Mechanisms of allergy and clinical immunology
Defective natural killer cell activity in a mouse model of eczema herpeticum

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Background

Patients with atopic dermatitis (AD) are susceptible to several viruses, including herpes simplex virus (HSV). Some patients experience 1 or more episodes of a severe skin infection caused by HSV termed eczema herpeticum (EH). There are numerous mouse models of AD, but no established model exists for EH.

Objective

We sought to establish and characterize a mouse model of EH.

Methods

We infected AD-like skin lesions with HSV1 to induce severe skin lesions in a dermatitis-prone mouse strain of NC/Nga. Gene expression was investigated by using a microarray and quantitative PCR; antibody titers were measured by means of ELISA; and natural killer (NK) cell, cytotoxic T-cell, regulatory T-cell, and follicular helper T-cell populations were evaluated by using flow cytometry. The role of NK cells in HSV1-induced development of severe skin lesions was examined by means of depletion and adoptive transfer.

Results

Inoculation of HSV1 induced severe erosive skin lesions in eczematous mice, which had an impaired skin barrier, but milder lesions in small numbers of normal mice. Eczematous mice exhibited lower NK cell activity but similar cytotoxic T-cell activity and humoral immune responses compared with normal mice. The role of NK cells in controlling HSV1-induced skin lesions was demonstrated by experiments depleting or transferring NK cells.

Conclusion

A murine model of EH with an impaired skin barrier was established in this study. We demonstrated a critical role of defective NK activities in the development of HSV1-induced severe skin lesions in eczematous mice.

Section snippets

HSV1 strains

The KOS strain of HSV116 and the green fluorescent protein–expressing KOS strain17 were provided by Dr Carl Ware, Sanford-Burnham Medical Research Institute. The McKrae strain (HSV1-McKrae)18, 19 was provided by Dr Homayon Ghiasi, Cedars-Sinai Medical Center, and Dr Feng Yao, Brigham and Women's Hospital.

Mouse model of EH

NC/Nga mice20 were used in all animal experiments. AD-like skin lesions were induced, as described previously.13 Briefly, mice were shaved on the back, and dermatitis was induced by 2 rounds of

Clinical features of a murine EH model

We sought to develop a model of EH in dermatitis-prone NC/Nga mice.20 First, eczema was induced by means of epicutaneous applications of D farinae extract and SEB. Seven days after the last D farinae/SEB administration, eczematous and normal (sham-treated) mice were infected with the McKrae strain of HSV1 (HSV1-McKrae)18, 19 on 4 sites of shaved back skin through a combination of scarification and pricking. Skin lesions with bleeding and exudates started to develop on day 2 after infection at

Discussion

Impaired skin barrier function is an underlying factor for AD, as well as increased susceptibility to HSV1 infection. In this study we showed that reduced NK cell activity (not number) plays a critical role in the HSV1-induced development of severe skin lesions in eczematous mice. The role of NK cells in defense against HSV1-induced skin lesions in our EH model is similar to that found in our eczema vaccinatum model.14 NK cell depletion and reconstitution were performed similarly in both eczema

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    This study was conducted as part of the Atopic Dermatitis Research Network funded by the National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIH; HHSN272201000020C). T.K. is also supported by NIH grants 5R01AR064418, 5R01HL124283, and 1R21AI115534.

    Disclosure of potential conflict of interest: K. Matsumoto is employed by National Research Institute for Child Health and Development, has received payment for lectures from Merck Sharp and Dohme (MSD), Ono Pharmaceutical, GlaxoSmithKline, Kyorin Pharmaceutical, Ohtsuka Pharmaceutical, Mitsubishi Tanabe Pharma, AstraZeneca, Siemens Healthcare, Maruho, and Teijin Pharma. T. Kawakami has received grants from the National Institute of Allergy and Infectious Diseases (HHSN272201000020C and 1R21AI115534); the National Heart, Lung, and Blood Institute (5R01HL124283); the National Institute of Arthritis and Musculoskeletal and Skin Diseases (5R01AR064418)l and the Nipponham Foundation for the Future of Food. The rest of the authors declare that they have no relevant conflicts of interest.

    Dr Lee is currently affiliated with the Department of Dermatology, Gil Medical Center, Gachon University, Incheon City, Republic of Korea.

    Dr Choi is currently affiliated with the Department of Medicine, College of Medicine, Seoul National University, Seoul, Republic of Korea.

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