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

潜在的EBV感染与多种恶性疾病有关，包括非洲Burkitt淋巴瘤、鼻咽癌、移植后淋巴组织增生性疾病、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，亚洲、墨西哥和秘鲁的特殊HV样疹患者被发现进展为EBV相关的恶性淋巴瘤。我们的研究表明，典型的和严重的HV都包括在EBV感染的T细胞介导的皮肤疾病的谱系中，并且重度HV组可能有明显的EBV相关的NK/T细胞淋巴增生性疾病，包括对蚊子叮咬的超敏反应、慢性活动性EB病毒感染、噬血细胞淋巴组织细胞增生症和NK/T细胞淋巴瘤，这些疾病往往是致命的。由于…的影响，严重的HV样病变的发生和进展可能是地方性的更多的是了解患者的遗传背景、EB病毒亚型、对EB病毒感染的免疫耐受性或环境因素。同一患者建立了不同的EB病毒感染T或NK细胞系，并在痘苗水痘和蚊子叮咬的皮损中渗透了不同的细胞类型。这些观察表明，患者的血液中含有EB病毒感染的T、NK和B细胞池，这可能解释了与EB病毒潜伏感染相关的各种临床症状。在皮损中，我们可以发现细胞毒性T细胞的参与和EBV重新激活的迹象。蚊子叮咬和紫外线照射等特定的触发因素可能会引起EBV的重新激活，进而可能引发继发性全身症状。我们与高知大学的S.Imai教授合作，证明了突变的EBNA1可以作为显性-负性效应因子，有效地阻止细胞中依赖EBV的恶性表型，而无论病毒潜伏期或组织来源如何。为了诊断的目的，我们建立了一种实时聚合酶链式反应检测EB病毒DNA载量的方法，并建立了一种新的非侵入性方法来检测皮肤结痂中的潜在EB病毒感染(专利：冈山大学，2005年-961917号)。我们认为，这些技术进步有助于早期诊断和监测疾病进展。较少

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