.A. Dhillon J.S. Armstrong A.W. Economic burden of psoriasis in the United States: a systematic review.JAMA Dermatol. 2015; 151: 651-658Crossref PubMed Scopus (164) Google Scholar As is seen with other chronic medical conditions, patients with psoriasis report a tremendous psychosocial burden and experience a significant reduction in their physical activity, cognitive function, and quality of life.5Rapp 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 (1278) Google Scholar The cause of psoriasis is complex and driven primarily by an aberrant immune response in the skin that is modified by genetic susceptibility and various environmental stimuli (eg, skin trauma, infections, and medications). The detrimental inflammatory events associated with psoriatic disease are not restricted to the skin and account for an increasing number of comorbid conditions, including cardiometabolic disease, stroke, metabolic syndrome (obesity, hypertension, dyslipidemia, and diabetes), chronic kidney disease, gastrointestinal disease, mood disorders, and malignancy.6Takeshita J. Grewal S. Langan S.M. Mehta N.N. Ogdie A. Van Voorhees A.S. et al.Psoriasis and comorbid diseases: epidemiology.J Am Acad Dermatol. 2017; 76: 377-390Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar These disease-associated comorbidities account in part for the increased mortality seen in patients with psoriasis and have substantial implications on disease management.7Gelfand J.M. Troxel A.B. Lewis J.D. Kurd S.K. Shin D.B. Wang X. et al.The risk of mortality in patients with psoriasis: results from a population-based study.Arch Dermatol. 2007; 143: 1493-1499Crossref PubMed Scopus (449) Google Scholar, 8Takeshita J. Grewal S. Langan S.M. Mehta N.N. Ogdie A. Van Voorhees A.S. et al.Psoriasis and comorbid diseases: implications for management.J Am Acad Dermatol. 2017; 76: 393-403Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar In the last decade, research discoveries have significantly expanded our understanding of the pathophysiology of psoriasis and have directly led to the development of highly effective targeted psoriasis therapies, such as those against IL-17 and IL-23. The superiority of these novel agents compared with traditional systemic agents underscores the central importance of the IL-23/type 17 T (T17) cell axis in psoriatic disease. In this review we will discuss recent updates in the working model of psoriasis pathogenesis, outline the effects of IL-23/T17 cell axis signaling on skin biology, and provide an overview of the development and clinical testing of IL-17 and IL-23 inhibitors for the treatment of psoriasis and related chronic inflammatory skin conditions. The requirement of the immune response for the development of psoriasis was suggested by early observations that characteristic skin lesions contained increased numbers of inflammatory cellular infiltrates.9Bos J.D. Hagenaars C. Das P.K. Krieg S.R. Voorn W.J. Kapsenberg M.L. Predominance of “memory” T cells (CD4+, CDw29+) over “naive” T cells (CD4+, CD45R+) in both normal and diseased human skin.Arch Dermatol Res. 1989; 281: 24-30Crossref PubMed Scopus (199) Google Scholar, 10Bos J.D. Hulsebosch H.J. Krieg S.R. Bakker P.M. Cormane R.H. Immunocompetent cells in psoriasis. In situ immunophenotyping by monoclonal antibodies.Arch Dermatol Res. 1983; 275: 181-189Crossref PubMed Scopus (230) Google Scholar Additionally, patients with psoriasis undergoing bone marrow transplantations11Eedy D.J. Burrows D. Bridges J.M. Jones F.G. Clearance of severe psoriasis after allogenic bone marrow transplantation.BMJ. 1990; 300: 908Crossref PubMed Scopus (160) Google Scholar or treatment with immunosuppressive agents, such as cyclosporine12Ellis 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 Scopus (486) Google Scholar, 13Griffiths C.E. Powles A.V. Leonard J.N. Fry L. Baker B.S. Valdimarsson H. Clearance of psoriasis with low dose cyclosporin.Br Med J (Clin Res Ed). 