Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis
01 Aug 2013-The Journal of Allergy and Clinical Immunology (J Allergy Clin Immunol)-Vol. 132, Iss: 2, pp 361-370
TL;DR: Although differences in TH17 and TH22 activation exist between patients with intrinsic AD and those with extrinsic AD, common disease-defining features of T-cell activation, production of polarized cytokines, and keratinocyte responses to immune products are identified.
Abstract: Background: Atopic dermatitis (AD) is classified as extrinsic and intrinsic, representing approximately 80% and 20% of patients with the disease, respectively. Although sharing a similar clinical phenotype, only extrinsic AD is characterized by high serum IgE levels. Because most patients with AD exhibit high IgE levels, an ‘‘allergic’’/IgE-mediated disease pathogenesis was hypothesized. However, current models associate AD with T-cell activation, particularly TH2/TH22 polarization, and epidermal barrier defects. Objective: We sought to define whether both variants share a common pathogenesis. Methods: We stratified 51 patients with severe AD into extrinsic AD (n 5 42) and intrinsic AD (n 5 9) groups (with similar mean disease activity/SCORAD scores) and analyzed the molecular and cellular skin pathology of lesional and nonlesional intrinsic AD and extrinsic AD by using gene expression (real-time PCR) and immunohistochemistry. Results: A significant correlation between IgE levels and SCORAD scores (r 5 0.76, P <1 0 25 ) was found only in patients with extrinsic AD. Marked infiltrates of T cells and dendritic cells and corresponding epidermal alterations (keratin 16, Mki67, and S100A7/A8/A9) defined lesional skin of patients with both variants. However, higher activation of all inflammatory axes (including TH2) was detected in patients with intrinsic AD, particularly TH17 and TH22 cytokines. Positive correlations between TH17-related molecules and SCORAD scores were only found in patients with intrinsic AD, whereas only patients with extrinsic AD showed positive correlations between SCORAD scores and TH2 cytokine (IL-4 and IL-5) levels and negative correlations with differentiation products (loricrin and periplakin). Conclusions: Although differences in TH17 and TH22 activation exist between patients with intrinsic AD and those with extrinsic AD, we identified common disease-defining features of T-cell activation, production of polarized cytokines, and keratinocyte responses to immune products. Our data indicate that a TH2 bias is not the sole cause of high IgE levels in patients with extrinsic AD, with important implications for similar therapeutic interventions. (J Allergy Clin Immunol 2013;132:361-70.)
Citations
More filters
TL;DR: The genetic background of psoriasis and its relationship to immune function, specifically genetic mutations, key PSORS loci, single nucleotide polymorphisms, and the skin transcriptome are discussed.
Abstract: The skin is the front line of defense against insult and injury and contains many epidermal and immune elements that comprise the skin-associated lymphoid tissue (SALT). The reaction of these components to injury allows an effective cutaneous response to restore homeostasis. Psoriasis vulgaris is the best-understood and most accessible human disease that is mediated by T cells and dendritic cells. Inflammatory myeloid dendritic cells release IL-23 and IL-12 to activate IL-17-producing T cells, Th1 cells, and Th22 cells to produce abundant psoriatic cytokines IL-17, IFN-γ, TNF, and IL-22. These cytokines mediate effects on keratinocytes to amplify psoriatic inflammation. Therapeutic studies with anticytokine antibodies have shown the importance of the key cytokines IL-23, TNF, and IL-17 in this process. We discuss the genetic background of psoriasis and its relationship to immune function, specifically genetic mutations, key PSORS loci, single nucleotide polymorphisms, and the skin transcriptome. The assoc...
1,174 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
Additional excerpts
...Day 29 3 (19) 30 (59)§ 11 (20) 38 (69) 5 (50) 21 (100)§...
[...]
TL;DR: Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose-dependent manner, without significant safety concerns, and shows that IL-4 and IL-13 are key drivers of atopic skinitis.
469 citations
TL;DR: Best evidence of the clinical efficacy of novel immunologic approaches using biological agents in patients with AD is available for the anti-IL-4 receptor α-chain antibody dupilumab, but a number of studies are currently ongoing with other specific antagonists to immune system players.
