Atopic dermatitis: immune deviation, barrier dysfunction, IgE autoreactivity and new therapies.
TL;DR: TSLP/Th2/Th22 pathway is a promising target for developing new therapeutics for AD and Enhancing filaggrin expression using ligands for the aryl hydrocarbon receptor may also be an adjunctive measure to restore the disrupted barrier function specifically for AD.
About: This article is published in Allergology International.The article was published on 2017-07-01 and is currently open access. It has received 193 citations till now. The article focuses on the topics: Thymic stromal lymphopoietin & Filaggrin.
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Dissertation•
01 Jan 2011
286 citations
University of Bristol1, Hannover Medical School2, University of Copenhagen3, Erasmus University Rotterdam4, QIMR Berghofer Medical Research Institute5, Imperial College London6, Technische Universität München7, University of Kiel8, University of Pennsylvania9, University of Western Australia10, University of Basel11, University of Manchester12, VU University Amsterdam13, Karolinska Institutet14, Wellcome Trust Sanger Institute15, University of Geneva16, University of Oulu17, University of the East18, University of Washington19, University of Melbourne20, Ludwig Maximilian University of Munich21, University of Bonn22, Aarhus University23, Tartu University Hospital24, Statens Serum Institut25, University of Iowa26, Children's Hospital of Philadelphia27, King's College London28, Telethon Institute for Child Health Research29, Children's Medical Research Institute30, Swiss Tropical and Public Health Institute31, Norwegian Institute of Public Health32, Manchester Academic Health Science Centre33, Utrecht University34, Copenhagen University Hospital35, Karolinska University Hospital36, Sahlgrenska University Hospital37, Ontario Institute for Cancer Research38, St George's, University of London39, Medical Research Council40
TL;DR: This paper conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals from 14 studies.
Abstract: Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10(-13)) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10(-9)), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.
272 citations
TL;DR: Novel targeted therapies for AD have recently been introduced to clinical practice with many more in development, including monoclonal antibodies that specifically target cytokines and their receptors, and a bacteriophage lysin that eliminates S. aureus from AD skin.
263 citations
Additional excerpts
...This triggers an immunoglobulin E (IgE) response with antibodies which react with both the allergen and self-antigens (reviewed in [12])....
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..., Langerhans cells) (reviewed in [12] and summarized in Figure 1)....
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TL;DR: This chapter will discuss the multifaceted etiology of atopic dermatitis which will help to elucidate potential therapeutic targets and review existing treatment options and their interaction with the complex inflammatory and molecular triggers of atopy dermatitis.
Abstract: The pathophysiology of atopic dermatitis is complex and multifactorial, involving elements of barrier dysfunction, alterations in cell mediated immune responses, IgE mediated hypersensitivity, and environmental factors. Loss of function mutations in filaggrin have been implicated in severe atopic dermatitis due to a potential increase in trans-epidermal water loss, pH alterations, and dehydration. Other genetic changes have also been identified which may alter the skin’s barrier function, resulting in an atopic dermatitis phenotype. The imbalance of Th2 to Th1 cytokines observed in atopic dermatitis can create alterations in the cell mediated immune responses and can promote IgE mediated hypersensitivity, both of which appear to play a role in the development of atopic dermatitis. One must additionally take into consideration the role of the environment on the causation of atopic dermatitis and the impact of chemicals such as airborne formaldehyde, harsh detergents, fragrances, and preservatives. Use of harsh alkaline detergents in skin care products may also unfavorably alter the skin’s pH causing downstream changes in enzyme activity and triggering inflammation. Environmental pollutants can trigger responses from both the innate and adaptive immune pathways. This chapter will discuss the multifaceted etiology of atopic dermatitis which will help us to elucidate potential therapeutic targets. We will also review existing treatment options and their interaction with the complex inflammatory and molecular triggers of atopic dermatitis.
240 citations
Cites background from "Atopic dermatitis: immune deviation..."
...House dust mite antigen has been used in patch testing to confirm the switch between mRNA types from IL-4 to INF-γ [59]....
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...Atopic dermatitis patients with anti-alpha-NAC IgE antibodies produced much larger amounts of IL-17, IL-22, and INF-γ [70]....
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...A generally acceptable definition of atopy is the overproduction of IgE antibodies or a personal history of asthma, allergic rhinitis, AD, or other allergic diseases [58]....
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...Histologically, cells expressing mRNA for Th2 cytokines, such as IL-4 and IL-13, are greatly expressed in acute lesions during atopic dermatitis while chronic lesions have a larger number of cells expressing mRNA for INF-γ [58]....
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TL;DR: The Atopic Dermatitis Yardstick as mentioned in this paper is part of a series developed in response to the need to proactively address the loss of disease control for atopic illnesses at all levels of severity.
