Specific IgA and CLA+ T-Cell IL-17 Response to Streptococcus pyogenes in Psoriasis (original) (raw)
Related papers
Microbe-dependent induction of IL-9 by CLA(+) T cells in psoriasis and relationship with IL-17A
The Journal of investigative dermatology, 2017
IL-9 is present in psoriatic lesions and produced by lymphocytes. However, it is not known whether this cytokine is induced by relevant pathogenic triggers of psoriasis, such as Streptococcus pyogenes. Here we addressed the production of IL-9 in response to various pathogens in a psoriatic ex vivo model. Extracts of S. pyogenes and C. albicans triggered the production of IL-9 and also IL-17A and IFN-γ. This induction was dependent on the interaction between CLA(+) T-cells and epidermal cells. Neutralization of IL-9 reduced S. pyogenes-induced IL-17A production by CLA(+) T cells but had no effect on IFN-γ production. Also, IL-9 increased the survival of circulating psoriatic CLA(+) T-cells. Cocultures from patients with guttate or plaque psoriasis with S. pyogenes produced similar amounts of IL-9. Interestingly, high cytokine responses in streptococcal-driven guttate patients paralleled peaks in PASI and ASO levels. Our results confirm that IL-9 promotes inflammation in psoriasis by ...
Journal of Allergy and Clinical Immunology, 2016
Background: Guttate psoriasis (GP) is characterized by acute onset of small, rounded psoriatic lesions. Although this particular phenotype of psoriasis is usually associated with streptococcal throat infections and mainly occurs in HLA-Cw6 1 patients, the specific immunologic response to this innate stimulus that causes these skin lesions is poorly understood. Objective: This study aims to elucidate how key cellular elements of patients with GP respond to Streptococcus pyogenes and whether this initial immune response is favored by the genetic and environmental background of these patients. Methods: Circulating memory T cells and autologous epidermal cells from samples from either patients with GP (n 5 14) or healthy control subjects (n 5 6) were cocultured ex vivo in the presence of an S pyogenes extract. Levels of the psoriasis-associated cytokines IL-17A, IL-17F, IFN-g, TNF-a, IL-6, and IL-8 were determined. The expression of several genes with increased (DEFB4, S100A7, LCN2, IL36G, IL8, CXCL9, CXCL10, and CXCL11) or decreased (FLG and LOR) transcripts in psoriatic lesions was examined in keratinocytes treated with coculture supernatants. Results: When skin-homing effector memory cutaneous lymphocyte antigen-positive T cells were used in cocultures, a T H 17-dominant response was observed, as reflected by the higher amounts of IL-17A and IL-17F than IFN-g. Moreover, a higher T H 17 response was observed in cells isolated from patients with flares associated with a streptococcal tonsillitis and with the HLA-Cw6 allele (cohort 1). In addition, in normal keratinocytes the supernatants from these cocultures induced an increase in IL-17-associated genes, such as DEFB4, S100A7, LCN2, IL36G, and IL8 but a decrease in FLG and LOR, thereby confirming the role of activated T H 17 cells. Conclusion: This study reveals a dominant T H 17 response of cutaneous lymphocyte antigen-positive T cells activated by epidermal cells and S pyogenes in patients with GP.
CLA+ T Cell Response to Microbes in Psoriasis
Frontiers in Immunology, 2018
Streptococcus pyogenes throat infection is a clinically relevant trigger of both guttate and chronic plaque psoriasis, and it provides an ideal context in which to study the pathogenesis of these diseases using an antigen-dependent approach. Circulating cutaneous lymphocyte-associated antigen (CLA) positive (+) memory T cells are a subset of peripheral lymphocytes whose phenotype and function are related to immunological mechanisms in the skin. These cells are considered peripheral biomarkers of T-cell-mediated skin diseases. The coculture of autologous epidermal cells with CLA + T cells from psoriasis patients activated by S. pyogenes allows the reproduction of the ex vivo initial molecular events that occur during psoriatic lesion formation. With cooperation of autologous epidermal cells, S. pyogenes selectively activates CLA + T cells both in guttate and plaque psoriasis, inducing key mediators, including an IL-17 response. Here, we explore potential new mechanisms of psoriasis development including the influence of HLA-Cw6 on S. pyogenes CLA + T cell activation in guttate psoriasis, the relevance of IL-9 on microbe induced IL-17 response in guttate and plaque psoriasis, and novel effector functions of Candida albicans. This review will summarize recent knowledge of psoriatic mechanisms elicited by microbes that have been studied through an innovative translational perspective based on CLA + T cell-mediated cutaneous immune response.
