Early kinetics of innate and adaptive immune responses during hepatitis B virus infection
Early kinetics of innate and adaptive immune responses during hepatitis B virus infection
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DOI：
10.1136/gut.2008.163600
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发表时间：
2009-07-01
期刊：
影响因子：
24.5
通讯作者：
Ferrari, C.
中科院分区：
文献类型：
--
作者：
Fisicaro, P.;Valdatta, C.;Ferrari, C.
背景与目的：基因芯片分析表明，在急性感染乙肝病毒的黑猩猩体内，先天免疫似乎是沉默的。这一观察结果是否也适用于人类的乙肝发病机制仍未确定。因此，本研究的目的是研究人类感染乙肝病毒后早期的自然杀伤(NK)和CD56(+)自然T(NT)细胞反应及其与适应性免疫诱导的关系。方法：对两名血清阴性的献血者进行追踪，这些献血者成为乙肝表面抗原(HBs Ag)和HBVDNA阳性，但丙氨酸氨基转移酶(ALT)持续正常。分析NK细胞和NT细胞的表型(CD69和NKG2D)和功能(细胞毒作用和干扰素-γ产生)。通过体外细胞内细胞因子染色(ICS)检测干扰素-γ、白介素2(IL-2)、IL-4和IL-10，并通过体外ELISPOT检测干扰素-γ，平行地研究了覆盖整个乙肝病毒序列的重叠多肽对CD4和CD8介导的应答。以健康受试者、慢性和急性乙肝感染患者为对照。结果：观察到先天和获得性反应的早期诱导。NK细胞和NT细胞的活性峰值早于乙肝病毒特异性T细胞，而CD4(+)和CD8(+)细胞的活性曲线相似，在高峰时产生干扰素-γ的CD8(+)细胞的频率较高。结论：天然免疫系统能够感知乙肝病毒感染，表现为NK和NT细胞反应的早期发展，这可能有助于遏制乙肝病毒感染，并及时诱导适应性反应。
Background and Aim: Innate immunity appears to be silent in acutely heptitis B virus (HBV)-infected chimpanzees, as shown by microarray analysis of intrahepatic gene expression. Whether this observation also applies to HBV pathogenesis in man remains undefined. The aim of this study was thus to characterise natural killer (NK) and CD56(+) natural T (NT) cell responses early after human HBV infection and their relationship to the induction of adaptive immunity.Methods: Two HBV-seronegative blood donors who became hepatitis B surface antigen (HBsAg) and HBV DNA positive but had persistently normal alanine aminotransferase (ALT) were followed from a very early stage of HBV infection. The phenotype (CD69 and NKG2D) and function (cytotoxicity and interferon gamma (IFN gamma) production) of NK and NT cells were analysed. CD4- and CD8- mediated responses were studied in parallel with overlapping peptides covering the entire HBV sequence by ex vivo intracellular cytokine staining (ICS) for IFN gamma, interleukin 2 (IL2), IL4 and IL10, and by ex vivo Elispot for IFN gamma. Healthy subjects, and patients with chronic and acute HBV infection were studied for comparison.Results: An early induction of both innate and adaptive responses was observed. NK and NT cells showed faster kinetics than HBV-specific T cells with an earlier peak of activity, while CD4(+) and CD8(+) cell responses were mounted with a similar profile, with higher frequencies of IFN gamma-producing CD8(+) cells at the peak of the response.Conclusions: The innate immune system is able to sense HBV infection, as shown by the early development of NK and NT cell responses, which probably contribute to contain the HBV infection and to allow timely induction of adaptive responses.