Abstract: Atopic dermatitis (AD) is a complex skin disease frequently associated with other diseases of the atopic diathesis. Recent evidence supports the concept that AD can also recognize other comorbidities, such as chronic inflammatory bowel or cardiovascular diseases. These comorbidities might result from chronic cutaneous inflammation or from a common, yet-to-be-defined immunologic background leading to immune deviations. The activation of immune cells and their migration to the skin play an essential role in the pathogenesis of AD. In patients with AD, an underlying immune deviation might result in higher susceptibility of the skin to environmental factors. There is a high unmet medical need to define immunologic endotypes of AD because it has significant implications on upcoming stratification of the phenotype of AD and the resulting targeted therapies in the development of precision medicine. This review article emphasizes studies on environmental factors affecting AD development and novel biological agents used in the treatment of AD. Best evidence of the clinical efficacy of novel immunologic approaches using biological agents in patients with AD is available for the anti-IL-4 receptor α-chain antibody dupilumab, but a number of studies are currently ongoing with other specific antagonists to immune system players. These targeted molecules can be expressed on or drive the cellular players infiltrating the skin (eg, T lymphocytes, dendritic cells, or eosinophils). Such approaches can have immunomodulatory and thereby beneficial clinical effects on the overall skin condition, as well as on the underlying immune deviation that might play a role in comorbidities. An effect of these immunologic treatments on pruritus and the disturbed microbiome in patients with AD has other potential consequences for treatment.
437 citations
TL;DR: The Asian AD phenotype presents (even in the presence of increased IgE levels) a blended phenotype between that of EA patients with AD and those with psoriasis, including increased hyperplasia, parakeratosis, higher TH17 activation, and a strong TH2 component.
Abstract: Background Atopic dermatitis (AD) shows very high prevalence in Asia, with a large unmet need for effective therapeutics. Direct comparisons between European American (EA) and Asian patients with AD are unavailable, but earlier blood studies detected increased IL-17 + –producing cell counts in Asian patients with AD. Objective We sought to characterize the Asian AD skin phenotype and compare it with the EA AD skin phenotype. Methods We performed genomic profiling (real-time PCR) and immunohistochemistry on lesional and nonlesional biopsy specimens from 52 patients with AD (25 EAs and 27 Asians), 10 patients with psoriasis (all EAs), and 27 healthy subjects (12 EAs and 15 Asians). Results Although disease severity/SCORAD scores were similar between the AD groups (58.0 vs 56.7, P = .77), greater acanthosis, higher Ki67 counts, and frequent parakeratosis were characteristics of lesional epidermis from Asian patients with AD ( P H 2 skewing characterized both Asian and EA patients with AD but not patients with psoriasis. Significantly higher T H 17 and T H 22 ( IL17A, IL19 , and S100A12 in lesional and IL-22 in nonlesional skin; P H 1/interferon ( CXCL9, CXCL10, MX1 , and IFNG in nonlesional skin; P Conclusion The Asian AD phenotype presents (even in the presence of increased IgE levels) a blended phenotype between that of EA patients with AD and those with psoriasis, including increased hyperplasia, parakeratosis, higher T H 17 activation, and a strong T H 2 component. The relative pathogenic contributions of the T H 17 and T H 2 axes in creating the Asian AD phenotype need to be tested in future clinical trials with appropriate targeted therapeutics.
436 citations
Cites background or result from "Intrinsic atopic dermatitis shows s..."
...TH17 blockers, which are now approved or being tested for psoriasis,(14,67,68) are candidates for future trials in patients with AD, especially for the Asian and intrinsic AD phenotypes, given the strong TH17 skewing seen in these populations.(10) Human studies with selective antagonists against the TH1, TH2, TH17, and TH22 pathways will continue to dissect disease mechanisms in different AD categories....
[...]
...We have shown distinct differences in patients with intrinsic versus extrinsic AD, as judged by skin profiling.(10) In patients with intrinsic AD, we detected significantly increased expression of IL12B (p40), IL17A, IL22, and respective keratinocyte-induced products (ie, S100As), whereas similar expression of TH2-related products...
[...]
...A strong induction of IL-13 cytokine in both Asian patients with AD and EA patients with AD, together with similar activation of TH2 cytokines in intrinsic/extrinsic and pediatric/ adult subtypes, indicates that TH2 expansion is a common feature of AD, regardless of race or phenotype.(10,41) However, other polar immune activation varies depending on individual phenotypes and racial groups....
[...]
...We have shown distinct differences in skin cytokine profiles between patients with intrinsic and those with extrinsic AD.(10) Despite high IgE levels, similar TH2 expression was detected, whereas significantly increased expression of TH17/IL-23 and TH22 pathway genes was detected in patients with intrinsic AD....
[...]
...In contrast, no increases were seen in IL-17 activation in European American (EA) patients with extrinsic AD.(10,11,23) Thus we sought to directly compare AD in EA and Asian (Japanese and Korean) AD populations, focusing mainly on extrinsic subsets and with a comparison with psoriasis vulgaris....
