Study on the mechanism of EBV reactivation and NK cell oncogenesis in hypersensitivity to mosquito bites

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Hypersensitivity to mosquito bites (HMB) is characterized by intense local skin symptoms, which consist of not only erythema or bulla but also ulceration or scarring, and systemic symptoms such as high fever, lymphadenopathy, and hepatosplenomegaly. Recent studies demonstrated the lymphoproliferation of EB virus (EBV) DNA-positive natural killer (NK) cells, including NK cell leukemia/lymphoma, in HMB patients. We previously demonstrated that CD4^+T cells of a patient with HMB proliferated well in response to mosquito salivary gland extracts (SGE) and played a key role in the reactivation of EBV from a latent state in NK cells. We also showed that mosquito bites can induce expression of the viral oncogene LMP1 in NK cells via mosquito antigen-specific CD4^+T cells, which is involved in the oncogenesis of NK cells in vivo. Here, we established long-term cultures of NK cells from the patients with HMB. When these cultured NK cells were cocultured with autologous CD4^+T cells stimulated by mosquito SGE, the expression of LMP1 and NK cell growth were enhanced. It was proved that mRNA and protein expressions of IL-4, IL-10, and TGF-β were upregulated in the CD4^+T cells by stimulation with the mosquito SGE. Adding a neutralizing antibody to IL-2 into the coculture of NK and mosquito SGE-stimulated CD4^+T inhibited the LMP1 mRNA expression, while adding a neutralizing antibody to TGF-β enhanced the LMP1 mRNA expression and suppressed the reactivation of EBV. On the other hand, neutralizing antibodies to IL-4 and IL-10 had no effects on LMP1 expression and NK cell growth. Furthermore, we investigated a patient with skin rash induced by ampicillin, and found that ampicillin might have played a key role in reactivation of EBV infection, implying that EBV reactivation contributed to the pathogenesis of skin rash in this patient. It suggests that the reactivation of EBV is related not only to HMB but also to other allergic diseases.