Brooks J M, Murray R J, Thomas W A, Kurilla M G, Rickinson A B
Department of Cancer Studies, University of Birmingham, UK.
J Exp Med. 1993 Sep 1;178(3):879-87. doi: 10.1084/jem.178.3.879.
An immunological basis has been postulated for the strong association between at least five subtypes of the HLA-B27 allele (B27.01, .02, .04, .05, and .06) and ankylosing spondylitis, namely that cytotoxic T lymphocyte (CTL) responses are induced against an "arthritogenic" peptide that these different subtypes can all present. This requires a degree of overlap between the peptide binding repertoires of different B27 molecules. The present work, using CTL responses to Epstein-Barr virus (EBV) as a model system in which to identify B27-restricted epitopes, provides the first direct evidence that different disease-related alleles can present the same immunodominant peptide. We first noted that EBV-specific CTL clones, whether from B27.05-, B27.02-, or B27.04-positive donors, were largely subtype-specific in their restriction, recognizing only EBV-transformed B cell lines of the relevant B27 subtype. However, when tested against targets expressing individual EBV proteins from recombinant vaccinia virus vectors, all B27.05-restricted, all B27.02-restricted, and a proportion of B27.04-restricted clones were reactive to the same viral nuclear antigen, Epstein-Barr nuclear antigen (EBNA)3C. In subsequent peptide sensitization assays, all the EBNA3C-specific clones tested and also the EBNA3C-specific component within polyclonal CTL preparations from B27.05-, B27.02-, or B27.04-positive donors recognized the same immunodominant viral peptide RRIYDLIEL (EBNA3C residues 258-266). This sequence accords well with the proposed B27.05 peptide motif and clearly must be accommodated within the different peptide binding grooves of B27.05, B27.02, and B27.04 molecules. Clonal analysis revealed a second component of the B27.04-restricted response that was not shared with other subtypes. This was directed against an EBV latent membrane protein LMP2 epitope whose sequence RRRWRRLTV satisfies some but not all requirements of the B27.05 peptide motif. We conclude that there is indeed a degree of functional overlap between different B27 subtypes in their selection and presentation of CTL epitopes.
人类白细胞抗原B27等位基因的至少五个亚型（B27.01、.02、.04、.05和.06）与强直性脊柱炎之间存在强关联，对此已提出一种免疫学基础，即细胞毒性T淋巴细胞（CTL）反应是由针对一种“致关节炎”肽诱导产生的，这些不同亚型都能呈递该肽。这需要不同B27分子的肽结合库之间有一定程度的重叠。本研究以针对爱泼斯坦-巴尔病毒（EBV）的CTL反应作为一个模型系统来鉴定B27限制性表位，首次提供了直接证据，证明不同的疾病相关等位基因可以呈递相同的免疫显性肽。我们首先注意到，EBV特异性CTL克隆，无论来自B27.05、B27.02还是B27.04阳性供体，在其限制性方面很大程度上是亚型特异性的，仅识别相关B27亚型的EBV转化B细胞系。然而，当用表达来自重组痘苗病毒载体的单个EBV蛋白的靶细胞进行检测时，所有B27.05限制性、所有B27.02限制性以及一部分B27.04限制性克隆都对相同的病毒核抗原，即爱泼斯坦-巴尔核抗原（EBNA）3C有反应。在随后的肽致敏试验中，所有检测的EBNA3C特异性克隆以及来自B27.05、B27.02或B27.04阳性供体的多克隆CTL制剂中的EBNA3C特异性成分都识别相同的免疫显性病毒肽RRIYDLIEL（EBNA3C第258 - 266位氨基酸残基）。该序列与所提出的B27.05肽基序非常吻合，并且显然必须容纳在B27.05、B27.02和B27.04分子的不同肽结合槽内。克隆分析揭示了B27.04限制性反应的第二个成分，该成分与其他亚型不共享。它针对的是EBV潜伏膜蛋白LMP2的一个表位，其序列RRRWRRLTV满足B27.05肽基序的部分但不是全部要求。我们得出结论，不同B27亚型在选择和呈递CTL表位方面确实存在一定程度的功能重叠。
