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• W2986832529 abstract "Despite the effectiveness of anti-tumor necrosis factor (TNF) therapies in treating inflammatory diseases, such as psoriasis, inflammatory bowel disease, and inflammatory arthritis (Toussirot and Aubin, 2016Toussirot É. Aubin F. Paradoxical reactions under TNF-alpha blocking agents and other biological agents given for chronic immune-mediated diseases: an analytical and comprehensive overview.RMD Open. 2016; 2e000239Crossref PubMed Scopus (119) Google Scholar), there is a small cohort that upon treatment, develop psoriasis-like lesions, termed paradoxical, or reactive, psoriasis. Although paradoxical psoriasis (P-Ps) can often be treated topically, discontinuation of the anti-TNF therapy is necessary in approximately one third of cases. The incidence of anti-TNF-induced P-Ps was reported to be 1.7% (Guerra et al., 2016Guerra I. Pérez-Jeldres T. Iborra M. Algaba A. Monfort D. Calvet X. et al.Incidence, clinical characteristics, and management of psoriasis induced by anti-TNF therapy in patients with inflammatory bowel disease: A nationwide cohort study.Inflamm Bowel Dis. 2016; 22: 894-901Crossref PubMed Scopus (62) Google Scholar), and the number of cases is likely to rise in parallel with the increasing use of biologics. Therefore, it is important to understand the pathogenesis of P-Ps. In order to investigate the role of T cells in P-Ps, we used multi-parameter flow cytometry to analyze the cytokine production by T cells in the lesional skin from patients with P-Ps and classical psoriasis (C-Ps) where the role of T cells, in particular T helper type 17 cells, is well established (Kim and Krueger, 2017Kim J. Krueger J.G. Highly effective new treatments for psoriasis target the IL-23/Type 17 T cell autoimmune axis.Annu Rev Med. 2017; 68: 255-269Crossref PubMed Scopus (109) Google Scholar). We recruited six patients with C-Ps; mean age 42 years (range 21–66), four females (67%), mean psoriasis area and severity index 7.5 (range 4–11.4). Two were on no treatment (33%); two had been treated with phototherapy (33%), one with Acitretin (17%), and one with ustekinumab (17%). We recruited six patients with P-Ps as a result of treatment with TNF inhibitors for ulcerative colitis (n = 1, 17%) or Crohn’s disease (n = 5, 83%); mean age 40 years (range 27–53), five females (83%). Three patients developed P-Ps while on adalimumab (50%) and three while on infliximab (50%) after a mean duration of 4.6 years of treatment (range 2 weeks–11 years). Two patients required cessation of the anti-TNF treatment and were then treated with ciclosporin (33%). Samples were taken from chronic plaque psoriasis lesions that were not acutely inflamed, and all lesions were grade 2-3 in erythema as per psoriasis area and severity index. Healthy control (Con) skin samples (n = 9) were also included; mean age 35 years (range 25–50), eight females (89%). The study received full ethical approval from the Medical Research Ethics Committee at Tallaght Hospital, Dublin, and all the patients provided written, informed consent. Skin samples from Cons and lesional C-Ps or P-Ps biopsies were dissociated, and the single cell suspension was treated and stained as previously described (Moran et al., 2017Moran B. Sweeney C.M. Hughes R. Malara A. Kirthi S. Tobin A.M. et al.Hidradenitis suppurativa is characterized by dysregulation of the Th17:Treg cell axis, which is corrected by anti-TNF therapy.J Invest Dermatol. 2017; 137: 2389-2395Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar) and analyzed by flow cytometry. In P-Ps skin, we observed a significant increase in the total number of T cells/mm skin (P < 0.05), of approximately one order of magnitude, and in the frequency of CD4 T cells (P < 0.05) compared with the Con skin, whereas despite an apparent increase, there were no significant differences between P-Ps and C-Ps (Figure 1a). Within CD4 T cells, there was a significant increase in the frequency of IL-17A- (P < 0.05) and IL-22- (P < 0.05) producing cells in P-Ps skin compared with the control skin (Figure 1b). There were no significant differences in TNF production by CD4 T cells between the groups (Figure 1b). The lack of significant differences between the Con and C-Ps may have been owing to the relatively small sample size. In P-Ps skin, there was also a significant increase in the frequency of CD8 T cells that produced IL-17A (P < 0.001) compared with the control skin (Figure 1c). IL-22-producing CD8 T cells were also significantly increased in both P-Ps (P < 0.01) and C-Ps (P < 0.05) compared with the control skin. Polyfunctional T cells capable of producing multiple pro-inflammatory cytokines are considered to be highly pathogenic in the context of inflammatory disease (Basdeo et al., 2015Basdeo S.A. Moran B. Cluxton D. Canavan M. McCormick J. Connolly M. et al.Polyfunctional, pathogenic CD161+ Th17 lineage cells are resistant to regulatory T cell-mediated suppression in the context of autoimmunity.J Immunol. 