Xie Li-Jun, Cui Zhao, Chen Fang-Jin, Pei Zhi-Yong, Hu Shui-Yi, Gu Qiu-Hua, Jia Xiao-Yu, Zhu Li, Zhou Xu-Jie, Zhang Hong, Liao Yun-Hua, Lai Lu-Hua, Hudson Billy G, Zhao Ming-Hui
Renal Division, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, China.
Renal Division, Department of Medicine, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China.
Immunology. 2017 Aug;151(4):395-404. doi: 10.1111/imm.12736. Epub 2017 May 16.
Goodpasture's disease is closely associated with HLA, particularly DRB11501. Other susceptible or protective HLA alleles are not clearly elucidated. The presentation models of epitopes by susceptible HLA alleles are also unclear. We genotyped 140 Chinese patients and 599 controls for four-digit HLA II genes, and extracted the encoding sequences from the IMGT/HLA database. T-cell epitopes of α3(IV)NC1 were predicted and the structures of DR molecule-peptide-T-cell receptor were constructed. We confirmed DRB11501 (OR = 4·6, P = 5·7 × 10 ) to be a risk allele for Goodpasture's disease. Arginine at position 13 (ARG13) (OR = 4·0, P = 1·0 × 10 ) and proline at position 11 (PRO11) (OR = 4·0, P = 2·0 × 10 ) on DRβ1, encoded by DRB11501, were associated with disease susceptibility. α (HGWISLWKGFSFIMF) was predicted as a T-cell epitope presented by DRB11501. Isoleucine , tryptophan , glycine , phenylalanine and phenylalanine , were presented in peptide-binding pockets 1, 4, 6, 7 and 9 of DR2b, respectively. ARG13 in pocket 4 interacts with tryptophan and forms a hydrogen bond. In conclusion, we propose a mechanism for DRB1*1501 susceptibility for Goodpasture's disease through encoding ARG13 and PRO11 on MHC-DRβ1 chain and presenting T-cell epitope, α , with five critical residues.
肺出血肾炎综合征与人类白细胞抗原（HLA）密切相关，尤其是DRB11501。其他易感或保护性HLA等位基因尚未明确阐明。易感HLA等位基因呈递表位的模式也不清楚。我们对140例中国患者和599例对照进行了四位数字的HLA II类基因分型，并从IMGT/HLA数据库中提取了编码序列。预测了α3（IV）NC1的T细胞表位，并构建了DR分子-肽-T细胞受体的结构。我们证实DRB11501（比值比[OR]=4.6，P=5.7×10）是肺出血肾炎综合征的风险等位基因。由DRB11501编码的DRβ1上第13位的精氨酸（ARG13）（OR=4.0，P=1.0×10）和第11位的脯氨酸（PRO11）（OR=4.0，P=2.0×10）与疾病易感性相关。α（HGWISLWKGFSFIMF）被预测为DRB11501呈递的T细胞表位。异亮氨酸、色氨酸、甘氨酸、苯丙氨酸和苯丙氨酸分别呈递于DR2b的肽结合口袋1、4、6、7和9中。口袋4中的ARG13与色氨酸相互作用并形成氢键。总之，我们提出了一种机制，即DRB1*1501通过在MHC-DRβ1链上编码ARG13和PRO11并呈递具有五个关键残基的T细胞表位α，从而导致肺出血肾炎综合征易感性。
