Pathogenic Mechanism of Der p 38 as a Novel Allergen Homologous to RipA and RipB Proteins in Atopic Dermatitis

Abstract

Atopic dermatitis (AD) is a chronic relapsing pruritic disease encompassing skin inflammation and barrier dysfunction. House dust mites are key allergens that augment the development of atopic dermatitis. We aimed to investigate the pathogenic mechanism of AD due to Der p 38, recently identified by us. The frequency of IgE reactivity to Der p 38 in AD subjects was 52.6% (10/19) in the skin prick test and 57.9% (11/19) in the dot blot assay. In human keratinocyte HaCaT cells, Der p 38 triggered the impairment of filaggrin expression and induced pro-inflammatory cytokines such as IL-6, IL-8 and MCP-1 through TLR4, PI3K, AKT, c−Jun N−terminal kinase (JNK) and NF-κB pathway. Supernatants from Der p 38-treated cells blocked filaggrin expression and neutrophil apoptosis. The anti-apoptotic effect of the Der p 38-released molecules on neutrophils was accomplished by inhibition of the caspase 9/3 pathway, and by increased MCL-1 expression and BCL-2/BAX expression ratio. In C57BL/6 wild type (WT) mice, Der p 38 induced a dose-dependent increase of AD-like skin lesions, with enhanced expressions of total and Der p 38-specific IgE. Der p 38 also diminished the expressions of skin barrier proteins and induced JNK activation. However, the AD-like features following cutaneous Der p 38 exposure were observed to be reduced in the TLR4 knockout (KO) group, as compared to the WT group. Skin infiltration of neutrophils, eosinophils and mast cells was increased in the WT mice, but was not portrayed in the TLR4 KO mice. These findings indicate that Der p 38 is a novel mite allergen that triggers AD by lowering skin barrier proteins and increasing inflammatory cells. Results of this study have thereby paved the way to unveil the pathogenic mechanisms of AD.

An Atopic Dermatitis-Like Mouse Model by Alternate Epicutaneous Application of Dinitrofluorobenzene and an Extract of Dermatophagoides Farinae

“…Immune modification by DNFB may be involved in this process ( 25 ). Besides, other factors also have an important influence on the stimulating ability of house dust mite antigens, such as antigen purity, dosage, and duration of action ( 13 , 14 , 26 ). In daily life, patients with AD are exposed to a complex environment of various haptens and protein antigens, and it may be necessary and meaningful to further study the mechanism of their interactions.…”

New approaches to immunotherapy in house dust mite allergy

“…novel TLR4-binding allergen, which acts as a bidirectional regulator in the transition of predominant eosinophils or/and neutrophils related to asthma severity, and it may be an alternative card in the AIT of HDM allergy. 49,50) A complex combination of current vaccine technologies and an unexpected novel approach will continuously be pursued towards contribution to the development of AIT.…”