AUTREV-01651; No of Pages 7 Autoimmunity Reviews xxx (2014) xxx–xxx
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Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
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Review
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T cell responses in psoriasis and psoriatic arthritis
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Article history: Received 15 November 2014 Accepted 21 November 2014 Available online xxxx
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Keywords: Psoriasis/psoriatic arthritis/immunology/ autoimmunity Psoriasis/psoriatic arthritis/inflammation Psoriasis/psoriatic arthritis/pathogenesis Psoriasis/psoriatic arthritis/genetics Antigen-specific T cells Self-antigen cross-presentation
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According to the current view the histological features of psoriasis arise as a consequence of the interplay between T cells, dendritic cells and keratinocytes giving rise to a self-perpetuating loop that amplifies and sustains inflammation in lesional skin. In particular, myeloid dendritic cell secretion of IL-23 and IL-12 activates IL-17-producing T cells, Th22 and Th1 cells, leading to the production of inflammatory cytokines such as IL-17, IFN-γ, TNF and IL-22. These cytokines mediate effects on keratinocytes thus establishing the inflammatory loop. Unlike psoriasis the immunopathogenic features of psoriatic arthritis are poorly characterized and there is a gap in the knowledge of the pathogenic link between inflammatory T cell responses arising in the skin and the development of joint inflammation. Here we review the knowledge accumulated over the years from the early evidence of autoreactive CD8 T cells that was studied mainly in the years 1990s and 2000s to the recent findings of the role of Th17, Tc17 cells and γδ T cells in psoriatic disease pathogenesis. The review will also focus on common and distinguishing features of T cell responses in psoriatic plaques and in synovial fluid of patients with psoriatic arthritis. The integration of this information could help to distinguish the role played by T cells in the initiation phase of the disease from the role of T cells as downstream effectors sustaining inflammation in psoriatic plaques and potentially leading to disease manifestation in distant joints. © 2014 Elsevier B.V. All rights reserved.
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Contents
Psoriasis and psoriatic arthritis clinical features . . . . . . 1.1. Genetic association in psoriasis and psoriatic arthritis 2. Pathogenesis of psoriasis and psoriatic arthritis . . . . . . 2.1. Dendritic cells . . . . . . . . . . . . . . . . . 2.2. γδ T cells and NK cells . . . . . . . . . . . . . . 2.3. Th1 and Th17 cells . . . . . . . . . . . . . . . 2.4. CD8 T cells . . . . . . . . . . . . . . . . . . . 2.5. Tertiary lymphoid tissues . . . . . . . . . . . . 3. Antigen-specific responses in psoriasis and psoriatic arthritis 4. Concluding remarks . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . .
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I.R.C.C.S Istituto Ortopedico Galeazzi, Department of Dermatology, University of Milan, Milan, Italy I.R.C.C.S Istituto Ortopedico Galeazzi, Department of Venereology, University of Milan, Milan, Italy I.R.C.C.S Istituto Ortopedico Galeazzi, Laboratory of Translational Immunology, Milan, Italy
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Marco Diani a,b, Gianfranco Altomare a,b, Eva Reali c,⁎
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1. Psoriasis and psoriatic arthritis clinical features
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Psoriasis is a chronic inflammatory skin disease affecting approximately 2%–4% of the population worldwide and is considered the ⁎ Corresponding author at: Laboratory of Translational Immunology, I.R.C.C.S Istituto Ortopedico Galeazzi, via Riccardo Galeazzi 4, 20161 Milan, Italy. Tel.: +39 02 66214780; fax: +39 02 66214048. E-mail address: [email protected] (E. Reali).
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most prevalent immune-mediated disease in humans. [1]. Plaque psoriasis, also known as psoriasis vulgaris, is the commonest form of the disease, representing almost 90% of psoriatic patients [2]. The lesions are characterized by erythematous dry, sharply demarcated plaques with loosely adherent silvery white scalest. The disease appears in other different clinical variants as inverse psoriasis pustular, palmoplantar, erythrodermic psoriasis, and guttate psoriasis, that usually affects children and adolescents following a streptococcal infection [3,4]. Usually guttate psoriasis spontaneously resolves however a fraction of patients
http://dx.doi.org/10.1016/j.autrev.2014.11.012 1568-9972/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Diani M, et al, T cell responses in psoriasis and psoriatic arthritis, Autoimmun Rev (2014), http://dx.doi.org/10.1016/ j.autrev.2014.11.012
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Genetic and epidemiological data, have indicated that psoriasis is a multifactorial disease, influenced by multiple genes as well as environmental factors including trauma and infections. The strong heritability of psoriasis has been originally evidenced by the 70% concordance in monozygotic twins and 20% in dizygotic [6, 14]. In recent years many progresses have been made in the characterization of the genetic basis of psoriasis. Linkage analysis studies have indeed identified nine chromosomal loci associated with psoriasis named PSORS1 to PSORS9. The major genetic determinant of psoriasis resides in the locus of susceptibility, PSORS1, encoding the gene variant HLA-Cw6, which is carried by up to 60% of patients with early-onset psoriasis [6,15]. Another locus of susceptibility associated with epidermal differentiation pathways is the epidermal differentiation complex gene cluster (PSORS4), that contains variations in copy numbers of genes belonging to the late cornified envelope complex as well as genes encoding the S100 calcium-binding proteins. In addition, increased copy number of the genes at the locus encoding human beta defensins has been reported [16]. Other gene variants associated with psoriasis, mostly single nucleotide polymorphisms, belong to the IL-23/IL-17 axis (Il23R, Il12B, Il23A genes) and the NF-κB pathway (TNFAIP3). Results from recent studies identified mutations and in the caspase recruitment domain-containing protein 14 (CARD14) linked to psoriasis and in IL36RN, the gene encoding the IL-36R antagonist (IL-36Ra, formerly IL-1F5), linked to generalized pustular psoriasis but not to psoriasis vulgaris [17,18] From the genetic point of view, patients with the cutaneous form of psoriasis and those with psoriatic arthritis share the majority of the predisposing gene variants, in particular the association with HLA-Cw6. Other class I antigens are also associated with psoriatic arthritis, including HLA-B13, HLA-B57, HLA-B39, and HLA-Cw7. Linkage analysis studies, have indicated that Killer-cell Immunoglobulin-like Receptor (KIR2D) gene polymorphisms, are specifically associated with psoriatic arthritis [19–22].
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2. Pathogenesis of psoriasis and psoriatic arthritis
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An important distinction has been recently made in psoriasis natural history by identifying 2 phases: an initiation phase that starts inflammation and a maintenance phase that perpetuates the inflammatory state [23]. This conceptual distinction can help to divide the cellular and molecular events that determine triggering of the disease from those that are the results of the self-perpetuating cycle and represent downstream effector arms of the inflammatory process. Psoriasis lesions are initiated by triggering events that are not fully characterized. These include streptococcal infections, trauma, and medications. Association between streptococcal infections is well established for guttate psoriasis [5] (56–97% association) and has recently been extended to the onset of exacerbation of plaque psoriasis [24,25]. Among the triggering events it should be taken into consideration that psoriasis often appears in areas of injury (Koebner phenomenon) and that plaques usually initiate on elbows and knees that are common areas exposed to trauma.
