Early-onset pediatric atopic dermatitis is TH2 but also TH17 polarized in skin

Esaki, Hideo; Brunner, Patrick M.; Renert‐Yuval, Yael; Czarnowicki, Tali; Huynh, Thy; Tran, Gary; Lyon, Sarah; Rodriguez, Giselle; Immaneni, Supriya; Johnson, Daniel N.; Bauer, Bruce S.; Fuentes‐Duculan, Judilyn; Zheng, Xiuzhong; Peng, Xiangyu; Estrada, Yeriel; Xu, Hui; Strong, Cristina de Guzman; Suárez‐Fariñas, Mayte; Krueger, James G.; Paller, Amy S.; Guttman‐Yassky, Emma

doi:10.1016/j.jaci.2016.07.013

Cited by 323 publications

(196 citation statements)

References 105 publications

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“…Over 90% of atopic dermatitis (AD) patients are colonized in the lesional epidermis by S. aureus, which is increased during disease flares (Kong et al, 2012; Rudikoff and Lebwohl, 1998). In adult AD, lesional skin has been associated with Th2, Th22 and Th17 immune polarization, but strong Th17 polarization is characteristic of new-onset pediatric AD (Esaki et al, 2016). Previous work revealed the expression of S. aureus Agr virulence factors that produce PSMs in the lesional skin in AD (Nakamura et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Staphylococcus aureus Virulent PSMα Peptides Induce Keratinocyte Alarmin Release to Orchestrate IL-17-Dependent Skin Inflammation

Nakagawa

Matsumoto

Katayama

et al. 2017

Cell Host & Microbe

197

166

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Summary Staphylococcus aureus commonly colonizes the epidermis, but the mechanisms by which the host senses virulent but not commensal S. aureus to trigger inflammation remain unclear. Using a murine epicutaneous infection model, we found that S. aureus expressed phenol-soluble modulin (PSM)α, a group of secreted virulence peptides, is required to trigger cutaneous inflammation. PSMα induces the release of keratinocyte IL-1α and IL-36α, and signaling via IL-1R and IL-36R was required for induction of the pro-inflammatory cytokine IL-17. The levels of released IL-1α and IL-36α, as well as IL-17 production by γδ T cells and ILC3 and neutrophil infiltration to the site of infection were greatly reduced in mice with total or keratinocyte-specific deletion of the IL-1R and IL-36R signaling adaptor Myd88. Further, Il17a−/−f−/− mice showed blunted S. aureus-induced inflammation. Thus, keratinocyte Myd88 signaling in response to S. aureus PSMα drives an IL-17-mediated skin inflammatory response to epicutaneous S. aureus infection.

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Section: Discussionmentioning

confidence: 99%

Staphylococcus aureus Virulent PSMα Peptides Induce Keratinocyte Alarmin Release to Orchestrate IL-17-Dependent Skin Inflammation

Nakagawa

Matsumoto

Katayama

et al. 2017

Cell Host & Microbe

197

166

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“…T helper 9/interleukin (IL)-9, IL-33, and innate markers were enhanced in pediatric atopic dermatitis skin. The activation of the T helper 2 and T helper 22 axis was observable in both [5 ▪▪ ]. The findings obtained in the skin of atopic dermatitis children differed in part from the results obtained from peripheral blood, where a high T helper cell 2 activation within the skin-homing T cells could be found [6,5 ▪▪ ].…”

Section: Atopic Dermatitis In Childhood and Adulthoodmentioning

confidence: 99%

“…The activation of the T helper 2 and T helper 22 axis was observable in both [5 ▪▪ ]. The findings obtained in the skin of atopic dermatitis children differed in part from the results obtained from peripheral blood, where a high T helper cell 2 activation within the skin-homing T cells could be found [6,5 ▪▪ ]. In serum, higher concentration of IL-31 and IL-33 was found in atopic dermatitis children as compared with adults with atopic dermatitis, whereas no differences could be found in thymic stromal lymphopoietin serum concentrations between both age groups [7].…”

