Juhan Yoon

Cellular and molecular mechanisms in atopic dermatitis.

Atopic dermatitis (AD) is a pruritic inflammatory skin disease associated with a personal or family history of allergy. The prevalence of AD is on the rise and estimated at approximately 17% in the USA. The fundamental lesion in AD is a defective skin barrier that results in dry itchy skin, and is aggravated by mechanical injury inflicted by scratching. This allows entry of antigens via the skin and creates a milieu that shapes the immune response to these antigens. This review discusses recent advances in our understanding of the abnormal skin barrier in AD, namely abnormalities in epidermal structural proteins, such as filaggrin, mutated in approximately 15% of patients with AD, epidermal lipids, and epidermal proteases and protease inhibitors. The review also dissects, based on information from mouse models of AD, the contributions of the innate and adaptive immune system to the pathogenesis of AD, including the effect of mechanical skin injury on the polarization of skin dendritic cells, mediated by keratinocyte-derived cytokines such as thymic stromal lymphopoietin (TSLP), IL-6, and IL-1, that results in a Th2-dominated immune response with a Th17 component in acute AD skin lesions and the progressive conversion to a Th1-dominated response in chronic AD skin lesions. Finally, we discuss the mechanisms of susceptibility of AD skin lesions to microbial infections and the role of microbial products in exacerbating skin inflammation in AD. Based on this information, we discuss current and future therapy of this common disease.

Exaggerated IL-17 response to epicutaneous sensitization mediates airway inflammation in the absence of IL-4 and IL-13

BACKGROUND Atopic dermatitis (AD) is characterized by local and systemic T(H)2 responses to cutaneously introduced allergens and is a risk factor for asthma. Blockade of T(H)2 cytokines has been suggested as therapy for AD. OBJECTIVES We sought to examine the effect of the absence of IL-4 and IL-13 on the T(H)17 response to epicutaneous sensitization in a murine model of allergic skin inflammation with features of AD. METHODS Wild-type, IL4 knockout (KO), IL13 KO and IL4/13 double KO (DKO) mice were subjected to epicutaneous sensitization with ovalbumin (OVA) or saline and airway challenged with OVA. Systemic immune responses to OVA, skin and airway inflammation, and airway hyperresponsiveness were examined. RESULTS OVA-sensitized DKO mice exhibited impaired T(H)2-driven responses with undetectable OVA-specific IgE levels and severely diminished eosinophil infiltration at sensitized skin sites but intact dermal infiltration with CD4(+) cells. DKO mice mounted exaggerated IL-17A but normal IFN-gamma and IL-5 systemic responses. Airway challenge of these mice with OVA caused marked upregulation of IL-17 mRNA expression in the lungs, increased neutrophilia in bronchoalveolar lavage fluid, airway inflammation characterized by mononuclear cell infiltration with no detectable eosinophils, and bronchial hyperresponsiveness to methacholine that were reversed by IL-17 blockade. IL-4, but not IL-13, was identified as the major T(H)2 cytokine that downregulates the IL-17 response in epicutaneously sensitized mice. CONCLUSION Epicutaneous sensitization in the absence of IL-4/IL-13 induces an exaggerated T(H)17 response systemically and in lungs after antigen challenge that results in airway inflammation and airway hyperresponsiveness.

Leukotriene B4-Driven Neutrophil Recruitment to the Skin Is Essential for Allergic Skin Inflammation

Scratching triggers skin flares in atopic dermatitis. We demonstrate that scratching of human skin and tape stripping of mouse skin cause neutrophil influx. In mice, this influx was largely dependent on the generation of leukotriene B4 (LTB4) by neutrophils and their expression of the LTB4 receptor BLT1. Allergic skin inflammation in response to epicutaneous (EC) application of ovalbumin to tape-stripped skin was severely impaired in Ltb4r1(-/-) mice and required expression of BLT1 on both T cells and non-T cells. Cotransfer of wild-type (WT) neutrophils, but not neutrophils deficient in BLT1 or the LTB4-synthesizing enzyme LTA4H, restored the ability of WT CD4(+) effector T cells to transfer allergic skin inflammation to Ltb4r1(-/-) recipients. Pharmacologic blockade of LTB4 synthesis inhibited allergic skin inflammation elicited by cutaneous antigen challenge in previously EC-sensitized mice. Our results demonstrate that a neutrophil-T cell axis reliant on LTB4-BLT1 interaction is required for allergic skin inflammation.