The Emerging Role of IL-17 in the Pathogenesis of Psoriasis: Preclinical and Clinical Findings
Journal of Investigative Dermatology, 2013
Abbreviations: AMPs, antimicrobial peptides; mRNA, messenger RNAs; PASI, psoriasis area and severity index; Tc, cytotoxic T; Th1, T-helper 1; TNF-a, tumor necrosis factor-a Chang SH, Dong C (2007) A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses. Cell Res 17:435-40 Chaudhari U, Romano P, Mulcahy LD et al. (2001) Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial. Lancet 357:1842-7 Chen S, Shimada K, Zhang W et al. (2010) IL-17A is proatherogenic in highfat diet-induced and Chlamydia pneumoniae infection-accelerated atherosclerosis in mice. J Immunol 185:5619-27 Chiricozzi A, Guttman-Yassky E, Suarez-Farinas M et al. (2011) Integrative responses to IL-17 and TNF-alpha in human keratinocytes account for key inflammatory pathogenic circuits in psoriasis. J Invest Dermatol 131:677-87 Ciric B, El-behi M, Cabrera R et al. (2009) IL-23 drives pathogenic IL-17producing CD8+ T cells. J Immunol 182:5296-305 Claudio E, Sonder SU, Saret S et al. (2009) The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation.
IL-17 and its role in psoriasis
Journal of Pakistan Association of Dermatology, 2017
IL-17 induces release of many cytokines (e.g. IL-6, G-CSF, GM-CSF, IL-1B, TGF-B, TNF∞), chemokines (e.g. IL-8, GRO-∞ and MCP1) and prostaglandins such as PGE2 from fibroblasts, endothelial cells, keratinocytes and macrophages. IL-17 along with IL-22 induces antimicrobial peptide production by keratinocytes. The release of cytokines results in keratinocyte and vascular response along with enhanced cell recruitment. Keratinocytes in response produce chemokines and cytokines, which specifically cause neutrophil recruitment. Il-17 also downregulates filaggrin, leading to disruption of skin barrier. IL-17A, the best-studied member of this family, is composed of 155 amino acids with molecular weight of 15KDa. It forms heterodimers or homodimers with IL-17F, binding with IL-17RA and IL17RC subunits leading to gene activation.
Journal of Investigative Dermatology, 2013
Streptococcal throat infection is associated with a specific variant of psoriasis and with HLA-Cw6 expression. In this study, activation of circulating psoriatic cutaneous lymphocyte-associated antigen (CLA) þ memory T cells cultured together with epidermal cells occurred only when streptococcal throat extracts were added. This triggered the production of Th1, Th17, and Th22 cytokines, as well as epidermal cell mediators (CXCL8, CXCL9, CXCL10, and CXCL11). Streptococcal extracts (SEs) did not induce any activation with either CLA À cells or memory T cells cultured together with epidermal cells from healthy subjects. Intradermal injection of activated culture supernatants into mouse skin induced epidermal hyperplasia. SEs also induced activation when we used epidermal cells from nonlesional skin of psoriatic patients with CLA þ memory T cells. Significant correlations were found between SE induced upregulation of mRNA expression for ifn-g, il-17, il-22, ip-10, and serum level of antistreptolysin O in psoriatic patients. This study demonstrates the direct involvement of streptococcal infection in pathological mechanisms of psoriasis, such as IL-17 production and epidermal cell activation.
Experimental dermatology, 2015
The response of psoriasis to antibodies targeting the interleukin (IL)-23/IL-17A pathway suggests a prominent role of T-helper-17 cells in this disease. We examined the clinical and immunological response patterns of 100 subjects with moderate-to-severe psoriasis receiving 3 different intravenous dosing regimens of the anti-IL-17A antibody secukinumab (1 x 3 mg/kg or 1 x 10 mg/kg on Day 1, or 3 x 10 mg/kg on Days 1, 15 and 29) or placebo in a phase 2 trial. Baseline biopsies revealed typical features of active psoriasis, including epidermal accumulation of neutrophils and formation of microabscesses in >60% of cases. Neutrophils were the numerically largest fraction of infiltrating cells containing IL-17, and may store the cytokine preformed, as IL-17A mRNA was not detectable in neutrophils isolated from active plaques. Significant clinical responses to secukinumab were observed 2 weeks after a single infusion, associated with extensive clearance of cutaneous neutrophils parallel...
IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis
Journal of Allergy and Clinical Immunology, 2012
Background: In subjects with psoriasis, inflammation and epidermal hyperplasia are thought to be controlled by T cellderived cytokines. Evidence suggests that the T H 17 cell cytokine IL-17A (IL-17) might play a role in disease pathogenesis. Objective: We sought to understand the effect that neutralization of IL-17 has on the clinical features of psoriasis and to understand the role that IL-17 has in inflammatory pathways underlying psoriasis in human subjects. Methods: We examined skin lesions obtained from 40 subjects participating in a phase I, randomized, double-blind, placebo-controlled trial of the anti-IL-17 mAb ixekizumab (previously LY2439821) in which subjects received 5, 15, 50, or 150 mg of subcutaneous ixekizumab or placebo at weeks 0, 2, and 4. Results: There were significant dose-dependent reductions from baseline in keratinocyte proliferation, hyperplasia, epidermal thickness, infiltration into the dermis and epidermis by T cells and dendritic cells, and keratinocyte expression of innate defense peptides at 2 weeks. By week 6, the skin appeared normal. Quantitative RT-PCR and microarrays revealed an ablation of the disease-defining mRNA expression profile by 2 weeks after the first dose of study drug. The effect of IL-17 blockade on expression of genes synergistically regulated by IL-17 and TNF-a was of higher magnitude at 2 weeks than in prior studies with TNF-a antagonism. Conclusion: Our data suggest that IL-17 is a key ''driver'' cytokine that activates pathogenic inflammation in subjects with psoriasis. Neutralizing IL-17 with ixekizumab might be a successful therapeutic strategy in psoriasis. (J Allergy Clin Immunol 2012;130:145-54.)
