Vaccinia virus inoculation in sites of allergic skin inflammation elicits a vigorous cutaneous IL-17 response

Abstract

Eczema vaccinatum (EV) is a complication of smallpox vaccination occurring in patients with atopic dermatitis. In affected individuals, vaccinia virus (VV) spreads through the skin, resulting in large primary lesions and satellite lesions, and infects internal organs. BALB/c mice inoculated with VV at sites of Th2-biased allergic skin inflammation elicited by epicutaneous ovalbumin (OVA) sensitization exhibited larger primary lesions that were erosive, more satellite lesions, and higher viral loads in skin and internal organs than mice inoculated in saline-exposed skin, unsensitized skin, or skin sites with Th1-dominant inflammation. VV inoculation in OVA-sensitized skin induced marked local expression of IL-17 transcripts and massive neutrophil infiltration compared to VV inoculation in saline-exposed skin. Treatment with anti-IL-17 decreased the size of primary lesions, numbers of satellite lesions, and viral loads. Addition of IL-17 promoted VV replication in skin explants. These results suggest that IL-17 may be a potential therapeutic target in EV.atopic dermatitis ͉ eczema vaccinatum V accinia virus (VV) belongs to the orthopoxvirus genus of the Poxviridae family, which includes variola virus, the agent that causes smallpox, and is a potent vaccine against smallpox (1). Smallpox was eradicated in 1980 and vaccination ceased in the U.S. in 1972 and in the rest of the world in 1979 (1). Recent concern that VV might be used as a bioterror weapon has led to selective vaccination of military personnel and to contingency plans for mass vaccination. A major concern is that patients with atopic dermatitis (AD), which affects 15-20% of children in industrialized countries, are susceptible to eczema vaccinatum (EV), a life-threatening complication in which VV disseminates in the skin, resulting in satellite skin lesions, and spreads to internal organs (2). Although smallpox vaccination is contraindicated in AD patients, they are at risk for EV following contact with recently immunized individuals (3).IL-4 and IL-10 promote VV spread (4, 5). In contrast, IFN-␥ (6), IgG antibody (7), CD8 ϩ cytotoxic T cells (8), NK cells (9), and the cathelicidin family of antimicrobial peptides (AMPs) (10) are thought to contribute to VV containment. It has been suggested that IL-4 driven down-regulation of AMPs in AD skin lesions predisposes to EV (10). IL-17 is expressed in acute skin lesions of patients with AD and in their peripheral blood CD4 ϩ T cells (11,12). There is controversy as to whether IL-17 promotes or attenuates VV infection (13,14).We have previously shown that epicutaneous (EC) sensitization of BALB/c mice with ovalbumin (OVA) results in skin inflammation with similarities to AD skin lesions, characterized by infiltration with CD4 ϩ cells and eosinophils and by increased expression of mRNA for Th2 cytokines and IL-17, but not 16). In this study, we show that inoculation of VV in OVA-sensitized skin results in larger primary lesions, more satellite lesions, and higher viral loads and markedly higher local expression...

An Atopic Dermatitis-Like Skin Disease with Hyper-IgE-emia Develops in Mice Carrying a Spontaneous Recessive Point Mutation in theTraf3ip2(Act1/CIKS) Gene

“…Two reports suggest that Th17 cells exacerbate dermatitis because increased numbers of Th17 cells were found in the peripheral blood and acute lesional skin of AD patients (31). Kawakami et al (32) also support this idea with their study of NK cell function in AD patients (23). In contrast, two reports suggest that low IL-17 expression or reduced responses to IL-17 in the skin cause AD-like symptoms (24,33).…”

“…Proteins (5 mg) were fractionated by 10% SDS-PAGE and transferred onto a Hybond-P polyvinylidene difluoride membrane (GE Healthcare, Buckinghamshire, U.K.). A rabbit polyclonal Ab raised against TRAF3IP2 (anti-Act1 [H-300]) was obtained commercially (Santa Cruz Biotechnology, Santa Cruz, CA) and has been characterized previously (23,24). The Ab was used at a dilution of 1:400.…”

T Helper Type 1/T Helper Type 17-Related Cytokines in Chronic Hepatitis C Patients before and after Interferon and Ribavirin Therapy

“…Hou et al [23] reported that Th17 cells promote persistent viral infection in a model of chronic virus infection and IL-17 upregulates anti-apoptotic molecules and consequently increases persistent infection by enhancing the survival of virus-infected cells and blocking target cell destruction by cytotoxic T cells. Also, Oyoshi et al [24] reported that IL-17 contributes to viral replication in a model of disseminated vaccinia infection rather than providing host defense against viral infection.…”

Susceptibility to Vaccinia Virus Infection and Spread in Mice Is Determined by Age at Infection, Allergen Sensitization and Mast Cell Status

“…Virus inoculation at sites of experimentally induced Th2-biased allergic skin inflammation resulted in more severe lesions, higher viral DNA loads in the skin and internal organs and more satellite lesions when compared to inoculation on unsensitized skin [36]. Local expression of IL-17 and ineffective T cell responses may also be involved in the susceptibility of patients with AD to EV [36,37,38]. …”

“…A number of animal models of EV have been explored by others to understand the biological and molecular basis for the potentially life-threatening VV dissemination which can be seen in some individuals after vaccination against smallpox [36,37,38]. Virus inoculation at sites of experimentally induced Th2-biased allergic skin inflammation resulted in more severe lesions, higher viral DNA loads in the skin and internal organs and more satellite lesions when compared to inoculation on unsensitized skin [36].…”