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2.1. Dendritic cells
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In human psoriatic skin, an overall increase of dendritic cells (DCs) has been found both in the epidermis and in the dermis [26,27]. In particular, myeloid DC types such as TNF and iNOS‐producing DCs (Tip‐DCs) [26], slanDCs, and plasmacytoid DCs (pDCs) [28] have been shown to infiltrate predominantly the dermal compartment of psoriatic skin. One of the initial triggering event for psoriasis development has been described by Lande and colleagues in 2007, showing that the alarmin cathelicidin/LL37 complexed to self-DNA or -RNA activates IFNα release by plasmacytoid DCs and activation of dermal myeloid DCs leading to DC maturation [29,30]. In this view, it is worth to underline that many of the genes encoded within the PSORS loci may also act as alarmins that favor myeloid DC maturation. These include S100 proteins, S100A12 (EN_RAGE or Calgranulin C], S100A7 (psoriasin), and S100A7A (S100A15 or koebnerisin) and β-defensins [8,31]. These elements could represent genetic predisposing factors to dendritic cell maturation and antigen presentation to T cells following trauma, microbial infection or the combination of the two. To this end a very recent study has reported that human beta defensins hBD2 and hBD3 represent additional triggers to plasmacytoid DC activation in psoriatic skin lesions [32]. The clinical association between psoriasis and trauma may represent an important phenomenon and together with the genetic link of the disease lead may suggest that cross-presentation of cellular antigens in association with HLA class I molecules by dendritic cells may represent an early and relevant event in disease pathogenesis. Once activated resident myeloid DCs produce IL-12 and IL-23, key psoriatic cytokines, which determine polarization of Th1 and Th17 cell subsets characterized for their role sustaining the self-perpetuating loop in the chronic phase of the disease [33–35]. The most recent advances in this field evidenced that IL-23 activates not only Th17 but also CD8+ Tc17 cells (collectively called T17) and the IL23R expressing γδ T cells [36].
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The overview of the genetic association of psoriasis and PsA points to a role for HLA class I restricted antigen presentation, which in turn brings to CD8 T cells as one of the immunopathogenic mechanism of the disease. The strong association of PsA with HLA class I alleles together with the evidence that this association distinguishes psoriatic arthritis from rheumatoid arthritis, which is associated with HLA class II alleles, definitively point to the need of understanding CD8 T cell responses in PsA and their link with T cell responses arising the skin.
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progress to plaque psoriasis. Patients recovering from guttate psoriasis still have a higher risk to develop plaque psoriasis [5]. In patients with psoriasis, new lesions may appear following direct cutaneous trauma, and this is known as the Koebner phenomenon. Psoriatic skin has three principal histological features: epidermal hyperplasia, leukocyte infiltrates, and an increased number of tortuous and leaky vessels in the dermis resembling the regenerative maturation observed during wound repair [6–8]. In recent studies we and others have reported the enhanced presence of lymphoid-like tissues in the dermis of psoriatic plaques as compared to normal skin [9]. Psoriatic arthritis (PsA) occurs in about 20–30% of patients with psoriasis and in approximately 80% of cases it follows the development of the cutaneous disease by a mean of 10 years [10,11]. In addition to synovitis, other common manifestations in PsA include enthesitis, dactylitis and anterior uveitis or iritis. Usually PsA appears between 30 and 50 years of age with equal distribution between men and women with the exception of axial disease, which favors men 3:1 [11]. The diagnosis of PsA is clinical as there are no pathognomonic, serological, imaging or other diagnostic tests. The majority of PsA patients are seronegative, as serum tests for Rheumatoid Factor and anticitrullinated peptide antibodies (ACPA) are negative; however, there is a greater prevalence of RF/ACPA positivity among PsA patients compared with the general population [12,13]. In addition to the development of inflammation of skin and joints, there is emerging evidence of systemic manifestations associated with psoriasis including diabetes mellitus, metabolic syndrome, and cardiovascular disease. For this reason the terminology psoriatic disease has been adopted encompassing the various manifestations of the disease.
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2.3. Th1 and Th17 cells
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Originally Th1 cells were considered to be the main mediators of the immune response in psoriatic plaques, then in recent years, the attention moved to the role of Th17 cells [42]. Th17 cytokines, in particular interleukin IL-17A, have been shown to be critical for sustaining inflammation in psoriatic plaques. IL-17A stimulates the production of antimicrobial peptides by keratinocytes, which in turn promote recruitment of inflammatory cells. IL-17 itself is capable of enhancing keratinocyte proliferation and inhibiting keratinocyte differentiation via the downstream mediator REG3A, a protein with antimicrobial functions involved in wound repair [43]. As a consequence of the emerging importance of IL-17A in psoriasis pathogenesis, the relevance of IFNγ is now less clear. Analysis of the cutaneous transcriptome in psoriatic skin lesions has indicated an increased expression of IFNγ-regulated genes and the down-regulation of IFNγ gene is consistently observed with response to patient treatment with etanercept [44]. Kryczek et al. have suggested that one of the main effects of IFNγ is activating antigen-presenting cells early in the psoriatic cascade. In particular IFNγ produced by Th1 and other cells would program myeloid dendritic cell to produce CCL20 ligand of CCR6 and secrete IL-23 thus favoring IL-17 producing cell recruitment and activation. In turn IFNγ would synergize with IL-17-producing cells in inducing human β-defensins production [45]. In a small pilot study humanized anti-IFNγ has been used in the treatment of psoriasis showing that although an improvement of histological and clinical parameters was observed, the treatment had only a minor therapeutic effect suggesting that IFNγ may not be a primary pathogenic cytokine in psoriasis [46]. It is however possible to speculate that IL-17A and IFNγ producing cells may play different roles in the different phases of the pathogenesis with IL-17A playing the most relevant role as the amplifying effector arm that causes clinical manifestation of skin inflammation and IFNγ taking part in the generation of T cell-dendritic cell aggregate that initiates the self-perpetuating cycle. The IL-23/IL-17 axis has also been linked to the pathogenesis of psoriasis based on the evidence that single polymorphisms in IL23R and TRAF3IP2 have been associated with PsA, on the increase of IL-23/
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The focus of the studies of the recent years has been maintained on CD4 T subsets however, genetic susceptibility factors, together with the recent evidence that in psoriatic lesions both CD4+ and CD8 + T cells produce IL-17A and IL-17F on ex vivo stimulation, underline the need to reevaluate the role of CD8 T cells not only as effector cells but also as possible drivers of the initial phase of the disease [49]. In psoriatic skin lesions the majority of T cells infiltrating the dermis are of the CD4 phenotype whereas CD8 + T cells predominate in lesional epidermis [50,45,51,52]. CD8+ T cells may represent key players that recognize self-epitopes presented by the binding pockets of HLA-Cw6 or other HLA class I molecules on the keratinocyte surface and repository of the autoimmune nature of the diseases [53]. According to this view priming of CD8+ T cells toward self- and microbial-antigens could occur in the early phase as a consequence of dendritic cell activation in the dermis. The pathogenic cycle therefore could be generated through the interplay between CD8+ T and CD4 T cells and antigen presenting cells (APCs), including DCs predisposed to alarmin-induced maturation and cross-presenting self-antigens [32]. In psoriatic arthritis, CD4+ T cells are more abundant in synovial tissue whereas CD8+ T cells prevail in synovial fluid. Accordingly, a very recent study has reported a markedly increased level of CD8+ T cells in synovial fluid of patients with psoriatic arthritis. These cells were shown to be IL17-producing cells and to correlate with disease severity measured by CRP and ESR level as well as by radiographical evaluation of the erosion status and the presence of active synovitis [54]. In this study CD4+ IL17 producing cells were also found to be present in the synovial fluid of patients with PsA and RA however they failed to correlate with disease activity in PsA. The results of this study point to a key contribution of IL-17-producing CD8 T cells in the pathogenesis of PsA.