1986; 293: 731-732Crossref PubMed Scopus (202) Google Scholar and methotrexate,14Ryan T.J. Baker H. Systemic corticosteroids and folic acid antagonists in the treatment of generalized pustular psoriasis. Evaluation and prognosis based on the study of 104 cases.Br J Dermatol. 1969; 81: 134-145Crossref PubMed Scopus (68) Google Scholar experienced dramatic improvements in their inflammatory skin lesions. Subsequent experiments found that the inflammatory infiltrate in lesional skin was largely composed of CD4+ and CD8+ T cells.9Bos J.D. Hagenaars C. Das P.K. Krieg S.R. Voorn W.J. Kapsenberg M.L. Predominance of “memory” T cells (CD4+, CDw29+) over “naive” T cells (CD4+, CD45R+) in both normal and diseased human skin.Arch Dermatol Res. 1989; 281: 24-30Crossref PubMed Scopus (199) Google Scholar, 15Chang 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 U S A. 1994; 91: 9282-9286Crossref PubMed Scopus (222) Google Scholar However, selective inhibition of activated T cells in patients through a novel fusion protein made of human IL-2 and diphtheria toxin fragments (DAB389IL-2) provided definitive proof for the pathogenic role of T cells in psoriasis.16Gottlieb 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 Scopus (588) Google Scholar Multiple proof-of-concept clinical trials targeting the activated immune response in psoriatic skin with abatacept (fusion protein of the Fc region of the immunoglobulin IgG1 and the extracellular domain of cytotoxic T lymphocyte–associated antigen 4),17Abrams J.R. Lebwohl M.G. Guzzo C.A. Jegasothy B.V. Goldfarb M.T. Goffe B.S. et al.CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris.J Clin Invest. 1999; 103: 1243-1252Crossref PubMed Scopus (569) Google Scholar alefacept (CD2-directed lymphocyte function-associated antigen 3/Fc fusion protein),18Krueger G.G. Callis K.P. Development and use of alefacept to treat psoriasis.J Am Acad Dermatol. 2003; 49: S87-97Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar and efalizumab (a recombinant humanized mAb against CD11a)19Lebwohl M. Tyring S.K. Hamilton T.K. Toth D. Glazer S. Tawfik N.H. et al.A novel targeted T-cell modulator, efalizumab, for plaque psoriasis.N Engl J Med. 2003; 349: 2004-2013Crossref PubMed Scopus (561) Google Scholar also proved effective in reversing the psoriasis phenotype and further established the role of the T lymphocyte in this condition. Such studies laid the groundwork for subsequent clinical trials aimed at other aspects of the immune response and the specific cell-signaling pathways outlined in greater detail below. The mounting evidence for the pathogenic role of T lymphocytes in patients with psoriasis and the observation that disease was more frequently observed in familial clusters20Farber E.M. Nall M.L. Watson W. Natural history of psoriasis in 61 twin pairs.Arch Dermatol. 1974; 109: 207-211Crossref PubMed Scopus (213) Google Scholar, 21Brandrup F. Holm N. Grunnet N. Henningsen K. Hansen H.E. Psoriasis in monozygotic twins: variations in expression in individuals with identical genetic constitution.Acta Derm Venereol. 1982; 62: 229-236PubMed Google Scholar led many to conclude that psoriasis was an autoimmune condition with a strong genetic basis. Early genome-wide association studies in the 1980s revealed multiple psoriasis-associated susceptibility loci, the strongest of which was the human leukocyte antigen locus (HLA-C*06:02).22Tiilikainen A. Lassus A. Karvonen J. Vartiainen P. Julin M. Psoriasis and HLA-Cw6.Br J Dermatol. 1980; 102: 179-184Crossref PubMed Scopus (265) Google Scholar Since that time, 63 unique susceptibility loci have been identified in patients of European descent with psoriasis,23Tsoi L.C. Stuart P.E. Tian C. Gudjonsson J.E. Das S. Zawistowski M. et al.Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.Nat Commun. 