IL-23 induced in keratinocytes by endogenous TLR4 ligands polarizes dendritic cells to drive IL-22 responses to skin immunization

Geha and collaborators show that IL-23 released by keratinocytes in response to TLR4 ligands stimulates skin DCs to produce IL-23, driving CD4 T cell IL-22 secretion, which causes epidermal thickening.

Defective lymphoid organogenesis underlies the immune deficiency caused by a heterozygous S32I mutation in IκBα

Mooster et al. created a knock-in mouse harboring a mutation (S32I) in IκBα that has been identified in a patient with ectodermal dysplasia with immunodeficiency. The mice are characterized by defective architectural cell function; they lack lymph nodes, Peyer’s patches, splenic marginal zones, and follicular DCs and fail to develop germinal centers. These features have not been previously recognized in patients.

IL-22 promotes allergic airway inflammation in epicutaneously sensitized mice

Background: Serum IL‐22 levels are increased in patients with atopic dermatitis, which commonly precedes asthma in the atopic march. Epicutaneous sensitization in mice results in TH2‐dominated skin inflammation that mimics atopic dermatitis and sensitizes the airways for antigen challenge–induced allergic inflammation characterized by the presence of both eosinophils and neutrophils. Epicutaneous sensitization results in increased serum levels of IL‐22. Objective: We sought to determine the role of IL‐22 in antigen‐driven airway allergic inflammation after inhalation challenge in epicutaneously sensitized mice. Methods: Wild‐type (WT) and Il22−/− mice were sensitized epicutaneously or immunized intraperitoneally with ovalbumin (OVA) and challenged intranasally with antigen. OVA T‐cell receptor–specific T cells were TH22 polarized in vitro. Airway inflammation, mRNA levels in the lungs, and airway hyperresponsiveness (AHR) were examined. Results: Epicutaneous sensitization preferentially elicited an IL‐22 response compared with intraperitoneal immunization. Intranasal challenge of mice epicutaneously sensitized with OVA elicited in the lungs Il22 mRNA expression, IL‐22 production, and accumulation of CD3+CD4+IL‐22+ T cells that coexpressed IL‐17A and TNF‐&agr;. Epicutaneously sensitized Il22−/− mice exhibited diminished eosinophil and neutrophil airway infiltration and decreased AHR after intranasal OVA challenge. Production of IL‐13, IL‐17A, and TNF‐&agr; was normal, but IFN‐&ggr; production was increased in lung cells from airway‐challenged and epicutaneously sensitized Il22−/− mice. Intranasal instillation of IFN‐&ggr;–neutralizing antibody partially reversed the defect in eosinophil recruitment. WT recipients of TH22‐polarized WT, but not IL‐22–deficient, T‐cell receptor OVA‐specific T cells, which secrete both IL‐17A and TNF‐&agr;, had neutrophil‐dominated airway inflammation and AHR on intranasal OVA challenge. Intranasal instillation of IL‐22 with TNF‐&agr;, but not IL‐17A, elicited neutrophil‐dominated airway inflammation and AHR in WT mice, suggesting that loss of IL‐22 synergy with TNF‐&agr; contributed to defective recruitment of neutrophils into the airways of Il22−/− mice. TNF‐&agr;, but not IL‐22, blockade at the time of antigen inhalation challenge inhibited airway inflammation in epicutaneously sensitized mice. Conclusion: Epicutaneous sensitization promotes generation of antigen‐specific IL‐22–producing T cells that promote airway inflammation and AHR after antigen challenge, suggesting that IL‐22 plays an important role in the atopic march. Graphical abstract Figure. No caption available.