白细胞表面HLA-I分子,参与肽向CD8+T细胞的抗原呈递,由非共价连接至β2-微球蛋白(β2m)(Face-1)的重链(HC)组成。HC氨基酸组成在HLA-I的所有六种同工型中有所不同,而β2m保持不变。每个HLA等位基因在HCα1和α2螺旋上的一个或多个氨基酸序列不同,而三个螺旋中的几个序列是保守的。在恶性肿瘤激活的人细胞上也观察到无β2m的HC(Face-2),病毒转化,和细胞因子或趋化因子介导的炎症。在没有β2m的情况下,如通过HLA-I单克隆抗体(LA45、L31、TFL-006和TFL-007)所证实的,单体Face-2暴露这些细胞上的免疫原性隐蔽序列。此外,这样的暴露使两个Face-2分子之间通过SH键进行二聚化,盐键,H-bonding,和范德华部队.在HLA-B27中,记录了在氨基酸残基的67位具有半胱氨酸的两条重链之间的连接。同样,HLA-A的几个等位基因,B,C,E,F和G在67、101和164表达半胱氨酸,此外,HLA-G在位置42表达半胱氨酸。因此,单体HC(Face-2)可以与它自己的等位基因的另一个HC二聚化,作为同源二聚体(Face-3),或者使用不同的HC等位基因,作为异二聚体(Face-4)。Face-4的存在在HLA-F中有很好的记录。缺乏β2m的翻译后HLA变体可以暴露几个隐秘的线性和非线性构象改变的序列以产生新的表位。这次审查的目的,在明确确认HLA-I的翻译后变体的同时,是为了强调HLA的四个面孔的科学和临床重要性,并促使进一步的研究阐明它们的功能以及它们在炎症期间与非HLA分子的相互作用,感染,恶性肿瘤和移植。的确,这些HLA面孔可能构成被动和主动特异性免疫治疗和疫苗的新靶点.
Leukocyte cell-surface HLA-I molecules, involved in antigen presentation of peptides to CD8+ T-cells, consist of a heavy chain (HC) non-covalently linked to β2-microglobulin (β2m) (Face-1). The HC amino acid composition varies across all six isoforms of HLA-I, while that of β2m remains the same. Each HLA-allele differs in one or more amino acid sequences on the HC α1 and α2 helices, while several sequences among the three helices are conserved. HCs without β2m (Face-2) are also observed on human cells activated by malignancy, viral transformation, and cytokine or chemokine-mediated inflammation. In the absence of β2m, the monomeric Face-2 exposes immunogenic cryptic sequences on these cells as confirmed by HLA-I monoclonal antibodies (LA45, L31, TFL-006, and TFL-007). Furthermore, such exposure enables dimerization between two Face-2 molecules by SH-linkage, salt linkage, H-bonding, and van der Waal forces. In HLA-B27, the linkage between two heavy chains with cysteines at position of 67 of the amino acid residues was documented. Similarly, several alleles of HLA-A, B, C, E, F and G express cysteine at 67, 101, and 164, and additionally, HLA-G expresses cysteine at position 42. Thus, the monomeric HC (Face-2) can dimerize with another HC of its own allele, as homodimers (Face-3), or with a different HC-allele, as heterodimers (Face-4). The presence of Face-4 is well documented in HLA-F. The post-translational HLA-variants devoid of β2m may expose several cryptic linear and non-linear conformationally altered sequences to generate novel epitopes. The objective of this review, while unequivocally confirming the post-translational variants of HLA-I, is to highlight the scientific and clinical importance of the four faces of HLA and to prompt further research to elucidate their functions and their interaction with non-HLA molecules during inflammation, infection, malignancy and transplantation. Indeed, these HLA faces may constitute novel targets for passive and active specific immunotherapy and vaccines.