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2.5. Tertiary lymphoid tissues
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In the dermis of psoriatic plaques, we and others have recently evidenced the presence of a lymphoid aggregate composed of CD11c + dendritic cells and T cells. In the formation of the lymphoid aggregate, the CCL19/CC7 axis was shown to play key role as its inhibition by TNF-blocking agents was the most critical event in psoriasis remission in treated patients [9]. Intriguingly, Canete and co-workers have reported that also in psoriatic arthritis lymphoid neogenesis occurs in synovial tissues and that TNF blockers can significantly reduce this phenomenon. These findings are in accordance with our results on the role of CCR7/CCL19 in the formation of lymphoid aggregates and in the pathogenesis of plaque psoriasis. Therefore it is tempting to speculate that recirculation of T cells through the tertiary lymphoid tissues in skin and joints may represent a pathogenic link between cutaneous psoriasis and psoriatic arthritis. [55].
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3. Antigen-specific responses in psoriasis and psoriatic arthritis
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The question of antigen specificity of T cell responses in psoriasis and psoriatic arthritis is still unanswered and is strongly linked the autoimmune nature of the disease [53]. An association between streptococcal throat infection and the acute guttate form of psoriasis (an early onset form) has been demonstrated in many studies, and the reported incidence of streptococcal infections preceding this type of psoriasis ranges between 56% and 97% [5]. Chronic plaque psoriasis is also exacerbated after these types of infections and it has been reported that the psoriasis patients have
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A recent study has reported the surprising finding that the major source of IL-17A in the skin is represented by the dermal CD3 + γδ T cells and that these cells are present in a significantly higher percentage in psoriatic skin lesion than in healthy skin. When stimulated ex vivo with IL-23, γδ T cells increase their expression of IL-17 many fold more than αβ T cells [37]. This unconventional T cells displaying lessspecific antigen responses have been proposed to initiate and precede the participation of Th17 cells in psoriasis. Mouse model of psoriasislike skin inflammation induced by treatment with Toll-like receptor (TLR)7/8 agonist imiquimod, has indeed indicated that innate rather than adaptive immune responses is involved in the primary formation of psoriatic skin lesions and showed the critical role of the IL-23/IL-17/ IL-22 axis for the psoriatic phenotype [38]. This finding adds a new important variable to the scenario of T cell responses in psoriasis pathogenesis [39,40]. As concerns psoriatic arthritis, association with natural killer cell pathways has been reported, as the presence of some allotypes of the killer cell immunoglobulin-like receptor (KIR) superfamily has been found to influence disease susceptibility [22,41]. Indeed, it has been suggested that KIR expression in the synovial fluid of patients with psoriatic arthritis is dominated by activating KIRs underlining the possibility to evaluate the role of innate lymphoid cells in determining psoriatic arthritis in parallel with the analysis of γδ T cells in the pathogenesis of cutaneous psoriasis.
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IL23R, IL-17/IL-17R in synovial fluid of patients with PsA and on the 253 link between IL-17 signaling and osteoclast differentiation [47,48]. 254
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2.2. γδ T cells and NK cells
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The massive activation of T cells in the tonsils would induce the expression of the skin-homing CLA molecules thus allowing T cells to egress from the tonsils and recirculate to the skin. In the skin CD8 T cells may migrate to the epidermis and cross-recognize keratin determinant on keratinocytes, whereas CD4 T cells could interact in the dermis with dendritic cells activated by peptidoglycans. This could possibly initiate the self-sustaining loop that drives chronic inflammation. Prolonged inflammatory reaction in turn could favor cross-presentation of autoantigens to CD8 T cells and the phenomenon of epitope spreading. Psoriasis could therefore be initiated by CD8 T cells that recognize the streptococcal M protein determinant in the palatin tonsils and homologous keratin determinant in the skin, be amplified by CD4 T cells stimulated by microbial antigens or bystander activation and spread to other self-epitopes cross-presented by alarmin-induced mature dendritic cells in predisposed individuals (Fig. 1). In this view CD8 T cells could represent the core of the autoimmune nature of the disease that recognize autoepitopes presented in the context of HLACw06 on the surface of antigen presenting cells or keratinocytes. The pathogenic activity of CD8 T cells is however likely to require a local interaction with CD4 T cells and involve crosspresenting dendritic cells. Skin homing CD4 T cells in this case could play the role of amplifier of inflammation with a central role in the generation of self-sustaining inflammatory loop in the dermis. From this loop IL-23-induced IL-17 mediated responses would be amplified and give rise to important clinical manifestation of the disease. CD4 T cells and possibly γδ T cells could therefore represent downstream amplifying effector arms of an autoimmune reaction.
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about a tenfold higher frequency of streptococcal throat infections than age-matched household controls [56]. Worsening of chronic psoriasis was associated only with throat infection by the three groups of β-hemolytic streptococci (A, C and G) that express M-protein on their surface [57]. Extensive homology between streptococcal M-protein and keratin was first reported in the early nineties leading to the initial hypothesis that psoriasis is maintained by T cells that recognize the streptococcal M protein determinant in the palatin tonsils and homologous keratin determinant in the skin [58]. This link is supported by the fact that skin T cells tend to be oligoclonal and that T cells isolated from the skin and tonsils have been shown to carry the same gene rearrangement indicating a common origin. Furthermore, dominant clones in the skin persisted also after drug treatment and disease remission whereas minor clones were transiently present. Importantly, oligoclonality was shown mainly for CD8 T cells rather than for CD4 [59]. Analysis of the Keratin 17 and M protein derived peptide binding to HLA CW06 showed psoriasis patients expressing HLACW06 responded to K17 peptides whereas control did not. T cells cross-reacting with human keratin could also be detected in the blood of psoriasis patients. The response was confined to CD8 + T cells and the majority of responding cells expressed CLA [60,61,58,62,56]. This evidence brings once more the attention to the central role of CD8 T cells in establishing the disease. CD4 T cells may therefore be activated by streptococcal superantigens or determinants derived from peptidoglycan or other microbial or stress-induced antigens.
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Fig. 1. Schematic representation of the triggering mechanisms and establishment of chronic inflammation in psoriatic plaques. (1) Streptococcal M-protein-derived antigens presented by dendritic cells to CD8+ T cells and induction of CLA expression (2) Re-localization of M-protein-specific CD8 T cells to the skin epidermis, cross-recognition of keratin-derived determinants (autoimmune mechanism). (3) Recruitment of dendritic cells and CD4 T cells and establishment of an inflammatory loop sustained by IL-23/IL-17 axis. (4) Cross-presentation of tissue-derived antigens by dendritic cells and epitope spreading. Amplification of the IL-23/IL-17 CD4 and γδ T cell loops.
