Clinical and immunological considerations in Epstein-Barr virus-associated diseases.
Clinical and immunological considerations in Epstein-Barr virus-associated diseases.
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EB 病毒相关疾病的临床和免疫学考虑。
DOI：
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发表时间：
1996
期刊：
影响因子：
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通讯作者：
J. Andersson
中科院分区：
文献类型：
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作者：
J. Andersson
尽管核苷类似物，如阿昔洛韦和更昔洛韦，以及DNA聚合酶抑制剂，如磷甲酸钠，已被证明对口咽-爱泼斯坦-巴尔病毒(EBV)复制有抗病毒效果，但它们无法显示出对传染性单核细胞增多症(IM)的严重程度或持续时间的任何影响，目前尚无确定的治疗方法。临床症状可能是由于EBV诱导的多克隆体液，以及由病毒复制本身引起的有限病理的细胞免疫反应。然而，尽管有广泛的免疫反应，90%的受测IM患者(n=36)在发病时有体内EBV感染的B淋巴细胞自发生长，这表明目前缺乏特异性的EBV限制性细胞毒性。EBV特异性T淋巴细胞反应发生在发病90-180天后(人类白细胞抗原对EBV感染的B细胞的细胞毒作用)。因此，特定的细胞毒性反应的发展是一个渐进和缓慢的过程。用免疫细胞化学技术和酶联免疫吸附试验在单细胞水平上评估细胞因子模式。这表明在所有IM患者中，IL-2、干扰素(IFN)-γ、IL-6和肿瘤坏死因子(TNF)β的产生均增加。播散性疾病的特点是缺乏干扰素-γ的产生。这种丢失是选择性的，因为在体外用超抗原刺激，如链球菌热原外毒素A，可诱导正常反应。这些患者在体外缺乏EBV特异性T细胞毒性的迹象。静脉或皮下注射干扰素-γ，每隔一天1.5MU，联合静脉注射丙种球蛋白(0.5g/kg，每周3次)和口服阿昔洛韦(800 mg，每日5次)，对一些患者显示了良好的疗效。4例暴发型IM并呼吸道梗阻患者扁桃体组织中细胞因子IL-2、干扰素-γ、IL-6、肿瘤坏死因子-β、转化生长因子-β1-3、粒细胞集落刺激因子、粒-巨噬细胞集落刺激因子、IL-4、IL-1α、IL-β和TNFα同时表达。与扁桃体肥大患儿的扁桃体组织相比，IL-2、干扰素-γ、IL-6和肿瘤坏死因子-β的产生细胞数显著增加。因此，IM与广泛的局部细胞因子的产生有关。提示这种广泛的细胞因子的产生与IM的病理密切相关，非典型IM患者存在细胞因子网络的失调。然而，EBV感染的B淋巴细胞触发这种细胞因子级联反应的机制仍不清楚。这些发现表明，有必要对免疫缺陷和EBV诱导的淋巴增生性疾病患者进行评估，并可能引入新的免疫调节治疗策略。
Despite the fact that nucleoside analogues, such as aciclovir and ganciclovir, and DNA-polymerase inhibitors, such as foscarnet, have a proven antiviral effect on oropharyngeal-Epstein-Barr virus (EBV) replication, they have been unable to show any effect on the severity or duration of infectious mononucleosis (IM), a condition for which there is currently no established treatment. Clinical symptoms may be due to an EBV-induced polyclonal humoral, as well as cellular, immunoreactivity with limited pathology caused by viral replication itself. However, despite an extensive immune response, 90% of tested IM patients (n = 36) had a spontaneous outgrowth of in vivo EBV-infected B-lymphocytes at onset of disease, indicating lack of specific EBV-restricted cellular cytotoxicity at this time. Establishment of an EBV-specific T-lymphocyte response occurred 90-180 days after onset of disease (human leukocyte antigen-restricted cytotoxicity against EBV-infected B-cells). Thus, development of a specific cytotoxic response was a gradual and slow process. Assessment of cytokine pattern, at the single cell level, was performed by immunocytochemical technique and by enzyme-linked immunosorbent assay. This revealed an increased production of interleukin (IL)-2, interferon (IFN)-gamma, IL-6 and tumour necrosis factor (TNF) beta in all IM patients. Those with disseminated disease were characterized by lack of IFN-gamma production. This loss was selective since in vitro stimulation with superantigen, such as streptococcal pyrogenic exotoxin A, induced a normal response. These patients lacked signs of EBV-specific T-cell cytotoxicity in vitro. Treatment with intravenous or subcutaneous IFN-gamma, 1.5 MU every second day, in combination with intravenous immunoglobulin G (0.5 g/kg three times per week) and oral aciclovir, 800 mg 5 times daily, has shown promising results in some patients. Cytokine production in tonsil tissue in 4 patients with fulminant IM and respiratory tract obstruction showed a concomitant expression of IL-2, IFN-gamma, IL-6, TNF beta, transforming growth factor (TGF) beta 1-3, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, IL-4 IL-1alpha, IL-beta and TNF alpha. The number of IL-2, IFN-gamma, IL-6 and TNF beta producing cells was significantly higher compared to tonsil tissue obtained from children with tonsillar hypertrophy. Thus, IM is associated with extensive local cytokine production. It is suggested that this extensive cytokine production is closely involved in the pathology of IM and that patients with atypical IM have a dysregulation in the cytokine network. However, the mechanism by which EBV-infected B-lymphocytes triggers this cytokine cascade is still unknown. These findings show the need for evaluation of patients with immunodeficiency and EBV-induced lymphoproliferative disorders and perhaps the introduction of new immunoregulatory treatment strategies.