Section: Atopic Dermatitis In Childhood and Adulthoodmentioning

confidence: 99%

Atopic dermatitis phenotypes and the need for personalized medicine

Cabanillas

Brehler²,

Novak³

2017

Current Opinion in Allergy &Amp; Clinical Immunology

117

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Purpose of reviewTo describe recent developments in therapies which target the molecular mechanisms in atopic dermatitis.Recent findingsCurrent advances in the understanding of the molecular basis of atopic dermatitis are leading to the stratification of different atopic dermatitis phenotypes. New therapies offer the option to target-specific molecules involved in the pathophysiology of atopic dermatitis. Current new therapies under investigation aim to modulate specific inflammatory pathways associated with distinctive atopic dermatitis phenotypes, which would potentially translate into the development of personalized, targeted-specific treatments of atopic dermatitis.SummaryDespite the unmet need for well tolerated, effective, and personalized treatment of atopic dermatitis, the current standard treatments of atopic dermatitis do not focus on the individual pathogenesis of the disease. The development of targeted, phenotype-specific therapies has the potential to open a new promising era of individualized treatment of atopic dermatitis.

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“…AD is characterized by aberrant and excessive Th2 cell and ILC2 activation, with robust expression of type 2 cytokines, including interleukin (IL)‐4, IL‐5, IL‐13 and IL‐31 (Table ) . While activation of a type 2 immune response is common to all patients with AD, variable activation of other cytokines (particularly IL‐22, but also IL‐17, IL‐9 and IFN‐γ) is additionally seen, contributing to the diversity of clinical AD subtypes . Analyses of transcriptomes from intra‐individual acute and chronic skin lesions, as well as non‐lesional skin from adult AD patients, indicate progressive changes in type 2 and type 22 (eg IL‐22) pathway activation from acute to chronic disease, with induction of type 1 cytokine responses (eg IFN‐γ) only in chronic lesions .…”

Section: Ad Pathophysiology: Complex Dysregulation Of Immune Pathwaysmentioning

confidence: 99%

Understanding the immune landscape in atopic dermatitis: The era of biologics and emerging therapeutic approaches

Moyle¹,

Cevikbas

Harden

et al. 2019

Experimental Dermatology

119

134

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Atopic dermatitis (AD) is a chronic, systemic, inflammatory disease that affects the skin and is characterized by persistent itch and marked redness. AD is associated with an increased risk of skin infections and a reduced quality of life. Most AD treatment options to date were not designed to selectively target disease‐causing pathways that have been established for this indication. Topical therapies have limited efficacy in moderate‐to‐severe disease, and systemic agents such as corticosteroids and immunosuppressants present with tolerability issues. Advances in the understanding of AD pathobiology have made possible a new generation of more disease‐specific AD therapies. AD is characterized by the inappropriate activation of type 2 T helper (Th2) cells and type 2 innate lymphoid (ILC2) cells, with a predominant increase in type 2 cytokines in the skin, including interleukin (IL)‐13 and IL‐4. Both cytokines are implicated in tissue inflammation and epidermal barrier dysfunction, and monoclonal antibodies targeting each of these interleukins or their receptors are in clinical development in AD. In March 2017, dupilumab, a human anti–IL‐4Rα antibody, became the first biologic to receive approval in the United States for the treatment of moderate‐to‐severe AD. The anti–IL‐13 monoclonal antibodies lebrikizumab and tralokinumab, which bind different IL‐13 epitopes with potentially different effects, are currently in advanced‐stage trials. Here, we briefly review the underlying pathobiology of AD, the scientific basis for current AD targets, and summarize current clinical studies of these agents, including new research to develop both predictive and response biomarkers to further advance AD therapy in the era of precision medicine.

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Early-onset pediatric atopic dermatitis is TH2 but also TH17 polarized in skin

Abstract: The skin phenotype of new-onset pediatric AD is substantially different from that of adult AD. Although excess T2 activation characterizes both, T9 and T17 are highly activated at disease initiation. Increases in IL-19 levels might link T2 and T17 activation.

Cited by 323 publications

References 105 publications

Staphylococcus aureus Virulent PSMα Peptides Induce Keratinocyte Alarmin Release to Orchestrate IL-17-Dependent Skin Inflammation

Staphylococcus aureus Virulent PSMα Peptides Induce Keratinocyte Alarmin Release to Orchestrate IL-17-Dependent Skin Inflammation

Atopic dermatitis phenotypes and the need for personalized medicine

Understanding the immune landscape in atopic dermatitis: The era of biologics and emerging therapeutic approaches

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