Journal of Investigative Dermatology, 2014
IL-17A is pivotal in the etiology of psoriasis, and CD8 þ T cells with the ability to produce this cytokine (Tc17 cells) are over-represented in psoriatic lesions. Here we demonstrate that the frequency of Tc17 cells in peripheral blood of psoriasis patients correlated with the clinical severity of the disease. Analysis of cutaneous-associated lymphocyte antigen expression showed that the blood Tc17 population contains a significantly higher proportion of cells with skin-homing potential compared with the CD8 þ T-cell population lacking IL-17A/IL-22 expression. IL-17A-producing CD8 þ T cells in blood have previously been reported to belong mainly to the mucosa-associated invariant T-cell (MAIT cell) lineage characterized by TCR Va7.2 chain, CD161, IL-18Ra, and multidrug transporter ABCB1 expression. We demonstrate the presence of CD8 þ MAIT cells in the dermis and epidermis of psoriatic plaques, as well as healthy skin; however, IL-17A-producing CD8 þ MAIT cells were predominantly found in psoriatic skin. Notably, we observed IL-17A production in a large proportion of psoriatic plaque-derived CD8 þ T cells devoid of MAIT cell characteristics, likely representing conventional CD8 þ T cells. In conclusion, we provide supporting evidence that implicates Tc17 cells in the pathogenesis of psoriasis and describe the presence of innate CD8 þ MAIT cells in psoriatic lesions as an alternative source of IL-17A.
Krüppel-like factor 4 (KLF4) is a transcription factor that regulate a diverse array of cellular processes, including development, differentiation, proliferation and apoptosis. The role of its function regarding keratinocytes has been widely studied, yet its exact role or function has not been elucidated. The objective of the study was to investigate the epidermal expression level of KLF4 in normal healthy donor skin and psoriatic lesional and non-lesional skin, and determine its roles of KLF4 in psoriasis. We compared the epidermal expression level of KLF4 in normal healthy donor skin and psoriatic lesional and non-lesional skin immunohistochemically and measured the epidermal level of KLF4 with RT-PCR. We also performed epidermal proliferation after knocking down of KLF4, using siRNA to evaluate the growth of keratinocyte in HaCaT cells. The entire epidermis, especially the suprabasal layer of the psoriatic epidermis showed increased KLF4 expression compared to the normal, non-lesional skin. After treatment, the expression level in the suprabasal layer of the psoriasis skin was decreased. The epidermal level of KLF4, as measured by RT-PCR, was increased after the treatment of the psoriasis skin and the proliferation of HaCaT cells was changed by knockingdown the KLF4 mRNA. In conclusion, these data demonstrates that KLF4 can be an important regulator in epidermal proliferation and can be associated with epidermal proliferation disorders, including psoriasis. Background: The contribution of to the pathogenesis of psoriasis is substantiated by the clinical efficacy of antibodies against the common IL-12/IL-23 subunit p40, like Ustekinumab, suppressing IL-17 and Th1 cytokine production. To further address the significance of IL-17 producing T cell subsets in psoriasis, CD18hypo PL/J mice, developing a psoriasiform dermatitis at 12-14 weeks of age as a consequence of reduced expression of CD18/β2 integrin to 2-16 % of wildtype levels, were systematically analyzed for the presence of gammadelta and CD4+ T cell subsets in blood, lymphnodes and skin and the effect of blocking different targets within the IL-23/IL-17 axis. Results: Severity of CD18hypo PL/J psoriasiform dermatitis generally correlated with a loss of skin-resident Vγ5+ T cells and concurrent skin infiltration with inflammatory γδTCR-low expressing Vγ4+ and Vγ6+ T cells preceded by an increase of IL-23R+ Vγ4+ T cells in local lymphnodes in this psoriasis mouse model. Both, γδ T cells and Th17 cells contributed to IL-17 production in situ and in in vitro restimulation experiments. Injection of diseased CD18hypo PL/J mice with anti-γδTCR-, -IL-17, and -IL-23 antibodies resulted in an almost complete resolution of skin inflammation and eliminated pathological Vγ4+ T cells. In peripheral blood and skin sections from psoriasis patients, we observed a variable increase in IL-17+ gammadelta T cells that correlated with a reduction of CD18 levels compared to age-matched healthy subjects. Conclusion: These results for the first time demonstrate a critical role of skin-infiltrating inflammatory gammadelta T cells in a complex psoriasis model as well as a role for wildtype CD18 expression levels in suppression of pathological gammadelta T cells and suggest the need for individualized therapy of psoriasis patients depending on the skin infiltrate.