Nayersina R, Fowler P, Guilhot S, Missale G, Cerny A, Schlicht H J, Vitiello A, Chesnut R, Person J L, Redeker A G, Chisari F V
Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA 92037.
J Immunol. 1993 May 15;150(10):4659-71.
Inasmuch as the hepatitis B virus (HBV) is not directly cytopathic for the infected hepatocyte, it is generally presumed that viral clearance and liver cell injury during viral hepatitis are due to a CTL response to HBV encoded Ag presented by HLA class I molecules. We have previously examined the peripheral blood CTL response to two HBV nucleocapsid epitopes in patients with acute and chronic viral hepatitis, one of which is restricted by HLA-A2, whereas the other is dually restricted by HLA-A31 and Aw68. In this study, we defined the HLA-A2-restricted CTL response to the hepatitis B surface Ag (HBsAg) by using a panel of HBsAg-derived synthetic peptides containing the ideal HLA-A2.1 binding motif (-L------V). Several novel aspects of HBV immunobiology and pathogenesis are evident from this study. First, the peripheral blood CTL response to HBV-encoded Ag is remarkably polyclonal and multispecific in most patients with acute hepatitis. Indeed, HLA-A2-restricted CTL specific for as many as four envelope epitopes and one nucleocapsid epitope were found to be present simultaneously in individual patients with acute viral hepatitis. Second, HBV-specific CTL are not detectable in the peripheral blood in a minority of patients with acute hepatitis, nor have we detected a CTL response in any of the patients with chronic hepatitis that we have studied thus far. Although the cellular and molecular basis for CTL nonresponse remains to be determined, the data suggest that it may contribute to viral persistence. Third, the diversity and the specificity of the CTL response is determined in part by the coding sequence of the viral genome present in each infected patient. Indeed, the apparent nonresponse of some acutely infected patients to at least one HBsAg-specific CTL epitope actually reflects infection by a viral variant that contains a critical substitution in one of the anchor residues within the epitope. Finally, at a fundamental level, the data suggest that the presence of the HLA-A2.1-binding motif in a peptide may not be sufficient for binding; and the capacity of a peptide to bind the class I molecule does not guarantee that it will be immunogenic.
由于乙型肝炎病毒（HBV）对被感染的肝细胞并无直接的细胞病变作用，因此一般认为，病毒性肝炎期间的病毒清除及肝细胞损伤是由于细胞毒性T淋巴细胞（CTL）对由HLA I类分子呈递的HBV编码抗原的应答所致。我们之前检测了急性和慢性病毒性肝炎患者外周血CTL对两个HBV核衣壳表位的应答，其中一个受HLA - A2限制，另一个则同时受HLA - A31和Aw68限制。在本研究中，我们通过使用一组含有理想HLA - A2.1结合基序（-L------V）的源自乙肝表面抗原（HBsAg）的合成肽，确定了HLA - A2限制的CTL对乙肝表面抗原（HBsAg）的应答。从本研究中可以明显看出HBV免疫生物学和发病机制的几个新方面。首先，在大多数急性肝炎患者中，外周血CTL对HBV编码抗原的应答具有显著的多克隆性和多特异性。事实上，在急性病毒性肝炎个体患者中，发现同时存在多达四种包膜表位特异性和一种核衣壳表位特异性的HLA - A2限制的CTL。其次，少数急性肝炎患者外周血中未检测到HBV特异性CTL，并且在我们目前研究的所有慢性肝炎患者中均未检测到CTL应答。尽管CTL无应答的细胞和分子基础仍有待确定，但数据表明这可能与病毒持续存在有关。第三，CTL应答的多样性和特异性部分由每个受感染患者体内病毒基因组的编码序列决定。事实上，一些急性感染患者对至少一种HBsAg特异性CTL表位明显无应答，实际上反映了感染了一种病毒变异体，该变异体在表位内的一个锚定残基中发生了关键替换。最后，从根本层面来看，数据表明肽中HLA - A2.1结合基序的存在可能不足以实现结合；并且肽与I类分子结合的能力并不能保证它具有免疫原性。