[...]
References
More filters
TL;DR: IL-22 is identified as a new cytokine expressed by Th17 cells that synergizes with IL- 17A or IL-17F to regulate genes associated with skin innate immunity.
Abstract: Th17 cells are a distinct lineage of effector CD4+ T cells characterized by their production of interleukin (IL)-17. We demonstrate that Th17 cells also expressed IL-22, an IL-10 family member, at substantially higher amounts than T helper (Th)1 or Th2 cells. Similar to IL-17A, IL-22 expression was initiated by transforming growth factor β signaling in the context of IL-6 and other proinflammatory cytokines. The subsequent expansion of IL-22–producing cells was dependent on IL-23. We further demonstrate that IL-22 was coexpressed in vitro and in vivo with both IL-17A and IL-17F. To study a functional relationship among these cytokines, we examined the expression of antimicrobial peptides by primary keratinocytes treated with combinations of IL-22, IL-17A, and IL-17F. IL-22 in conjunction with IL-17A or IL-17F synergistically induced the expression of β-defensin 2 and S100A9 and additively enhanced the expression of S100A7 and S100A8. Collectively, we have identified IL-22 as a new cytokine expressed by Th17 cells that synergizes with IL-17A or IL-17F to regulate genes associated with skin innate immunity.
2,225 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: IL-22 induces keratinocytes migration in an in vitro injury model and down-regulates the expression of at least seven genes associated with keratinocyte differentiation, and it is shown that IL-22 strongly induces hyperplasia of reconstituted human epidermis.
Abstract: IL-22 belongs to a family of cytokines structurally related to IL-10, including IL-19, IL-20, IL-24, and IL-26 In contrast to IL-10, IL-22 has proinflammatory activities IL-22 signals through a class II cytokine receptor composed of an IL-22-binding chain, IL-22RA1, and the IL-10RB subunit, which is shared with the IL-10R In the present study, we show that short-term cultured human epidermal keratinocytes express a functional IL-22R but no IL-10R Accordingly, IL-22 but not IL-10 induces STAT3 activation in keratinocytes Using a cDNA array screening approach, real-time RT-PCR, and Western blot analysis, we demonstrate that IL-22 up-regulates, in a dose-dependent manner, the expression of S100A7, S100A8, S100A9, a group of proinflammatory molecules belonging to the S100 family of calcium-binding proteins, as well as the matrix metalloproteinase 3, the platelet-derived growth factor A, and the CXCL5 chemokine In addition, IL-22 induces keratinocyte migration in an in vitro injury model and down-regulates the expression of at least seven genes associated with keratinocyte differentiation Finally, we show that IL-22 strongly induces hyperplasia of reconstituted human epidermis Taken together, these results suggest that IL-22 plays an important role in skin inflammatory processes and wound healing
815 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: In this article, the authors investigated intrapersonal sets of transcriptomes from non-lesional skin and acute and chronic lesions of 10 patients with AD through genomic, molecular, and cellular profiling.
Abstract: Background Atopic dermatitis (AD) is a common disease with an increasing prevalence. The primary pathogenesis of the disease is still elusive, resulting in the lack of specific treatments. AD is currently considered a biphasic disease, with T H 2 predominating in acute disease and a switch to T H 1 characterizing chronic disease. Elucidation of the molecular factors that participate in the onset of new lesions and maintenance of chronic disease is critical for the development of targeted therapeutics. Objectives We sought to characterize the mechanisms underlying the onset and maintenance of AD. Methods We investigated intrapersonal sets of transcriptomes from nonlesional skin and acute and chronic lesions of 10 patients with AD through genomic, molecular, and cellular profiling. Results Our study associated the onset of acute lesions with a striking increase in a subset of terminal differentiation proteins, specifically the cytokine-modulated S100A7, S100A8, and S100A9. Acute disease was also associated with significant increases in gene expression levels of major T H 22 and T H 2 cytokines and smaller increases in IL-17 levels. A lesser induction of T H 1-associated genes was detected in acute disease, although some were significantly upregulated in chronic disease. Further significant intensification of major T H 22 and T H 2 cytokines was observed between acute and chronic lesions. Conclusions Our data identified increased S100A7, S100A8, and S100A9 gene expression with AD initiation and concomitant activation of T H 2 and T H 22 cytokines. Our findings support a model of progressive activation of T H 2 and T H 22 immune axes from the acute to chronic phases, expanding the prevailing view of pathogenesis with important therapeutic implications.
667 citations