2015; 195: 528-540Crossref PubMed Scopus (53) Google Scholar). Therefore, in order to compare the polyfunctionality of T cells from P-Ps and C-Ps skin, we used a SPICE analysis (Roederer et al., 2011Roederer M. Nozzi J.L. Nason M.C. SPICE: exploration and analysis of post-cytometric complex multivariate datasets.Cytometry A. 2011; 79: 167-174Crossref PubMed Scopus (620) Google Scholar) to examine the multiple populations of CD4 (Figure 2a) and CD8 (Figure 2b) T cells producing different combinations of six different cytokines. The slices within the pie charts in Figure 2a depict the proportion of CD4 T cells in either P-Ps (left) or C-Ps (right) skin producing the various combinations of cytokines, heat map coded from black (zero cytokines produced) through to deep red (six cytokines). The outer arcs identify the specific cytokines produced by each population. The analysis indicates the trend of an increased proportion of both CD4 and CD8 T cells producing multiple cytokines in P-Ps versus C-Ps skin. The role of T helper type 17 cells and IL-17A in C-Ps is well established and underscored by the remarkable success of therapies targeting IL-17 (Kim and Krueger, 2017Kim J. Krueger J.G. Highly effective new treatments for psoriasis target the IL-23/Type 17 T cell autoimmune axis.Annu Rev Med. 2017; 68: 255-269Crossref PubMed Scopus (109) Google Scholar). Thus, the increased frequency of IL-17A- and IL-22-producing CD4 and CD8 T cells in P-Ps skin relative to Con skin, with a trend toward an increase relative to the C-Ps skin, suggests that these cells are likely to play an important inflammatory role in P-Ps. IL-17A activates keratinocytes to produce inflammatory mediators, including IL-17C and IL-36γ, both of which have been shown to sustain a self-amplifying loop in P-Ps lesions (Friedrich et al., 2014Friedrich M. Tillack C. Wollenberg A. Schauber J. Brand S. IL-36γ sustains a proinflammatory self-amplifying loop with IL-17C in anti-TNF-induced psoriasiform skin lesions of patients with Crohn's disease.Inflamm Bowel Dis. 2014; 20: 1891-1901Crossref PubMed Scopus (53) Google Scholar, Pfaff et al., 2017Pfaff C.M. Marquardt Y. Fietkau K. Baron J.M. Lüscher B. The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function.Sci Rep. 2017; 7: 15631Crossref PubMed Scopus (77) Google Scholar). IL-22 also plays a key role in psoriasis by promoting keratinocyte activation and proliferation (Boniface et al., 2005Boniface K. Bernard F.X. Garcia M. Gurney A.L. Lecron J.C. Morel F. IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes.J Immunol. 2005; 174: 3695-3702Crossref PubMed Scopus (674) Google Scholar). The mechanism underlying P-Ps is intriguing; it has been shown that in the absence of the TNF blockade, TNF negatively regulates the generation of plasmacytoid dendritic cells and their production of IFN-1 in response to stimulation (Palucka et al., 2005Palucka A.K. Blanck J.P. Bennett L. Pascual V. Banchereau J. Cross-regulation of TNF and IFN-alpha in autoimmune diseases.Proc Natl Acad Sci USA. 2005; 102: 3372-3377Crossref PubMed Scopus (451) Google Scholar). However, in the presence of anti-TNF, IFN-1 production is not constrained and triggers inappropriate inflammation (Conrad et al., 2018Conrad C. Di Domizio J. Mylonas A. Belkhodja C. Demaria O. Navarini A.A. et al.TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis.Nat Commun. 2018; 9: 25Crossref PubMed Scopus (146) Google Scholar, Palucka et al., 2005Palucka A.K. Blanck J.P. Bennett L. Pascual V. Banchereau J. Cross-regulation of TNF and IFN-alpha in autoimmune diseases.Proc Natl Acad Sci USA. 2005; 102: 3372-3377Crossref PubMed Scopus (451) Google Scholar). IFN-1 is thought to play a role in triggering C-Ps, and although the mechanisms have not yet been elucidated, it presumably promotes the induction of IL-17 (Grine et al., 2015Grine L. Dejager L. Libert C. Vandenbroucke R.E. An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17.Cytokine Growth Factor Rev. 2015; 26: 25-33Crossref PubMed Scopus (129) Google Scholar). Indeed, activated plasmacytoid dendritic cells and IFN-1 have been shown to promote T helper type 17 cells (Yu et al., 2010Yu C.F. Peng W.M. Oldenburg J. Hoch J. Bieber T. Limmer A. et al.Human plasmacytoid dendritic cells support Th17 cell effector function in response to TLR7 ligation.J Immunol. 