CD4+ T-lymphocyte-induced Epstein-Barr virus reactivation in a patient with severe hypersensitivity to Mosquito bites and Epstein-Barr virus-infected NK cell lymphocytosis

Background: Natural killer (NK) cell lymphocytosis associated with Epstein-Barr virus (EBV) infection often shows severe hypersensitivity to mosquito bites (HMB) characterized by intense local skin reactions and systemic symptoms such as high fever, lymphadenopathy, and hepatosplenomegaly. However, the induction mechanism of HMB is still unclear. Observations: We investigated a typical case of HMB with EBV-positive NK cell lymphocytosis. CD4(+) T cells dominantly infiltrated the site of the mosquito bite, while EBV-positive cells were few in comparison. CD4(+) T cells, but not CD8(+) T cells or NK cells, responded to the mosquito salivary gland extracts. Interestingly, coculturing of the NK cells and CD4(+) T cells activated by mosquito extracts induced expression of EBV lytic-cycle proteins in the NK cells. Furthermore, the expression of BZLF1, a viral lytic-cycle transactivator, was detectable at the skin lesion induced by scratch patch testing with mosquito extract. The EBV DNA copy number levels in the plasma were elevated in systemic HMB symptoms compared with the normal condition. Conclusions: CD4(+) T cells are important for the primary skin reaction to mosquito bites and might play a key role in reactivation of latent EBV infection in NK cells. This viral reactivation contributed to the pathogenesis of the infectious mononucleosis-like systemic symptoms of HMB in our present case.