Freed Brian M, Schuyler Ronald P, Aubrey Michael T
ClinImmune Labs and University of Colorado School of Medicine, Aurora, CO 80045, USA.
Arthritis Rheum. 2011 Dec;63(12):3733-9. doi: 10.1002/art.30636.
Although rheumatoid arthritis (RA) has long been associated with an HLA-DRB1 shared epitope, a systematic search for other epitopes has never been conducted. In addition, the relationship between these epitopes and the binding of citrullinated autoantigens has not been investigated. We developed a program that can analyze HLA data for all possible epitopes of up to 5 amino acids and used this program to assess the shared epitope hypothesis in RA.
We analyzed high-resolution data from the International Histocompatibility Working Group, which included a group of 488 patients with RA and a group of 448 racially and ethnically balanced control subjects, for all combinations of up to 5 amino acids among polymorphic HLA-DRB1 positions 8-93. Statistical significance was determined by chi-square and Fisher's exact tests, with a false discovery rate correction.
Three residues (V(11), H(13), and L(67)) were found to have the highest degree of association with RA susceptibility (P < 10(-11)), and D(70) was found to correlate best with RA resistance (P = 2 × 10(-11)). Of >2 million epitopes examined, LA(67, 74) exhibited the highest correlation with RA susceptibility (P = 2 × 10(-20); odds ratio 4.07 [95% confidence interval 3.07-5.39]). HLA alleles containing the LA(67, 74) epitope exhibited significantly greater binding to citrullinated vimentin(65-77) than did alleles containing D(70). Only 1 allele (DRB1*16:02) contained both LA(67, 74) and D(70); it bound citrullinated vimentin weakly and was not associated with RA.
The findings of these studies confirm the importance of HLA-DRB1 amino acids in pocket 4 for the binding of citrullinated autoantigens and susceptibility to RA.
尽管类风湿关节炎（RA）长期以来一直与HLA - DRB1共享表位相关联，但从未对其他表位进行过系统搜索。此外，这些表位与瓜氨酸化自身抗原结合之间的关系也未得到研究。我们开发了一个程序，该程序可以分析HLA数据中的所有可能的至多5个氨基酸的表位，并使用此程序评估RA中的共享表位假说。
我们分析了国际组织相容性工作组的高分辨率数据，其中包括一组488例RA患者和一组448例种族和民族均衡的对照受试者，针对多态性HLA - DRB1第8 - 93位中至多5个氨基酸的所有组合。通过卡方检验和Fisher精确检验确定统计学显著性，并进行错误发现率校正。
发现三个残基（V(11)、H(13)和L(67)）与RA易感性的关联程度最高（P < 10^(-11)），而D(70)与RA抗性的相关性最佳（P = 2×10^(-11)）。在检查的超过200万个表位中，LA(67, 74)与RA易感性的相关性最高（P = 2×10^(-20)；优势比4.07 [95%置信区间3.07 - 5.39]）。含有LA(67, 74)表位的HLA等位基因与瓜氨酸化波形蛋白(65 - 77)的结合显著强于含有D(70)的等位基因。只有1个等位基因（DRB1*16:02）同时包含LA(67, 74)和D(70)；它与瓜氨酸化波形蛋白的结合较弱，且与RA无关。
这些研究结果证实了HLA - DRB1第4口袋中的氨基酸对于瓜氨酸化自身抗原结合和RA易感性的重要性。