Please cite this article as: Diani M, et al, T cell responses in psoriasis and psoriatic arthritis, Autoimmun Rev (2014), http://dx.doi.org/10.1016/ j.autrev.2014.11.012
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(a) One major population consisted of nonclonally expanded polyclonal CD4 T cells that did not persist in the tissue during methotrexate treatment. (b) A second major population of moderately expanded inflammationrelated clones were identified only in active arthritis tissue and/ or active joint fluid that were either of CD4 or CD8 lineage. These clones were only present as single clonal expansions and could not be grouped together by structural homology among their CDR3 regions to form clonal sets that indicated Ag drive and potential determinant spread. (c) A third and small population of highly expanded clones exclusively CD8 in lineage, distinguished by marked expansion in both blood and joint fluid and persisted during methotrexate treatment.
4. Concluding remarks
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Analyzing these data together with those obtained in psoriasis patients it can be postulated that persisting CD8 clones with highly homologous CDR3 amino acid sequences could represent the potential driver clones and could be a common feature of psoriasis and psoriatic arthritis (Fig. 2). As regards the major polyclonal CD4 T cell population that has been described both in blood and in inflamed tissue could potentially represent a recirculating population of the Th17/Th1 subset originating in psoriatic plaques that traffic through the joints (Fig. 2). The numerous clones of the second major population were distinguished from the putatively Ag-driven population by several features.
The triggering event of the initial phase of the disease is unclear as the autoimmune etiology of psoriasis is unclear. By integrating information on recent advances on Th17/Th1 γδT cell contribution in determining inflammation on psoriatic skin together with early data on keratin cross-reactive CD8 T cells with specificity for streptococcal antigens, we have highlighted the role of the different subpopulations of T cells in psoriasis and psoriatic arthritis and hypothesized a hierarchical role for T cell responses in determining the initial phase of the disease and chronic inflammation. In the proposed model of psoriasis pathogenesis CD8 T cells may represent the core mechanism of psoriasis pathogenesis possibly linked to its autoimmune nature whereas CD4 and γδ T cells could play a central role in amplifying and maintaining the pathogenic inflammatory cycle in psoriatic plaques leading to the main clinical manifestation of the disease. Psoriasis could therefore be initiated by CD8 T cells that recognize the streptococcal M protein determinant in the palatin tonsils and homologous keratin determinant in the skin, be amplified by Th17 T cells and γδ T cells stimulated by microbial antigens or bystander activation and spread to other self-epitopes cross-presented by alarmininduced mature dendritic cells in genetically predisposed individuals following trauma or microbial stimulation.
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In terms of distribution, they were mainly found in the actively inflamed sites of joint fluid and/or tissue, and nearly all were not detectably expanded in blood. These clones did not persist during methotrexate treatment and were unlikely to contribute to disease reactivation after treatment cessation. The high frequency of these clones could be a distinguishing feature of psoriatic arthritis and could generate form epitope spreading upon prolonged inflammation. Cross-presentation of self-antigens could favor in these patients cross-recognition of self-antigen presented by HLA-B alleles associated with PsA. Alternatively this population could be present in both the skin and joints being differentially represented in the two diseases and originating from independently occurring epitope spreading phenomenon.
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The association of psoriatic arthritis with MHC class I susceptibility alleles including HLACw06, B13, B27, and B57, a predominant CD8 + CD45RO + T cell phenotype in joint fluid provide evidence for a critical role of CD8 T cells and suggested the hypothesis that the disease is driven by presentation of self-peptides by susceptibility MHC class I molecules to autoreactive Ag-specific CD8 T cells. A very exhaustive study published in 2004 used nucleotide sequencing of TCRβ chains to analyze T cell clones infiltrating the inflamed joint tissue in patients with PsA [63]. Three populations of T cells were identified:
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Fig. 2. Schematic representation of the putative hierarchical role of CD8 and CD4 T cells in the pathogenesis of psoriatic disease relative to their amount and antigen-specificity.
Please cite this article as: Diani M, et al, T cell responses in psoriasis and psoriatic arthritis, Autoimmun Rev (2014), http://dx.doi.org/10.1016/ j.autrev.2014.11.012
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Acknowledgments
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We thank Prof. Giuseppe Banfi, I.R.C.C.S. Istituto Ortopedico Galeazzi, Milan (Italy); Dr. Daniela Talarico, S. Raffaele Research Hospital, Milan (Italy) and Prof. Riccardo Gavioli, University of Ferrara, Ferrara (Italy) for critical reading of the manuscript. This work received support from National Psoriasis Foundation.
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• Keratin cross-reactive CD8 T cells with specificity for microbial antigens can represent the core autoimmune mechanism of psoriasis pathogenesis. • Th17 T cells and γδ T cells act as downstream effectors stimulated by common-antigens or bystander activation • Th17 driven inflammatory cycle can lead to the main clinical manifestations in the skin and extend inflammation to the joint. • Dendritic cells in genetically predisposed individuals could crosspresent self-epitopes leading to epitope spreading in the skin and joints.
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Identification of cellular pathways of “type 1,” Th17 T cells, and TNF- and inducible nitric oxide synthase-producing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine A in psoriasis. J Immunol 2008; 180:1913–20. [34] Zaba LC, Cardinale I, Gilleaudeau P, Sullivan-Whalen M, Suarez-Farinas M, FuentesDuculan J, et al. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J Exp Med 2007;204:3183–94. [35] Zaba LC, Fuentes-Duculan J, Eungdamrong NJ, Abello MV, Novitskaya I, Pierson KC, et al. Psoriasis is characterized by accumulation of immunostimulatory and Th1/Th17 cell-polarizing myeloid dendritic cells. J Invest Dermatol 2009;129: 79–88. [36] Lowes MA, Russell CB, Martin DA, Towne JE, Krueger JG. The IL-23/T17 pathogenic axis in psoriasis is amplified by keratinocyte responses. Trends Immunol 2013;34: 174–81. [37] Cai Y, Shen X, Ding C, Qi C, Li K, Li X, et al. Pivotal role of dermal IL-17-producing gammadelta T cells in skin inflammation. Immunity 2011;35:596–610. [38] Russell SE, Stefanska AM, Kubica M, Horan RM, Mantovani A, Garlanda C, et al. Toll IL-1R8/single Ig IL-1-related receptor regulates psoriasiform inflammation through direct inhibition of innate IL-17A expression by gammadelta T cells. J Immunol 2013;191:3337–46. [39] Teunissen MB, Munneke JM, Bernink JH, Spuls PI, Res PC, Te Velde A, et al. Composition of innate lymphoid cell subsets in the human skin: enrichment of NCR(+) ILC3 in lesional skin and blood of psoriasis patients. J Invest Dermatol 2014;134: 2351–60. [40] Girardi M. Immunosurveillance and immunoregulation by gammadelta T cells. J Invest Dermatol 2006;126:25–31. [41] Conigliaro P, Scrivo R, Valesini G, Perricone R. Emerging role for NK cells in the pathogenesis of inflammatory arthropathies. Autoimmun Rev 2011;10:577–81. [42] Di Cesare A, Di Meglio P, Nestle FO. The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Invest Dermatol 2009;129:1339–50. [43] Lai Y, Li D, Li C, Muehleisen B, Radek KA, Park HJ, et al. The antimicrobial protein REG3A regulates keratinocyte proliferation and differentiation after skin injury. Immunity 2012;37:74–84. [44] Zaba LC, Suarez-Farinas M, Fuentes-Duculan J, Nograles KE, Guttman-Yassky E, Cardinale I, et al. Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes. J Allergy Clin Immunol 2009;124 [1022-10 e1-395]. [45] Kryczek I, Bruce AT, Gudjonsson JE, Johnston A, Aphale A, Vatan L, et al. Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis. J Immunol 2008;181:4733–41. [46] Harden JL, Johnson-Huang LM, Chamian MF, Lee E, Pearce T, Leonardi CL, et al. Humanized anti-IFN-gamma (HuZAF) in the treatment of psoriasis. J Allergy Clin Immunol 2014. [47] Chimenti MS, Ballanti E, Perricone C, Cipriani P, Giacomelli R, Perricone R. Immunomodulation in psoriatic arthritis: focus on cellular and molecular pathways. Autoimmun Rev 2013;12:599–606. [48] Suzuki E, Mellins ED, Gershwin ME, Nestle FO, Adamopoulos IE. The IL-23/IL-17 axis in psoriatic arthritis. Autoimmun Rev 2014;13:496–502. [49] Anandarajah AP, Schwarz EM, Totterman S, Monu J, Feng CY, Shao T, et al. The effect of etanercept on osteoclast precursor frequency and enhancing bone marrow oedema in patients with psoriatic arthritis. Ann Rheum Dis 2008;67:296–301. [50] Teunissen MB, Yeremenko NG, Baeten DL, Chielie S, Spuls PI, de Rie MA, et al. The IL-17A-producing CD8(+) T-cell population in psoriatic lesional skin comprises mucosa-associated invariant T cells and conventional T cells. J Invest Dermatol 2014;134:2898–907. [51] Boyman O, Conrad C, Tonel G, Gilliet M, Nestle FO. The pathogenic role of tissueresident immune cells in psoriasis. Trends Immunol 2007;28:51–7.