2017; 8: 15382Crossref PubMed Scopus (162) Google Scholar although these loci only explain approximately 50% of the heritability of psoriasis. Additionally, the absence of expanded T-cell receptor (TCR) clones24Harden J.L. Hamm D. Gulati N. Lowes M.A. Krueger J.G. Deep sequencing of the T-cell receptor repertoire demonstrates polyclonal T-cell infiltrates in psoriasis.F1000Res. 2015; 4: 460Crossref PubMed Scopus (36) Google Scholar and the failure to identify any consistent exogenous or self-antigens caused others to question the autoimmune basis of psoriasis. However, the recent identification of 3 psoriasis autoantigens and their potential role in the pathogenesis of this condition has renewed interest in the autoimmune hypothesis.25Hawkes J.E. Gonzalez J.A. Krueger J.G. Autoimmunity in psoriasis: evidence for specific autoantigens.Curr Dermatol Rep. 2017; 6: 104-112Crossref Scopus (5) Google Scholar In a recent study of 56 patients, Lande et al26Lande R. Botti E. Jandus C. Dojcinovic D. Fanelli G. Conrad C. et al.The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis.Nat Commun. 2014; 5: 5621Crossref PubMed Scopus (334) Google Scholar found that peripheral blood in 75% of patients with moderate-to-severe psoriasis contained autoreactive CD4+ or CD8+ T cells against LL-37/cathelicidin, a cationic antimicrobial peptide (AMP) produced by keratinocytes and other immune cells (eg, neutrophils) in response to bacterial/viral infections27Zanetti M. The role of cathelicidins in the innate host defenses of mammals.Curr Issues Mol Biol. 2005; 7: 179-196PubMed Google Scholar, 28Zasloff M. Antimicrobial peptides of multicellular organisms.Nature. 2002; 415: 389-395Crossref PubMed Scopus (6744) Google Scholar or skin trauma.29Lande R. Gregorio J. Facchinetti V. Chatterjee B. Wang Y.H. Homey B. et al.Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide.Nature. 2007; 449: 564-569Crossref PubMed Scopus (1360) Google Scholar The cytokine profile of these autoreactive T cells revealed increased levels of skin-homing receptors (eg, cutaneous lymphocyte antigen, CCR6, and CCR10) and a strong IFN-γ and IL-17 phenotype consistent with previous studies examining the T-cell populations found in psoriatic skin.30Lowes M.A. Suarez-Farinas M. Krueger J.G. Immunology of psoriasis.Annu Rev Immunol. 2014; 32: 227-255Crossref PubMed Scopus (973) Google Scholar Importantly, the authors also showed that LL-37 expression is upregulated in psoriatic plaques, correlates with disease activity, and results in direct activation of plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells (mDCs) by forming a complex with nucleic acids (DNA and RNA) released after skin trauma.29Lande R. Gregorio J. Facchinetti V. Chatterjee B. Wang Y.H. Homey B. et al.Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide.Nature. 2007; 449: 564-569Crossref PubMed Scopus (1360) Google Scholar, 31Ganguly D. Chamilos G. Lande R. Gregorio J. Meller S. Facchinetti V. et al.Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8.J Exp Med. 2009; 206: 1983-1994Crossref PubMed Scopus (523) Google Scholar These multimeric LL-37–nucleic acid complexes are protected from enzymatic degradation and enter dendritic cells (DCs) by way of specific Toll-like receptors. LL-37–mediated activation of DCs in the skin results in overproduction of type I interferons (IFN-α and IFN-β) by pDCs and increased amounts of TNF and IL-6 by mDCs.31Ganguly D. Chamilos G. Lande R. Gregorio J. Meller S. Facchinetti V. et al.Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8.J Exp Med. 2009; 206: 1983-1994Crossref PubMed Scopus (523) Google Scholar, 32Nestle F.O. Conrad C. Tun-Kyi A. Homey B. Gombert M. Boyman O. et al.Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production.J Exp Med. 2005; 202: 135-143Crossref PubMed Scopus (872) Google Scholar A similar mechanism for pDC activation has also been described for human β-defensin (hBD) 2, hBD3, and lysozyme.33Lande R. Chamilos G. Ganguly D. Demaria O. Frasca L. Durr S. et al.Cationic antimicrobial peptides in psoriatic skin cooperate to break innate tolerance to self-DNA.Eur J Immunol. 