2010; 184: 1159-1167Crossref PubMed Scopus (83) Google Scholar), and the induction of both IL-17A and IL-22 in response to tape stripping was dependent on IFN-1 (Gregorio et al., 2010Gregorio J. Meller S. Conrad C. Di Nardo A. Homey B. Lauerma A. et al.Plasmacytoid dendritic cells sense skin injury and promote wound healing through type I interferons.J Exp Med. 2010; 207: 2921-2930Crossref PubMed Scopus (242) Google Scholar). Hence, it might be expected that the dysregulated IFN-1 production that occurs in P-Ps could promote IL-17-producing T cells in a similar manner. Conrad et al., 2018Conrad C. Di Domizio J. Mylonas A. Belkhodja C. Demaria O. Navarini A.A. et al.TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis.Nat Commun. 2018; 9: 25Crossref PubMed Scopus (146) Google Scholar reported that P-Ps was independent of T cells and demonstrated a relative reduction in the frequency of epidermal CD8 T cells by histology, while the CD4 T cells were not analyzed (Mylonas and Conrad, 2018Mylonas A. Conrad C. Psoriasis: classical vs. paradoxical. The Yin-Yang of TNF and Type I interferon.Front Immunol. 2018; 9: 2746Crossref PubMed Scopus (71) Google Scholar). On the other hand, our flow cytometric analysis of digested skin revealed a trend toward a reduction in CD8 T cells and a significant increase in CD4 T cells in P-Ps skin compared with healthy skin and a trend toward an increase relative to C-Ps. Furthermore, our study demonstrated the increased expression of IL-17A and IL-22 directly by T cells, whereas Conrad et al., 2018Conrad C. Di Domizio J. Mylonas A. Belkhodja C. Demaria O. Navarini A.A. et al.TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis.Nat Commun. 2018; 9: 25Crossref PubMed Scopus (146) Google Scholar found increased expression of IL-22 but not IL-17 mRNA in P-Ps versus C-Ps. These contradictions may be accounted for by differences in experimental design and technique. Two histological studies in which increased numbers of T helper type 17 cells were observed are consistent with our findings (Moy et al., 2018Moy A.P. Murali M. Kroshinsky D. Horn T.D. Nazarian R.M. T-helper immune phenotype may underlie 'paradoxical' tumour necrosis factor-alpha inhibitor therapy-related psoriasiform dermatitis.Clin Exp Dermatol. 2018; 43: 19-26Crossref PubMed Scopus (8) Google Scholar, Tillack et al., 2014Tillack C. Ehmann L.M. Friedrich M. Laubender R.P. Papay P. Vogelsang H. et al.Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-gamma-expressing Th1 cells and IL-17A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment.Gut. 2014; 63: 567-577Crossref PubMed Scopus (224) Google Scholar). In summary, we report a significant increase in both CD4 and CD8 T cells that produce IL-17A and IL-22 within P-Ps lesions and propose that these cells contribute to the pathogenesis of this adverse event. The datasets related to this article can be found at https://doi.org/10.17632/ncnpmc7m8t.1, hosted at Mendeley Data. Barry Moran: http://orcid.org/0000-0002-8243-1079 Catriona Gallagher: http://orcid.org/0000-0003-1437-7311 Anne Marie Tobin: http://orcid.org/0000-0003-2730-9561 Jean M Fletcher: http://orcid.org/0000-0002-0670-6659 AMT has received unrestricted grants from AbbVie and served on Advisory Boards for AbbVie. JMF has received honoraria from Novartis and served on their advisory board and has received research grant funding from AbbVie. BM and CG state no conflict of interest. We would like to thank all the patients and healthy volunteers for participating in this study. Conceptualization: BM, AMT, JF; Data curation: CG; Formal analysis: BM; Funding Acquisition: JF; Investigation: BM; Resources: CG, AMT; Supervision: AMT, JF; Visualization: BM; Writing - original draft preparation: BM, JF; Writing - review and editing: BM, CG, AMT, and JF" @default.
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• W2986832529 date "2020-05-01" @default.
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• W2986832529 title "Enrichment of Polyfunctional IL-17-Producing T Cells in Paradoxical Psoriasis Skin Lesions" @default.
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