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[58] McFadden J, Valdimarsson H, Fry L. Cross-reactivity between streptococcal M surface antigen and human skin. Br J Dermatol 1991;125:443–7. [59] Valdimarsson H, Thorleifsdottir RH, Sigurdardottir SL, Gudjonsson JE, Johnston A. Psoriasis—as an autoimmune disease caused by molecular mimicry. Trends Immunol 2009;30:494–501. [60] Sigmundsdottir H, Sigurgeirsson B, Troye-Blomberg M, Good MF, Valdimarsson H, Jonsdottir I. Circulating T cells of patients with active psoriasis respond to streptococcal M-peptides sharing sequences with human epidermal keratins. Scand J Immunol 1997;45:688–97. [61] Valdimarsson H, Sigmundsdottir H, Jonsdottir I. Is psoriasis induced by streptococcal superantigens and maintained by M-protein-specific T cells that cross-react with keratin? Clin Exp Immunol 1997;107(Suppl. 1):21–4. [62] Valdimarsson H, Baker BS, Jonsdottir I, Powles A, Fry L. Psoriasis: a T-cell-mediated autoimmune disease induced by streptococcal superantigens? Immunol Today 1995;16:145–9. [63] Curran SA, FitzGerald OM, Costello PJ, Selby JM, Kane DJ, Bresnihan B, et al. Nucleotide sequencing of psoriatic arthritis tissue before and during methotrexate administration reveals a complex inflammatory T cell infiltrate with very few clones exhibiting features that suggest they drive the inflammatory process by recognizing autoantigens. J Immunol 2004;172:1935–44.
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Contents lists available at ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
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T cell responses in psoriasis and psoriatic arthritis
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Article history: Received 15 November 2014 Accepted 21 November 2014 Available online xxxx
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Keywords: Psoriasis/psoriatic arthritis/immunology/ autoimmunity Psoriasis/psoriatic arthritis/inflammation Psoriasis/psoriatic arthritis/pathogenesis Psoriasis/psoriatic arthritis/genetics Antigen-specific T cells Self-antigen cross-presentation
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According to the current view the histological features of psoriasis arise as a consequence of the interplay between T cells, dendritic cells and keratinocytes giving rise to a self-perpetuating loop that amplifies and sustains inflammation in lesional skin. In particular, myeloid dendritic cell secretion of IL-23 and IL-12 activates IL-17-producing T cells, Th22 and Th1 cells, leading to the production of inflammatory cytokines such as IL-17, IFN-γ, TNF and IL-22. These cytokines mediate effects on keratinocytes thus establishing the inflammatory loop. Unlike psoriasis the immunopathogenic features of psoriatic arthritis are poorly characterized and there is a gap in the knowledge of the pathogenic link between inflammatory T cell responses arising in the skin and the development of joint inflammation. Here we review the knowledge accumulated over the years from the early evidence of autoreactive CD8 T cells that was studied mainly in the years 1990s and 2000s to the recent findings of the role of Th17, Tc17 cells and γδ T cells in psoriatic disease pathogenesis. The review will also focus on common and distinguishing features of T cell responses in psoriatic plaques and in synovial fluid of patients with psoriatic arthritis. The integration of this information could help to distinguish the role played by T cells in the initiation phase of the disease from the role of T cells as downstream effectors sustaining inflammation in psoriatic plaques and potentially leading to disease manifestation in distant joints. © 2014 Elsevier B.V. All rights reserved.
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Contents
Psoriasis and psoriatic arthritis clinical features . . . . . . 1.1. Genetic association in psoriasis and psoriatic arthritis 2. Pathogenesis of psoriasis and psoriatic arthritis . . . . . . 2.1. Dendritic cells . . . . . . . . . . . . . . . . . 2.2. γδ T cells and NK cells . . . . . . . . . . . . . . 2.3. Th1 and Th17 cells . . . . . . . . . . . . . . . 2.4. CD8 T cells . . . . . . . . . . . . . . . . . . . 2.5. Tertiary lymphoid tissues . . . . . . . . . . . . 3. Antigen-specific responses in psoriasis and psoriatic arthritis 4. Concluding remarks . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . .
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I.R.C.C.S Istituto Ortopedico Galeazzi, Department of Dermatology, University of Milan, Milan, Italy I.R.C.C.S Istituto Ortopedico Galeazzi, Department of Venereology, University of Milan, Milan, Italy I.R.C.C.S Istituto Ortopedico Galeazzi, Laboratory of Translational Immunology, Milan, Italy
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1. Psoriasis and psoriatic arthritis clinical features
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Psoriasis is a chronic inflammatory skin disease affecting approximately 2%–4% of the population worldwide and is considered the ⁎ Corresponding author at: Laboratory of Translational Immunology, I.R.C.C.S Istituto Ortopedico Galeazzi, via Riccardo Galeazzi 4, 20161 Milan, Italy. Tel.: +39 02 66214780; fax: +39 02 66214048. E-mail address: [email protected] (E. Reali).