Abstract: The implementation of treatment guidelines for atopic dermatitis is challenging, in part because of different guidance documents being used by different groups of specialists and in part because the language of guidelines often reflects the evidence base rather than the practical "how to." The Atopic Dermatitis Yardstick is part of a series developed in response to the need to proactively address the loss of disease control for atopic illnesses at all levels of severity. It presents a comprehensive update on how to conduct a sustained step-up in therapy for the patient with inadequately controlled or poorly controlled atopic dermatitis. Patient profiles, based on current guidelines and the authors' combined clinical experience, provide a practical and clinically meaningful guide to aid physicians in helping their patients achieve the goal of clear to almost clear. The intent is not to replace guidelines but to complement their recommendations incorporating the latest research and therapies.
193 citations
References
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TL;DR: This review summarizes recent progress in the understanding of the pathophysiology of atopic dermatitis and the implications for new management strategies.
Abstract: Atopic dermatitis is a chronic inflammatory skin disease associated with cutaneous hyperreactivity to environmental triggers and is often the first step in the atopic march that results in asthma and allergic rhinitis. The clinical phenotype that characterizes atopic dermatitis is the product of interactions between susceptibility genes, the environment, defective skin barrier function, and immunologic responses. This review summarizes recent progress in our understanding of the pathophysiology of atopic dermatitis and the implications for new management strategies.
1,375 citations
TL;DR: Patients treated with dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity, and side-effect profiles were not dose-limiting.
Abstract: BACKGROUND Dupilumab, a fully human monoclonal antibody that blocks interleukin-4 and interleukin-13, has shown efficacy in patients with asthma and elevated eosinophil levels. The blockade by dupilumab of these key drivers of type 2 helper T-cell (Th2)–mediated inflammation could help in the treatment of related diseases, including atopic dermatitis. METHODS We performed randomized, double-blind, placebo-controlled trials involving adults who had moderate-to-severe atopic dermatitis despite treatment with topical glucocorticoids and calcineurin inhibitors. Dupilumab was evaluated as monotherapy in two 4-week trials and in one 12-week trial and in combination with topical glucocorticoids in another 4-week study. End points included the Eczema Area and Severity Index (EASI) score, the investigator’s global assessment score, pruritus, safety assessments, serum biomarker levels, and disease transcriptome. RESULTS In the 4-week monotherapy studies, dupilumab resulted in rapid and dose-dependent improvements in clinical indexes, biomarker levels, and the transcriptome. The results of the 12-week study of dupilumab monotherapy reproduced and extended the 4-week findings: 85% of patients in the dupilumab group, as compared with 35% of those in the placebo group, had a 50% reduction in the EASI score (EASI-50, with higher scores in the EASI indicating greater severity of eczema) (P<0.001); 40% of patients in the dupilumab group, as compared with 7% in the placebo group, had a score of 0 to 1 (indicating clearing or near-clearing of skin lesions) on the investigator’s global assessment (P<0.001); and pruritus scores decreased (indicating a reduction in itch) by 55.7% in the dupilumab group versus 15.1% in the placebo group (P<0.001). In the combination study, 100% of the patients in the dupilumab group, as compared with 50% of those who received topical glucocorticoids with placebo injection, met the criterion for EASI-50 (P = 0.002), despite the fact that patients who received dupilumab plus glucocorticoids used less than half the amount of topical glucocorticoids used by those who received placebo plus the topical medication (P = 0.16). Adverse events, such as skin infection, occurred more frequently with placebo; nasopharyngitis and headache were the most frequent adverse events with dupilumab. CONCLUSIONS Patients treated with dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity. Side-effect profiles were not doselimiting. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01259323, NCT01385657, NCT01639040, and NCT01548404.)
1,096 citations
TL;DR: Patients with AD have an acquired defect in filaggrin expression that can be modulated by the atopic inflammatory response, and neutralization of IL-4 and IL-13 could improve skin barrier integrity.
Abstract: Background Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by a defective skin barrier function. Recent studies have reported mutations of the skin barrier gene encoding filaggrin in a subset of patients with AD. Objective We investigated whether reduced filaggrin expression was found in patients with AD who were not carriers of known filaggrin mutations and whether filaggrin expression was modulated by the atopic inflammatory response. Methods Filaggrin expression was measured in skin biopsies and cultured keratinocytes using real-time RT-PCR and immunohistochemistry. Filaggrin loss-of-function mutations were screened in a total of 69 subjects. Results Compared with normal skin, filaggrin expression was significantly reduced (P Conclusion Patients with AD have an acquired defect in filaggrin expression that can be modulated by the atopic inflammatory response. Clinical implications The atopic immune response contributes to the skin barrier defect in AD; therefore, neutralization of IL-4 and IL-13 could improve skin barrier integrity.
