The rheumatoid arthritis-associated allele HLA-DR10 (DRB1*1001) shares part of its repertoire with HLA-DR1 (DRB1*0101) and HLA-DR4 (DRB*0401)
The rheumatoid arthritis-associated allele HLA-DR10 (DRB1*1001) shares part of its repertoire with HLA-DR1 (DRB1*0101) and HLA-DR4 (DRB*0401)
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DOI：
10.1002/art.23503
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发表时间：
2008-06-01
影响因子：
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通讯作者：
Jaraquemada, Dolores
中科院分区：
文献类型：
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作者：
Alvarez, Inaki;Collado, Javier;Jaraquemada, Dolores
目标。目的确定类风湿关节炎(RA)相关等位基因DR10的肽锚基序，并寻找与其他疾病相关等位基因DR1和DR4有共同的天然配体或序列相似性。纯化了人类白细胞抗原-DR10相关多肽，并对部分天然配体进行了重新测序。根据晶体结构，对流感病毒血凝素RA306-318与DR1、DR4、DR10形成的复合物进行了模型化，得到了结合分数。共测定了238个多肽的序列，确定了人类白细胞抗原-DR10多肽库的锚定基序。很大比例的DR10相关多肽不具备结合DR1和DR4的结构特征，但理论上却是负相关等位基因DR15和DR7的非结合体。在测序的配体中，有10个被报道为其他RA相关等位基因的配体。模拟数据显示，HA306-318多肽与DR1、DR4和DR10具有相似的亲和力。这些数据表明，在RA相关的HLA等位基因谱系中存在共同的多肽。DR1、DR4和DR10中存在的共同表位与共同的可能的致关节炎多肽(S)的结合可能会影响疾病的发生或预后。
Objective. To identify the peptide anchor motif for the rheumatoid arthritis (RA)-related HLA allele, DR10, and find shared natural ligands or sequence similarities with the other disease-associated alleles, DR1 and DR4.Methods. The HLA-DR10-associated peptides were purified, and a proportion of these natural ligands were de novo sequenced by mass spectrometry. Based on crystallographic structures, the complexes formed by peptide influenza virus hemagglutinin RA306-318 with DR1, DR4, and DR10 were modeled, and binding scores were obtained.Results. A total of 238 peptides were sequenced, and the anchor motif of the HLA-DR10 peptide repertoire was defined. A large proportion of the DR10-associated peptides bad the structural features to bind DR1 and DR4 but were theoretical nonbinders to the negatively associated alleles DR15 and DR7. Among the sequenced ligands, 10 had been reported as ligands to other RA-associated alleles. Modeling data showed that peptide HA306-318 can bind DR1, DR4, and DR10 with similar affinities.Conclusion. The data show the presence of common peptides in the repertoires of RA-associated HLA alleles. The combination of the shared epitope present in DR1, DR4, and DR10 together with common putative arthritogenic peptide(s) could influence disease onset or outcome.