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most prevalent immune-mediated disease in humans. [1]. Plaque psoriasis, also known as psoriasis vulgaris, is the commonest form of the disease, representing almost 90% of psoriatic patients [2]. The lesions are characterized by erythematous dry, sharply demarcated plaques with loosely adherent silvery white scalest. The disease appears in other different clinical variants as inverse psoriasis pustular, palmoplantar, erythrodermic psoriasis, and guttate psoriasis, that usually affects children and adolescents following a streptococcal infection [3,4]. Usually guttate psoriasis spontaneously resolves however a fraction of patients
http://dx.doi.org/10.1016/j.autrev.2014.11.012 1568-9972/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Diani M, et al, T cell responses in psoriasis and psoriatic arthritis, Autoimmun Rev (2014), http://dx.doi.org/10.1016/ j.autrev.2014.11.012
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Genetic and epidemiological data, have indicated that psoriasis is a multifactorial disease, influenced by multiple genes as well as environmental factors including trauma and infections. The strong heritability of psoriasis has been originally evidenced by the 70% concordance in monozygotic twins and 20% in dizygotic [6, 14]. In recent years many progresses have been made in the characterization of the genetic basis of psoriasis. Linkage analysis studies have indeed identified nine chromosomal loci associated with psoriasis named PSORS1 to PSORS9. The major genetic determinant of psoriasis resides in the locus of susceptibility, PSORS1, encoding the gene variant HLA-Cw6, which is carried by up to 60% of patients with early-onset psoriasis [6,15]. Another locus of susceptibility associated with epidermal differentiation pathways is the epidermal differentiation complex gene cluster (PSORS4), that contains variations in copy numbers of genes belonging to the late cornified envelope complex as well as genes encoding the S100 calcium-binding proteins. In addition, increased copy number of the genes at the locus encoding human beta defensins has been reported [16]. Other gene variants associated with psoriasis, mostly single nucleotide polymorphisms, belong to the IL-23/IL-17 axis (Il23R, Il12B, Il23A genes) and the NF-κB pathway (TNFAIP3). Results from recent studies identified mutations and in the caspase recruitment domain-containing protein 14 (CARD14) linked to psoriasis and in IL36RN, the gene encoding the IL-36R antagonist (IL-36Ra, formerly IL-1F5), linked to generalized pustular psoriasis but not to psoriasis vulgaris [17,18] From the genetic point of view, patients with the cutaneous form of psoriasis and those with psoriatic arthritis share the majority of the predisposing gene variants, in particular the association with HLA-Cw6. Other class I antigens are also associated with psoriatic arthritis, including HLA-B13, HLA-B57, HLA-B39, and HLA-Cw7. Linkage analysis studies, have indicated that Killer-cell Immunoglobulin-like Receptor (KIR2D) gene polymorphisms, are specifically associated with psoriatic arthritis [19–22].
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2. Pathogenesis of psoriasis and psoriatic arthritis
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An important distinction has been recently made in psoriasis natural history by identifying 2 phases: an initiation phase that starts inflammation and a maintenance phase that perpetuates the inflammatory state [23]. This conceptual distinction can help to divide the cellular and molecular events that determine triggering of the disease from those that are the results of the self-perpetuating cycle and represent downstream effector arms of the inflammatory process. Psoriasis lesions are initiated by triggering events that are not fully characterized. These include streptococcal infections, trauma, and medications. Association between streptococcal infections is well established for guttate psoriasis [5] (56–97% association) and has recently been extended to the onset of exacerbation of plaque psoriasis [24,25]. Among the triggering events it should be taken into consideration that psoriasis often appears in areas of injury (Koebner phenomenon) and that plaques usually initiate on elbows and knees that are common areas exposed to trauma.
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In human psoriatic skin, an overall increase of dendritic cells (DCs) has been found both in the epidermis and in the dermis [26,27]. In particular, myeloid DC types such as TNF and iNOS‐producing DCs (Tip‐DCs) [26], slanDCs, and plasmacytoid DCs (pDCs) [28] have been shown to infiltrate predominantly the dermal compartment of psoriatic skin. One of the initial triggering event for psoriasis development has been described by Lande and colleagues in 2007, showing that the alarmin cathelicidin/LL37 complexed to self-DNA or -RNA activates IFNα release by plasmacytoid DCs and activation of dermal myeloid DCs leading to DC maturation [29,30]. In this view, it is worth to underline that many of the genes encoded within the PSORS loci may also act as alarmins that favor myeloid DC maturation. These include S100 proteins, S100A12 (EN_RAGE or Calgranulin C], S100A7 (psoriasin), and S100A7A (S100A15 or koebnerisin) and β-defensins [8,31]. These elements could represent genetic predisposing factors to dendritic cell maturation and antigen presentation to T cells following trauma, microbial infection or the combination of the two. To this end a very recent study has reported that human beta defensins hBD2 and hBD3 represent additional triggers to plasmacytoid DC activation in psoriatic skin lesions [32]. The clinical association between psoriasis and trauma may represent an important phenomenon and together with the genetic link of the disease lead may suggest that cross-presentation of cellular antigens in association with HLA class I molecules by dendritic cells may represent an early and relevant event in disease pathogenesis. Once activated resident myeloid DCs produce IL-12 and IL-23, key psoriatic cytokines, which determine polarization of Th1 and Th17 cell subsets characterized for their role sustaining the self-perpetuating loop in the chronic phase of the disease [33–35]. The most recent advances in this field evidenced that IL-23 activates not only Th17 but also CD8+ Tc17 cells (collectively called T17) and the IL23R expressing γδ T cells [36].
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The overview of the genetic association of psoriasis and PsA points to a role for HLA class I restricted antigen presentation, which in turn brings to CD8 T cells as one of the immunopathogenic mechanism of the disease. The strong association of PsA with HLA class I alleles together with the evidence that this association distinguishes psoriatic arthritis from rheumatoid arthritis, which is associated with HLA class II alleles, definitively point to the need of understanding CD8 T cell responses in PsA and their link with T cell responses arising the skin.
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progress to plaque psoriasis. Patients recovering from guttate psoriasis still have a higher risk to develop plaque psoriasis [5]. In patients with psoriasis, new lesions may appear following direct cutaneous trauma, and this is known as the Koebner phenomenon. Psoriatic skin has three principal histological features: epidermal hyperplasia, leukocyte infiltrates, and an increased number of tortuous and leaky vessels in the dermis resembling the regenerative maturation observed during wound repair [6–8]. In recent studies we and others have reported the enhanced presence of lymphoid-like tissues in the dermis of psoriatic plaques as compared to normal skin [9]. Psoriatic arthritis (PsA) occurs in about 20–30% of patients with psoriasis and in approximately 80% of cases it follows the development of the cutaneous disease by a mean of 10 years [10,11]. In addition to synovitis, other common manifestations in PsA include enthesitis, dactylitis and anterior uveitis or iritis. Usually PsA appears between 30 and 50 years of age with equal distribution between men and women with the exception of axial disease, which favors men 3:1 [11]. The diagnosis of PsA is clinical as there are no pathognomonic, serological, imaging or other diagnostic tests. The majority of PsA patients are seronegative, as serum tests for Rheumatoid Factor and anticitrullinated peptide antibodies (ACPA) are negative; however, there is a greater prevalence of RF/ACPA positivity among PsA patients compared with the general population [12,13]. In addition to the development of inflammation of skin and joints, there is emerging evidence of systemic manifestations associated with psoriasis including diabetes mellitus, metabolic syndrome, and cardiovascular disease. For this reason the terminology psoriatic disease has been adopted encompassing the various manifestations of the disease.
