IL-25 enhances HSV-1 replication by inhibiting filaggrin expression, and acts synergistically with Th2 cytokines to enhance HSV-1 replication.

Atopic dermatitis (AD) is characterized by epidermal barrier defects and recurrent microbial skin infections. AD patients with a history of eczema herpeticum (ADEH+) have more severe skin disease and more highly T helper type 2 (Th2)-polarized immune responses as compared with uncomplicated AD (ADEH-). However, the mechanisms linking epidermal barrier defects and viral skin infection are not well understood. Recently, it has been reported that interleukin-25 may play a role in augmenting Th2 responses. We examined protein expression of IL-25 in the skin biopsies from normal subjects (n=10), ADEH- (n=18), ADEH+ (n=7), and psoriasis (n=9). IL-25 expression was increased in the skin from ADEH-, ADEH+, and psoriasis as compared with normal skin, and was significantly greater in lesional ADEH+ skin than in lesional ADEH- skin. Importantly, we demonstrated that IL-25 enhances herpes simplex virus (HSV)-1 and vaccinia virus replication by inhibiting filaggrin expression, and IL-25 acts synergistically with IL-4 and IL-13 to enhance HSV-1 replication in vitro. In contrast, IFN-γ inhibited HSV-1 replication in vitro. In addition, we demonstrate that filaggrin is a critical protein to inhibit HSV-1 replication because filaggrin small interfering RNA knockdown enhances HSV-1 replication in vitro. Filaggrin breakdown products, however, inhibited HSV-1 replication in vitro.

Comparative proteomic profiling of patients with atopic dermatitis based on history of eczema herpeticum infection and Staphylococcus aureus colonization.

BACKGROUND: Atopic dermatitis (AD) is the most common inflammatory skin disorder in the general population worldwide, and the majority of patients are colonized with Staphylococcus aureus. Eczema herpeticum is a disseminated herpes simplex virus infection that occurs in a small subset of patients. OBJECTIVES: The goal was to conduct proteomic profiling of patients with AD based on S. aureus colonization status and history of eczema herpeticum. We hoped to identify new biomarkers for improved diagnosis and prediction of eczema herpeticum and S. aureus susceptibility and to generate new hypotheses regarding disease pathogenesis. METHODS: Skin taping was performed on nonlesional skin of nonatopic control subjects and on lesional and nonlesional skin of patients with AD. Subjects were classified according to the history of eczema herpeticum and S. aureus colonization. Proteins were analyzed by using mass spectrometry; diagnostic groups were compared for statistically significant differences in protein expression. RESULTS: Proteins related to the skin barrier (filaggrin-2, corneodesmosin, desmoglein-1, desmocollin-1, and transglutaminase-3) and generation of natural moisturizing factor (arginase-1, caspase-14, and gamma-glutamyl cyclotransferase) were expressed at significantly lower levels in lesional versus nonlesional sites of patients with AD with and without history of eczema herpeticum; epidermal fatty acid-binding protein was expressed at significantly higher levels in patients with methicillin-resistant S. aureus. CONCLUSION: This noninvasive, semiquantitative profiling method has revealed novel proteins likely involved in the pathogenesis of AD. The lower expression of skin barrier proteins and enzymes involved in the generation of the natural moisturizing factor could further exacerbate barrier defects and perpetuate water loss from the skin. The greater expression of epidermal fatty acid-binding protein, especially in patients colonized with methicillin-resistant S. aureus, might perpetuate the inflammatory response through eicosanoid signaling.

Filaggrin mutations that confer risk of atopic dermatitis confer greater risk for eczema herpeticum.

BACKGROUND: Loss-of-function null mutations R501X and 2282del4 in the skin barrier gene, filaggrin (FLG), represent the most replicated genetic risk factors for atopic dermatitis (AD). Associations have not been reported in African ancestry populations. Atopic dermatitis eczema herpeticum (ADEH) is a rare but serious complication of AD resulting from disseminated cutaneous herpes simplex virus infections. OBJECTIVE: We aimed to determine whether FLG polymorphisms contribute to ADEH susceptibility. METHODS: Two common loss-of-function mutations plus 9 FLG single nucleotide polymorphisms were genotyped in 278 European American patients with AD, of whom 112 had ADEH, and 157 nonatopic controls. Replication was performed on 339 African American subjects. RESULTS: Significant associations were observed for both the R501X and 2282del4 mutations and AD among European American subjects (P = 1.46 x 10(-5), 3.87 x 10(-5), respectively), but the frequency of the R501X mutation was 3 times higher (25% vs 9%) for ADEH than for AD without eczema herpeticum (EH) (odds ratio [OR], 3.4; 1.7-6.8; P = .0002). Associations with ADEH were stronger with the combined null mutations (OR, 10.1; 4.7-22.1; P = 1.99 x 10(-11)). Associations with the R501X mutation were replicated in the African American population; the null mutation was absent among healthy African American subjects, but present among patients with AD (3.2%; P = .035) and common among patients with ADEH (9.4%; P = .0049). However, the 2282del4 mutation was absent among African American patients with ADEH and rare (<1%) among healthy individuals. CONCLUSION: The R501X mutation in the gene encoding filaggrin, one of the strongest genetic predictors of AD, confers an even greater risk for ADEH in both European and African ancestry populations, suggesting a role for defective skin barrier in this devastating condition.

Revisit to Kaposi's varicelliform eruption: role of IL-4.

BACKGROUND: Kaposi's varicelliform eruption (KVE) is characterized by disseminated cutaneous eruptions usually caused by infection with herpes simplex virus (HSV). Kaposi's varicelliform eruption is commonly observed among patients with atopic dermatitis (AD). Why AD patients are prone to HSV infections is still an enigma. Recent findings suggest that an increased number of IL-4-secreting cells can be cloned from lesions of AD. Because IL-4 is a known Th1 cell inhibitor, theoretically, by inhibiting the Th1 cells, it could downregulate the immune response against HSV. In this study, we have evaluated the role of IL-4 on HSV replication. METHODS: Peripheral blood mononuclear cells (PBMC) from 10 HSV seronegative and five seropositive healthy individuals were stimulated with PHA, recall antigen (tetanus toxoid), and HSV antigen in combination with IL-4 and anti-IL-4. Supernatants were assessed for interferon (IFN) gamma, IL-4 by enzyme-linked immunosorbent assay (ELISA), and for anti-HSV effect. Anti-HSV effect was assessed by measuring inhibition of the cytopathic effect (CPE) of HSV on a Vero cell line. RESULTS: Both seropositive and seronegative groups showed significant inhibition of IFN-gamma secretion with addition of IL-4 (P < .001, Wilcoxon rank sum test) and this effect could be neutralized by anti-IL-4. There was a direct relationship between the IFN-gamma concentration and the HSV cytopathic effect and an inverse relationship between IL-4 concentration and HSV CPE: CONCLUSIONS: This study provides evidence that IL-4 can enhance HSV infection. Therefore, it is conceivable that patients with conditions of increased activity of IL-4, as in AD, would be prone to extensive forms of HSV infection.