A STUDY ON PATHOGENESIS AND PROGNOSIS OF EPSTEIN-BARR VIRUS-ASSOCIATED CUTANEOUS LYMPHOPROLIFERATIVE DISORDERS

潜伏性EBV感染与多种恶性疾病有关，包括非洲伯基特淋巴瘤、鼻咽癌、移植后淋巴增生性疾病、自然杀伤（NK）/T细胞淋巴瘤、慢性活动性EBV感染、胃癌、脓胸相关淋巴瘤和平滑肌肿瘤。最近，在亚洲、墨西哥和秘鲁，发现有特殊的HV样皮疹的患者进展为EBV相关的恶性淋巴瘤。我们的研究已经阐明，典型和重度HV都包括在由EBV感染的T细胞介导的皮肤疾病谱中，并且重度HV组可能具有明显的EBV相关NK/T细胞淋巴增殖性疾病，包括对蚊虫叮咬的超敏反应、慢性活动性EB病毒感染、噬血细胞性淋巴组织细胞增多症和NK/T细胞淋巴瘤，其经常具有致命的结果。发展和进展为严重的HV样病变可能会发生地方性的影响， 关于我们 从同一患者体内建立了EB病毒感染的不同T细胞系或NK细胞系，并在种痘样水疱和蚊虫叮咬的皮损中发现了不同类型的细胞浸润。这些观察结果表明，患者的血液中含有EB病毒感染的T、NK和B细胞，这可以解释与潜伏性EB病毒感染相关的多种临床症状。在皮损中可发现细胞毒性T细胞的参与和EBV再活化的线索。某些触发因素，如蚊虫叮咬和紫外线照射，可能会诱发EBV的重新激活，这反过来又可能引起继发性全身症状。我们已经证明突变型EBNA 1可以作为显性负效应物，有效地阻止细胞中EBV依赖性恶性表型，而不管病毒潜伏期或组织来源。为了诊断目的，我们建立了一种测定EBV DNA载量的实时PCR方法，以及一种新的、非侵入性的检测皮肤结痂中潜伏性EBV感染的方法（专利：2005-961917，冈山大学）。我们相信这些技术进步有助于早期诊断和监测疾病进展。少

Latent EBV infection has been implicated in a variety of malignant conditions, including African Burkitt's lymphoma, nasopharyngeal carcinoma, post-transplantation lymphoproliferative disorders, natural killer (NK)/T-cell lymphomas, chronic active EBV infection, gastric cancer, pyothorax-associated lymphoma, and smooth-muscle tumors. Recently, patients in Asia, Mexico, and Peru with peculiar HV-like eruptions were found to progress to EBV-associated malignant lymphoma. Our study has clarified that both typical and severe HV are included within the spectrum of cutaneous disorders mediated by EBV-infected T cells, and the severe HV group may have overt EBV-associated NK/T cell lymphoproliferative disorders including hypersensitivity to mosquito bites, chronic active EB virus infection, hemophagocytic lymphohistiocytosis and NK/T cell lymphomas with a frequently fatal outcome. The development of and the progression to the severe HV-like lesions might occur endemically due to the influence … More s of the patient's genetic background, EBV subtypes, immunological tolerance to EBV infection, or environmental factors.Different T or NK cell lines infected with EB virus were established from the same patient, and different cell types were infiltrated in cutaneous lesions of hydroa vacciniforme and mosquito bites. These observations have demonstrated that the patients'blood contains a pool of EB virus-infected T, NK and B cells, which may explain a diversity of clinical symptoms related to latent EB virus infection. In the cutaneous lesions, we could find the involvement of cytotoxic T-cells and the clues of reactivation of EBV. A certain trigger such as mosquito bites and ultraviolet exposure may induce reactivation of EBV, which may in turn evoke secondary systemic symptoms.In collaboration with Prof.S.Imai (Kochi Univ.), we have demonstrated that mutant EBNA1 can act as a dominant-negative effector that efficiently impedes the EBV-dependent malignant phenotypes in cells regardless of viral latency or tissue origin. This mutant will afford an additional therapeutic strategy specifically targeting EBV-associated malignancies.For diagnostic purpose, we have established a real-time PCR method to determine the EBV DNA load, and a novel, noninvasive method to detect latent EBV infection in the skin crusts (PATENT : 2005-961917, Okayama Univ.). We believe that these technical advances contribute to the early diagnosis and the monitoring of the disease progression. Less