930 citations
TL;DR: This data indicates that suppression of Th1 and Th17 cytokines in Psoriasis vulgaris is a pro-inflammatory disease and the relative contribution of interferon, IFN,γ, interleukin and IL‐22 on disease pathogenesis is still unknown.
Abstract: Psoriasis vulgaris is a common chronic inflammatory skin disease characterized by hyperproliferative epidermis and mixed cutaneous lymphocytic infiltrate. While initially regarded as a primary disease of keratinocyte differentiation, effective immune-modulating therapies demonstrate the vital role played by the immune system in psoriatic disease pathogenesis.1–4 The T cells involved in lesion formation were initially thought to be Th1 differentiated based on interferon (IFN)-γ and interleukin (IL)-2 production.5–7 However, the recent discovery of the Th17 T-helper cell subset, and its potential involvement in psoriasis, generates even more complexity to this disease.
Th17 cells have recently been classified as distinct from Th1 and Th2 subsets.8,9 They are defined by the ability to synthesize IL-17 in response to antigen-presenting cell-derived IL-23 and other differentiating cytokines.10–13 In addition, Th17 cells have been reported to cosynthesize IL-17 and IFN-γ14 as well as IL-22.15,16 Indeed, in murine systems, IL-22 production occurs overwhelmingly within the Th17 subset.15
Psoriatic skin lesions are reported to have increased gene expression of IL-23,17 IL-17 and IL-22,18–21 prompting investigators to probe deeper into the potential involvement of Th17 cells in psoriasis. While models of epidermal hyperproliferation have focused on IL-22 as being central to psoriasis pathogenesis via induction of keratinocyte proliferation and acanthosis,22–24 both IL-22 and IL-17 have been shown to induce keratinocyte gene expression of antimicrobials β-defensin 2, β-defensin 3, S100A8 and S100A9, all upregulated in psoriatic lesions.15,22,25 Besides the increased expression of antimicrobial genes, however, the contribution of IL-17 to psoriasis pathogenesis has not been thoroughly investigated. This is in contrast to IL-17 being extensively implicated in chemokine-induced neutrophil recruitment in asthma, chronic obstructive pulmonary disease and cystic fibrosis.26–28
The chemokines that are considered to be neutrophil chemoattractants belong to the ELR+ CXC subfamily, named by the presence of a Glu-Leu-Arg motif at residues 4–6.29,30 Members of this subfamily include CXCL1–8, except CXCL4.29 Indeed, IL-17 has previously been shown to induce the production of CXCL1 and CXCL8 in bronchial epithelial cells,27,28 fibroblasts31 and keratinocytes,32 and neutralizing antibodies to IL-17 or its receptor can block this induction.28,32
Even with increasing evidence for the involvement of Th17 cells in psoriasis pathogenesis, the relative effects of the Th17 cytokines IL-17 and IL-22 and the Th1 cytokine IFN-γ on the skin are unknown. In this study, we sought to identify the cytokines produced by skin-resident T cells in normal skin, localize the receptors for these cytokines, and examine how these cytokines alter gene expression profiles of the cells bearing cognate receptors.
764 citations
TL;DR: Investigation of the expression of interleukin 4, IL-5, and interferon-gamma messenger RNA in skin biopsies from acute and chronic skin lesions of patients with atopic dermatitis indicates that initiation of acute skin inflammation in AD is associated with a predominance of IL-4 expression whereas maintenance of chronic inflammation is predominantly associated with increasedIL-5 expression and eosinophil infiltration.
Abstract: The mechanisms involved in the initiation and maintenance of skin inflammation in atopic dermatitis (AD) are poorly understood. Recent data suggest that the pattern of cytokines expressed locally plays a critical role in modulating the nature of tissue inflammation. In this study, we used in situ hybridization to investigate the expression of interleukin 4 (IL-4), IL-5, and interferon-gamma (IFN-gamma) messenger RNA (mRNA) in skin biopsies from acute and chronic skin lesions of patients with AD. As compared with normal control skin or uninvolved skin of patients with AD, acute and chronic skin lesions had significantly greater numbers of cells that were positive for mRNA, IL-4 (P < 0.01), and IL-5 (P < 0.01), but not for IFN-gamma mRNA expressing cells. However, as compared with acute AD skin lesions, chronic AD skin lesions had significantly fewer IL-4 mRNA-expressing cells (P < 0.01), but significantly greater IL-5 mRNA (P < 0.01). T cells constituted the majority of IL-5-expressing cells in acute and chronic AD lesions. Chronic lesions also expressed significantly greater numbers of activated EG2+ eosinophils than acute lesions (P < 0.01). These data indicate that although acute and chronic AD lesions are associated with increased activation of IL-4 and IL-5 genes, initiation of acute skin inflammation in AD is associated with a predominance of IL-4 expression whereas maintenance of chronic inflammation is predominantly associated with increased IL-5 expression and eosinophil infiltration.
759 citations