Study on the induction mechanism of hydroa vacciniforme and hypersensitivity to mosquito bites in the Epstein-Barr virus-associated lymphoma

最近的研究表明，与Epstein-Ban病毒（EBV）感染相关的NK细胞淋巴细胞增多症通常表现为对蚊子叮咬（HMB）的严重超敏反应，其特征为强烈的局部皮肤反应和全身症状，如高热、淋巴结病和肝脾肿大。然而，HMB的诱导机制仍不清楚。我们研究了6例HMB，以阐明HMB与EB病毒阳性NK细胞淋巴细胞增多之间关系的机制。增殖实验显示，白纹伊蚊唾液腺提取物对CD 4 + T细胞有明显的刺激作用，而对CD 8 + T细胞和NK细胞无明显刺激作用。我们发现，患者的NK细胞和蚊子提取物激活的CD 4 + T细胞共培养可以诱导NK细胞中EBV裂解周期蛋白的表达。不同蚊种唾液腺提取物的皮肤点刺试验表明，白纹伊蚊的提取物引起的皮肤反应最强烈。此外，RT-PCR分析表明，BZLF 1，一种病毒裂解周期反式激活因子，在蚊子叮咬引起的皮肤病变的表达是可检测的。与正常情况相比，在全身HMB症状中血浆中的EBV DNA拷贝数水平升高。这些结果表明，CD 4 + T细胞是蚊子叮咬的主要皮肤反应的重要，并可能在潜伏的EBV感染NK细胞的再激活中发挥关键作用。这种病毒再活化导致患者中HMB的感染性单核细胞增多症样全身症状的发病机制。

Recent studies suggest that NK cell lymphocytosis associated with Epstein-Ban virus (EBV) infection often shows severe hypersensitivity to mosquito bites (HMB) characterized by intense local skin reactions and systemic symptoms such high fever, lymphadenopathy, and hepatosplenomegaly. However, the induction mechanism of HMB is still unclear. We investigated 6 cases of HMB to elucidate the mechanism explaining the relation between HMB and EBV-positive NK cell lymphocytosis. Proliferation assay showed that CD4+ T cells, but not CD8+ T cells or NK cells, responded to the mosquito extracts, especially to salivary gland extracts of Aedes albopictus. We showed that coculturing of the patients' NK cells and CD4+ T cells activated by mosquito extracts could induce expression of EBV lytic-cycle proteins in the NK cells. Prick test with the salivary gland extracts from various species of mosquito showed that the extracts from Aedes albopictus induced the most intensive skin reaction. Furthermore, RT-PCR analysis demonstrated that expression of BZLF1 , a viral lytic-cycle transactivator, was detectable at the skin lesions induced by mosquito bites. EBV DNA copy number levels in the plasma were elevated in systemic HMB symptoms compared to normal condition. These results suggest that CD4+ T cells are important for the primary skin reaction to mosquito bite 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 the patients.