2015; 45: 203-213Crossref PubMed Scopus (102) Google Scholar This mechanism wherein 1 or more AMPs are released by keratinocytes and other immune cells in response to skin damage or external stimuli provides a framework for how these proteins can break tolerance and promote autoimmunity in patients with psoriasis. In 2015, a second potential psoriasis autoantigen, a disintegrin-like and metalloprotease domain containing thrombospondin type 1 motif-like 5 (ADAMTSL5), was described by Arakawa et al.34Arakawa A. Siewert K. Stohr J. Besgen P. Kim S.M. Ruhl G. et al.Melanocyte antigen triggers autoimmunity in human psoriasis.J Exp Med. 2015; 212: 2203-2212Crossref PubMed Scopus (219) Google Scholar ADAMTSL5 (also known as ADAMTS-like protein 5) is a secreted zinc metalloprotease–related protein35Apte S.S. A disintegrin-like and metalloprotease (reprolysin-type) with thrombospondin type 1 motif (ADAMTS) superfamily: functions and mechanisms.J Biol Chem. 2009; 284: 31493-31497Crossref PubMed Scopus (375) Google Scholar thought to regulate components of the extracellular matrix.36Bader H.L. Wang L.W. Ho J.C. Tran T. Holden P. Fitzgerald J. et al.A disintegrin-like and metalloprotease domain containing thrombospondin type 1 motif-like 5 (ADAMTSL5) is a novel fibrillin-1-, fibrillin-2-, and heparin-binding member of the ADAMTS superfamily containing a netrin-like module.Matrix Biol. 2012; 31: 398-411Crossref PubMed Scopus (35) Google Scholar Using a reconstituted TCR of an epidermal CD8+ T-cell clone collected from a HLA-C*06:02–positive patient with psoriasis, Arakawa et al34Arakawa A. Siewert K. Stohr J. Besgen P. Kim S.M. Ruhl G. et al.Melanocyte antigen triggers autoimmunity in human psoriasis.J Exp Med. 2015; 212: 2203-2212Crossref PubMed Scopus (219) Google Scholar observed that HLA-C*06:02–restricted melanocytes resulted in TCR activation. The authors also observed a close spatial association between CD8+ T cells and HLA-C*06:02–restricted melanocytes, which were found to express increased amounts of ADAMTSL5. These findings suggest that the increased number of ADAMTSL5-expressing melanocytes in HLA-C*06:02–positive patients can serve as direct autoimmune targets for pathogenic T17 cell populations in psoriatic skin. This hypothesis is further supported by the finding that ADAMTSL5 stimulation of PBMCs isolated from patients with psoriasis, regardless of HLA-C*06:02 status, resulted in increased expression of IL-17A and IFN-γ in approximately two thirds of patients compared with healthy control subjects.34Arakawa A. Siewert K. Stohr J. Besgen P. Kim S.M. Ruhl G. et al.Melanocyte antigen triggers autoimmunity in human psoriasis.J Exp Med. 2015; 212: 2203-2212Crossref PubMed Scopus (219) Google Scholar Importantly, recent results from our laboratory suggest that the possibility of ADAMTSL5 antigen presentation and the subsequent activation of IL-17–producing T cells in psoriatic skin might involve other immune cell populations, such as keratinocytes and DCs.37Bonifacio K.M. Kunjravia N. Krueger J.G. Fuentes-Duculan J. Cutaneous expression of a disintegrin-like and metalloprotease domain containing thrombospondin type 1 motif-like 5 (ADAMTSL5) in psoriasis goes beyond melanocytes.J Pigment Disord. 2016; 3Crossref PubMed Google Scholar, 38Fuentes-Duculan J. Bonifacio K.M. Hawkes J.E. Kunjravia N. Cueto I. Li X. et al.Autoantigens ADAMTSL5 and LL37 are significantly upregulated in active Psoriasis and localized with keratinocytes, dendritic cells and other leukocytes.Exp Dermatol. 