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Originally Th1 cells were considered to be the main mediators of the immune response in psoriatic plaques, then in recent years, the attention moved to the role of Th17 cells [42]. Th17 cytokines, in particular interleukin IL-17A, have been shown to be critical for sustaining inflammation in psoriatic plaques. IL-17A stimulates the production of antimicrobial peptides by keratinocytes, which in turn promote recruitment of inflammatory cells. IL-17 itself is capable of enhancing keratinocyte proliferation and inhibiting keratinocyte differentiation via the downstream mediator REG3A, a protein with antimicrobial functions involved in wound repair [43]. As a consequence of the emerging importance of IL-17A in psoriasis pathogenesis, the relevance of IFNγ is now less clear. Analysis of the cutaneous transcriptome in psoriatic skin lesions has indicated an increased expression of IFNγ-regulated genes and the down-regulation of IFNγ gene is consistently observed with response to patient treatment with etanercept [44]. Kryczek et al. have suggested that one of the main effects of IFNγ is activating antigen-presenting cells early in the psoriatic cascade. In particular IFNγ produced by Th1 and other cells would program myeloid dendritic cell to produce CCL20 ligand of CCR6 and secrete IL-23 thus favoring IL-17 producing cell recruitment and activation. In turn IFNγ would synergize with IL-17-producing cells in inducing human β-defensins production [45]. In a small pilot study humanized anti-IFNγ has been used in the treatment of psoriasis showing that although an improvement of histological and clinical parameters was observed, the treatment had only a minor therapeutic effect suggesting that IFNγ may not be a primary pathogenic cytokine in psoriasis [46]. It is however possible to speculate that IL-17A and IFNγ producing cells may play different roles in the different phases of the pathogenesis with IL-17A playing the most relevant role as the amplifying effector arm that causes clinical manifestation of skin inflammation and IFNγ taking part in the generation of T cell-dendritic cell aggregate that initiates the self-perpetuating cycle. The IL-23/IL-17 axis has also been linked to the pathogenesis of psoriasis based on the evidence that single polymorphisms in IL23R and TRAF3IP2 have been associated with PsA, on the increase of IL-23/
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The focus of the studies of the recent years has been maintained on CD4 T subsets however, genetic susceptibility factors, together with the recent evidence that in psoriatic lesions both CD4+ and CD8 + T cells produce IL-17A and IL-17F on ex vivo stimulation, underline the need to reevaluate the role of CD8 T cells not only as effector cells but also as possible drivers of the initial phase of the disease [49]. In psoriatic skin lesions the majority of T cells infiltrating the dermis are of the CD4 phenotype whereas CD8 + T cells predominate in lesional epidermis [50,45,51,52]. CD8+ T cells may represent key players that recognize self-epitopes presented by the binding pockets of HLA-Cw6 or other HLA class I molecules on the keratinocyte surface and repository of the autoimmune nature of the diseases [53]. According to this view priming of CD8+ T cells toward self- and microbial-antigens could occur in the early phase as a consequence of dendritic cell activation in the dermis. The pathogenic cycle therefore could be generated through the interplay between CD8+ T and CD4 T cells and antigen presenting cells (APCs), including DCs predisposed to alarmin-induced maturation and cross-presenting self-antigens [32]. In psoriatic arthritis, CD4+ T cells are more abundant in synovial tissue whereas CD8+ T cells prevail in synovial fluid. Accordingly, a very recent study has reported a markedly increased level of CD8+ T cells in synovial fluid of patients with psoriatic arthritis. These cells were shown to be IL17-producing cells and to correlate with disease severity measured by CRP and ESR level as well as by radiographical evaluation of the erosion status and the presence of active synovitis [54]. In this study CD4+ IL17 producing cells were also found to be present in the synovial fluid of patients with PsA and RA however they failed to correlate with disease activity in PsA. The results of this study point to a key contribution of IL-17-producing CD8 T cells in the pathogenesis of PsA.
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In the dermis of psoriatic plaques, we and others have recently evidenced the presence of a lymphoid aggregate composed of CD11c + dendritic cells and T cells. In the formation of the lymphoid aggregate, the CCL19/CC7 axis was shown to play key role as its inhibition by TNF-blocking agents was the most critical event in psoriasis remission in treated patients [9]. Intriguingly, Canete and co-workers have reported that also in psoriatic arthritis lymphoid neogenesis occurs in synovial tissues and that TNF blockers can significantly reduce this phenomenon. These findings are in accordance with our results on the role of CCR7/CCL19 in the formation of lymphoid aggregates and in the pathogenesis of plaque psoriasis. Therefore it is tempting to speculate that recirculation of T cells through the tertiary lymphoid tissues in skin and joints may represent a pathogenic link between cutaneous psoriasis and psoriatic arthritis. [55].
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The question of antigen specificity of T cell responses in psoriasis and psoriatic arthritis is still unanswered and is strongly linked the autoimmune nature of the disease [53]. An association between streptococcal throat infection and the acute guttate form of psoriasis (an early onset form) has been demonstrated in many studies, and the reported incidence of streptococcal infections preceding this type of psoriasis ranges between 56% and 97% [5]. Chronic plaque psoriasis is also exacerbated after these types of infections and it has been reported that the psoriasis patients have
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A recent study has reported the surprising finding that the major source of IL-17A in the skin is represented by the dermal CD3 + γδ T cells and that these cells are present in a significantly higher percentage in psoriatic skin lesion than in healthy skin. When stimulated ex vivo with IL-23, γδ T cells increase their expression of IL-17 many fold more than αβ T cells [37]. This unconventional T cells displaying lessspecific antigen responses have been proposed to initiate and precede the participation of Th17 cells in psoriasis. Mouse model of psoriasislike skin inflammation induced by treatment with Toll-like receptor (TLR)7/8 agonist imiquimod, has indeed indicated that innate rather than adaptive immune responses is involved in the primary formation of psoriatic skin lesions and showed the critical role of the IL-23/IL-17/ IL-22 axis for the psoriatic phenotype [38]. This finding adds a new important variable to the scenario of T cell responses in psoriasis pathogenesis [39,40]. As concerns psoriatic arthritis, association with natural killer cell pathways has been reported, as the presence of some allotypes of the killer cell immunoglobulin-like receptor (KIR) superfamily has been found to influence disease susceptibility [22,41]. Indeed, it has been suggested that KIR expression in the synovial fluid of patients with psoriatic arthritis is dominated by activating KIRs underlining the possibility to evaluate the role of innate lymphoid cells in determining psoriatic arthritis in parallel with the analysis of γδ T cells in the pathogenesis of cutaneous psoriasis.
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The massive activation of T cells in the tonsils would induce the expression of the skin-homing CLA molecules thus allowing T cells to egress from the tonsils and recirculate to the skin. In the skin CD8 T cells may migrate to the epidermis and cross-recognize keratin determinant on keratinocytes, whereas CD4 T cells could interact in the dermis with dendritic cells activated by peptidoglycans. This could possibly initiate the self-sustaining loop that drives chronic inflammation. Prolonged inflammatory reaction in turn could favor cross-presentation of autoantigens to CD8 T cells and the phenomenon of epitope spreading. Psoriasis could therefore be initiated by CD8 T cells that recognize the streptococcal M protein determinant in the palatin tonsils and homologous keratin determinant in the skin, be amplified by CD4 T cells stimulated by microbial antigens or bystander activation and spread to other self-epitopes cross-presented by alarmin-induced mature dendritic cells in predisposed individuals (Fig. 1). In this view CD8 T cells could represent the core of the autoimmune nature of the disease that recognize autoepitopes presented in the context of HLACw06 on the surface of antigen presenting cells or keratinocytes. The pathogenic activity of CD8 T cells is however likely to require a local interaction with CD4 T cells and involve crosspresenting dendritic cells. Skin homing CD4 T cells in this case could play the role of amplifier of inflammation with a central role in the generation of self-sustaining inflammatory loop in the dermis. From this loop IL-23-induced IL-17 mediated responses would be amplified and give rise to important clinical manifestation of the disease. CD4 T cells and possibly γδ T cells could therefore represent downstream amplifying effector arms of an autoimmune reaction.
