HLA-DR1 (DRB1*0101) and DR4 (DRB1*0401) use the same anchor residues for binding an immunodominant peptide derived from human type II collagen
HLA-DR1 (DRB1*0101) and DR4 (DRB1*0401) use the same anchor residues for binding an immunodominant peptide derived from human type II collagen
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DOI：
10.4049/jimmunol.168.1.253
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发表时间：
2002-01-01
影响因子：
4.4
通讯作者：
Kang, AH
中科院分区：
文献类型：
--
作者：
Rosloniec, EF;Whittington, KB;Kang, AH
风湿性关节炎是一种自身免疫性疾病，其易感性与特定HLA-DR单倍型的表达密切相关，包括DR 1（DRB 1 *0101）和DR 4（DRB 1 *0401）。作为转基因，这两种II类分子都介导对由人II型胶原（hCII）免疫诱导的自身免疫性关节炎的易感性。DR 1和DR 4转基因小鼠对hCII的显性T细胞应答集中在相同的决定簇核心CII（263-270）。肽结合研究显示，DR 1和DR 4对CII（263-270）的亲和力至少比模型Ag HA（307-319）低10倍，DR 4对CII肽的亲和力比DR 1低3倍。根据晶体结构预测，DR 1和DR 4的大部分CII-肽结合亲和力由Phe（263）控制;然而，出乎意料的是，相邻的Lys（264）也对肽的结合亲和力有显著贡献。仅发现这两个CII氨基酸提供结合锚。在其余位置的氨基酸取代没有影响或显着增加的hCII肽的亲和力。增强亲和力的取代通常涉及替换负电荷，或Gly或Pro，CII结构的标志性氨基酸。这些数据表明，DR 1和DR 4以几乎相同的方式结合该CII肽，并且CII的一级结构可能决定了DR 1和DR 4的结合基序与已描述的结合这些等位基因的其他肽不同。
Rheumatoid arthritis is an autoimmune disease in which susceptibility is strongly associated with the expression of specific HLA-DR haplotypes, including DR1 (DRB1*0101) and DR4 (DRB1*0401). As transgenes, both of these class II molecules mediate susceptibility to an autoimmune arthritis induced by immunization with human type II collagen (hCII). The dominant T cell response of both the DR1 and DR4 transgenic mice to hCII is focused on the same determinant core, CII(263-270). Peptide binding studies revealed that the affinity of DR1 and DR4 for CII(263-270) was at least 10 times less than that of the model Ag HA(307-319), and that the affinity of DR4 for the CII peptide is 3-fold less than that of DR1. As predicted based on the crystal structures, the majority of the CII-peptide binding affinity for DR1 and DR4 is controlled by the Phe(263); however, unexpectedly the adjacent Lys(264) also contributed significantly to the binding affinity of the peptide. Only these two CII amino acids were found to provide binding anchors. Amino acid substitutions at the remaining positions had either no effect or significantly increased the affinity of the hCII peptide. Affinity-enhancing substitutions frequently involved replacement of a negative charge, or Gly or Pro, hallmark amino acids of CII structure. These data indicate that DR1 and DR4 bind this CII peptide in a nearly identical manner and that the primary structure of CII may dictate a different binding motif for DR1 and DR4 than has been described for other peptides that bind to these alleles.