2017; ([Epub ahead of print])Crossref Scopus (65) Google Scholar Most recently, phospholipase A2 group IVD (PLA2G4D) was reported as a possible psoriasis autoantigen.39Cheung K.L. Jarrett R. Subramaniam S. Salimi M. Gutowska-Owsiak D. Chen Y.L. et al.Psoriatic T cells recognize neolipid antigens generated by mast cell phospholipase delivered by exosomes and presented by CD1a.J Exp Med. 2016; 213: 2399-2412Crossref PubMed Google Scholar Unlike related phospholipase enzymes, PLA2G4D is a novel protein found to be upregulated in psoriatic plaques.40Chiba H. Michibata H. Wakimoto K. Seishima M. Kawasaki S. Okubo K. et al.Cloning of a gene for a novel epithelium-specific cytosolic phospholipase A2, cPLA2delta, induced in psoriatic skin.J Biol Chem. 2004; 279: 12890-12897Crossref PubMed Scopus (63) Google Scholar, 41Quaranta M. Knapp B. Garzorz N. Mattii M. Pullabhatla V. Pennino D. et al.Intraindividual genome expression analysis reveals a specific molecular signature of psoriasis and eczema.Sci Transl Med. 2014; 6: 244ra90Crossref PubMed Scopus (144) Google Scholar Its expression is increased in psoriatic keratinocytes and mast cells and results in the generation of nonpeptide neolipid antigens presented on CD1a-expressing DCs for recognition by autoreactive T cells.39Cheung K.L. Jarrett R. Subramaniam S. Salimi M. Gutowska-Owsiak D. Chen Y.L. et al.Psoriatic T cells recognize neolipid antigens generated by mast cell phospholipase delivered by exosomes and presented by CD1a.J Exp Med. 2016; 213: 2399-2412Crossref PubMed Google Scholar These autoreactive T cells were also found to be enriched in the peripheral blood of patients with psoriasis and produced high amounts of IFN-γ and IL-17A when coincubated with PLA2G4D- and CD1a-expressing cells. Unexpectedly, PLA2G4D activity was shown to localize with tryptase in mast cells, and neolipid antigens could be transferred to neighboring antigen-presenting cells through mast cell–derived exosomes in a clathrin-dependent manner.39Cheung K.L. Jarrett R. Subramaniam S. Salimi M. Gutowska-Owsiak D. Chen Y.L. et al.Psoriatic T cells recognize neolipid antigens generated by mast cell phospholipase delivered by exosomes and presented by CD1a.J Exp Med. 2016; 213: 2399-2412Crossref PubMed Google Scholar Theses findings provide convincing evidence for the immunogenicity of nonprotein lipid antigens in psoriasis in addition to traditional peptide antigens, such as LL-37 or ADAMTSL5. In summary, the requirement for T cells in the development of psoriasis is undeniable. However, the precise mechanisms by which environmental factors and known susceptibility loci trigger the onset of psoriasis is not well understood. The link between psoriasis-related autoreactive T cells and distinct HLA-restricted autoantigens provides a possible mechanism for disease onset in predisposed subjects. It might also help explain why increased numbers of CD1a+ T cells found in the peripheral blood of patients with psoriasis are also positive for cutaneous lymphocyte antigen. Unfortunately, little is known about the exact immune events leading to the loss of immune tolerance in subjects susceptible to psoriasis. It is essential that future studies explore these molecular mechanisms and carefully characterize the expression profiles of potential autoantigens in all cell types found in the skin and blood of patients with psoriasis,38Fuentes-Duculan J. Bonifacio K.M. Hawkes J.E. Kunjravia N. Cueto I. Li X. et al.Autoantigens ADAMTSL5 and LL37 are significantly upregulated in active Psoriasis and localized with keratinocytes, dendritic cells and other leukocytes.Exp Dermatol. 2017; ([Epub ahead of print])Crossref Scopus (65) Google Scholar as well as their relationship to major psoriasis susceptibility loci. For many years, psoriasis was primarily characterized as a TH1-driven disease based on increased production of IFN-γ by CD4+ T cells found in psoriatic tissues compared with low production of cytokines that define the TH2 T-cell subset (ie, IL-4, IL-5, and IL-13). However, with the characterization of a novel TH17 cell subset discovered in the experimental autoimmune encephalomyelitis mouse model commonly used to study multiple sclerosis,42Li J. Gran B. Zhang G.X. Ventura E.S. Siglienti I. Rostami A. et al.Differential expression and regulation of IL-23 and IL-12 subunits and receptors in adult mouse microglia.J Neurol