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about a tenfold higher frequency of streptococcal throat infections than age-matched household controls [56]. Worsening of chronic psoriasis was associated only with throat infection by the three groups of β-hemolytic streptococci (A, C and G) that express M-protein on their surface [57]. Extensive homology between streptococcal M-protein and keratin was first reported in the early nineties leading to the initial hypothesis that psoriasis is maintained by T cells that recognize the streptococcal M protein determinant in the palatin tonsils and homologous keratin determinant in the skin [58]. This link is supported by the fact that skin T cells tend to be oligoclonal and that T cells isolated from the skin and tonsils have been shown to carry the same gene rearrangement indicating a common origin. Furthermore, dominant clones in the skin persisted also after drug treatment and disease remission whereas minor clones were transiently present. Importantly, oligoclonality was shown mainly for CD8 T cells rather than for CD4 [59]. Analysis of the Keratin 17 and M protein derived peptide binding to HLA CW06 showed psoriasis patients expressing HLACW06 responded to K17 peptides whereas control did not. T cells cross-reacting with human keratin could also be detected in the blood of psoriasis patients. The response was confined to CD8 + T cells and the majority of responding cells expressed CLA [60,61,58,62,56]. This evidence brings once more the attention to the central role of CD8 T cells in establishing the disease. CD4 T cells may therefore be activated by streptococcal superantigens or determinants derived from peptidoglycan or other microbial or stress-induced antigens.
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Fig. 1. Schematic representation of the triggering mechanisms and establishment of chronic inflammation in psoriatic plaques. (1) Streptococcal M-protein-derived antigens presented by dendritic cells to CD8+ T cells and induction of CLA expression (2) Re-localization of M-protein-specific CD8 T cells to the skin epidermis, cross-recognition of keratin-derived determinants (autoimmune mechanism). (3) Recruitment of dendritic cells and CD4 T cells and establishment of an inflammatory loop sustained by IL-23/IL-17 axis. (4) Cross-presentation of tissue-derived antigens by dendritic cells and epitope spreading. Amplification of the IL-23/IL-17 CD4 and γδ T cell loops.
Please cite this article as: Diani M, et al, T cell responses in psoriasis and psoriatic arthritis, Autoimmun Rev (2014), http://dx.doi.org/10.1016/ j.autrev.2014.11.012
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(a) One major population consisted of nonclonally expanded polyclonal CD4 T cells that did not persist in the tissue during methotrexate treatment. (b) A second major population of moderately expanded inflammationrelated clones were identified only in active arthritis tissue and/ or active joint fluid that were either of CD4 or CD8 lineage. These clones were only present as single clonal expansions and could not be grouped together by structural homology among their CDR3 regions to form clonal sets that indicated Ag drive and potential determinant spread. (c) A third and small population of highly expanded clones exclusively CD8 in lineage, distinguished by marked expansion in both blood and joint fluid and persisted during methotrexate treatment.
4. Concluding remarks
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Analyzing these data together with those obtained in psoriasis patients it can be postulated that persisting CD8 clones with highly homologous CDR3 amino acid sequences could represent the potential driver clones and could be a common feature of psoriasis and psoriatic arthritis (Fig. 2). As regards the major polyclonal CD4 T cell population that has been described both in blood and in inflamed tissue could potentially represent a recirculating population of the Th17/Th1 subset originating in psoriatic plaques that traffic through the joints (Fig. 2). The numerous clones of the second major population were distinguished from the putatively Ag-driven population by several features.
The triggering event of the initial phase of the disease is unclear as the autoimmune etiology of psoriasis is unclear. By integrating information on recent advances on Th17/Th1 γδT cell contribution in determining inflammation on psoriatic skin together with early data on keratin cross-reactive CD8 T cells with specificity for streptococcal antigens, we have highlighted the role of the different subpopulations of T cells in psoriasis and psoriatic arthritis and hypothesized a hierarchical role for T cell responses in determining the initial phase of the disease and chronic inflammation. In the proposed model of psoriasis pathogenesis CD8 T cells may represent the core mechanism of psoriasis pathogenesis possibly linked to its autoimmune nature whereas CD4 and γδ T cells could play a central role in amplifying and maintaining the pathogenic inflammatory cycle in psoriatic plaques leading to the main clinical manifestation of the disease. Psoriasis could therefore be initiated by CD8 T cells that recognize the streptococcal M protein determinant in the palatin tonsils and homologous keratin determinant in the skin, be amplified by Th17 T cells and γδ T cells stimulated by microbial antigens or bystander activation and spread to other self-epitopes cross-presented by alarmininduced mature dendritic cells in genetically predisposed individuals following trauma or microbial stimulation.
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In terms of distribution, they were mainly found in the actively inflamed sites of joint fluid and/or tissue, and nearly all were not detectably expanded in blood. These clones did not persist during methotrexate treatment and were unlikely to contribute to disease reactivation after treatment cessation. The high frequency of these clones could be a distinguishing feature of psoriatic arthritis and could generate form epitope spreading upon prolonged inflammation. Cross-presentation of self-antigens could favor in these patients cross-recognition of self-antigen presented by HLA-B alleles associated with PsA. Alternatively this population could be present in both the skin and joints being differentially represented in the two diseases and originating from independently occurring epitope spreading phenomenon.
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The association of psoriatic arthritis with MHC class I susceptibility alleles including HLACw06, B13, B27, and B57, a predominant CD8 + CD45RO + T cell phenotype in joint fluid provide evidence for a critical role of CD8 T cells and suggested the hypothesis that the disease is driven by presentation of self-peptides by susceptibility MHC class I molecules to autoreactive Ag-specific CD8 T cells. A very exhaustive study published in 2004 used nucleotide sequencing of TCRβ chains to analyze T cell clones infiltrating the inflamed joint tissue in patients with PsA [63]. Three populations of T cells were identified:
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Fig. 2. Schematic representation of the putative hierarchical role of CD8 and CD4 T cells in the pathogenesis of psoriatic disease relative to their amount and antigen-specificity.
Please cite this article as: Diani M, et al, T cell responses in psoriasis and psoriatic arthritis, Autoimmun Rev (2014), http://dx.doi.org/10.1016/ j.autrev.2014.11.012
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Acknowledgments
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We thank Prof. Giuseppe Banfi, I.R.C.C.S. Istituto Ortopedico Galeazzi, Milan (Italy); Dr. Daniela Talarico, S. Raffaele Research Hospital, Milan (Italy) and Prof. Riccardo Gavioli, University of Ferrara, Ferrara (Italy) for critical reading of the manuscript. This work received support from National Psoriasis Foundation.
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References
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• Keratin cross-reactive CD8 T cells with specificity for microbial antigens can represent the core autoimmune mechanism of psoriasis pathogenesis. • Th17 T cells and γδ T cells act as downstream effectors stimulated by common-antigens or bystander activation • Th17 driven inflammatory cycle can lead to the main clinical manifestations in the skin and extend inflammation to the joint. • Dendritic cells in genetically predisposed individuals could crosspresent self-epitopes leading to epitope spreading in the skin and joints.
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Please cite this article as: Diani M, et al, T cell responses in psoriasis and psoriatic arthritis, Autoimmun Rev (2014), http://dx.doi.org/10.1016/ j.autrev.2014.11.012
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