Friede T, Gnau V, Jung G, Keilholz W, Stevanović S, Rammensee H G
Department of Tumor Virus Immunology (0620), German Cancer Research Center, Heidelberg, Germany.
Biochim Biophys Acta. 1996 Jun 7;1316(2):85-101. doi: 10.1016/0925-4439(96)00010-5.
Rheumatoid arthritis (RA), one of the most common autoimmune disorders, is believed to be mediated via. T lymphocytes and genetic studies have shown that it is strongly associated with HLA-DR4. The DR4 subtypes DR4Dw4, DR4Dw14 and DR4Dw15 represent increased risk factors for RA, whereas DR4Dw10 is not associated with the disorder. Our study determines and compares the natural ligand motifs of these MHC class II molecules and identifies 60 natural ligands. At relative position 4 (P4), only the RA-associated DR4 molecules allow, or even prefer, negatively charged amino acids, but do not allow those which are positively charged (Arg, Lys). In the case of DR4Dw10 the preference for these amino acids is reversed. The results predict features of the putative RA-inducing peptide(s). A remarkable specificity, almost exclusively for negative charges (Asp, Glu), is found at P9 of the DR4Dw15 motif. This specificity can be ascribed to amino acid beta57 of the DR beta chain, and gives an important insight into the beta57-association of another autoimmune disease, insulin-dependent diabetes mellitus type I.
类风湿性关节炎（RA）是最常见的自身免疫性疾病之一，据信是由T淋巴细胞介导的，基因研究表明它与HLA - DR4密切相关。DR4亚型DR4Dw4、DR4Dw14和DR4Dw15是RA的风险增加因素，而DR4Dw10与该疾病无关。我们的研究确定并比较了这些II类主要组织相容性复合体分子的天然配体基序，并鉴定出60种天然配体。在相对位置4（P4），只有与RA相关的DR4分子允许甚至偏好带负电荷的氨基酸，但不允许带正电荷的氨基酸（精氨酸、赖氨酸）。对于DR4Dw10，对这些氨基酸的偏好则相反。这些结果预测了假定的RA诱导肽的特征。在DR4Dw15基序的P9处发现了一种显著的特异性，几乎只针对负电荷（天冬氨酸、谷氨酸）。这种特异性可归因于DRβ链的β57氨基酸，这为另一种自身免疫性疾病——I型胰岛素依赖型糖尿病的β57关联提供了重要见解。
