Scally Stephen W, Law Soi-Cheng, Ting Yi Tian, Heemst Jurgen van, Sokolove Jeremy, Deutsch Aaron J, Bridie Clemens E, Moustakas Antonis K, Papadopoulos George K, van der Woude Diane, Smolik Irene, Hitchon Carol A, Robinson David B, Ferucci Elizabeth D, Bernstein Charles N, Meng Xiaobo, Anaparti Vidyanand, Huizinga Tom, Kedzierska Katherine, Reid Hugh H, Raychaudhuri Soumya, Toes René E, Rossjohn Jamie, El-Gabalawy Hani, Thomas Ranjeny
Department of Biochemistry and Molecular Biology, Infection and Immunity Program, Biomedicine Discovery Institute Monash University, Clayton, Australia.
The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.
Ann Rheum Dis. 2017 Nov;76(11):1915-1923. doi: 10.1136/annrheumdis-2017-211300. Epub 2017 Aug 11.
The pathogenetic mechanisms by which alleles are associated with anticitrullinated peptide antibody (ACPA)-positive rheumatoid arthritis (RA) are incompletely understood. RA high-risk alleles are known to share a common motif, the 'shared susceptibility epitope (SE)'. Here, the electropositive P4 pocket of HLA-DRB1 accommodates self-peptide residues containing citrulline but not arginine. HLA-DRB1 His/Phe13β stratifies with ACPA-positive RA, while His13βSer polymorphisms stratify with ACPA-negative RA and RA protection. Indigenous North American (INA) populations have high risk of early-onset ACPA-positive RA, whereby HLA-DRB104:04 and HLA-DRB114:02 are implicated as risk factors for RA in INA. However, HLA-DRB1*14:02 has a His13βSer polymorphism. Therefore, we aimed to verify this association and determine its molecular mechanism.
HLA genotype was compared in 344 INA patients with RA and 352 controls. Structures of HLA-DRB1*1402-class II loaded with vimentin-64Arg, vimentin-64Cit and fibrinogen β-74Cit were solved using X-ray crystallography. Vimentin-64Cit-specific and vimentin-specific CD4+ T cells were characterised by flow cytometry using peptide-histocompatibility leukocyte antigen (pHLA) tetramers. After sorting of antigen-specific T cells, TCRα and β-chains were analysed using multiplex, nested PCR and sequencing.
ACPA RA in INA was independently associated with . Consequent to the His13βSer polymorphism and altered P4 pocket of HLA-DRB114:02, both citrulline and arginine were accommodated in opposite orientations. Oligoclonal autoreactive CD4+ effector T cells reactive with both citrulline and arginine forms of vimentin were observed in patients with HLA-DRB114:02 RA and at-risk ACPA first-degree relatives. HLA-DRB114:02-vimentin-specific and HLA-DRB114:02-vimentin-64Cit-specific CD4+ memory T cells were phenotypically distinct populations.
HLA-DRB1*14:02 broadens the capacity for citrullinated and native self-peptide presentation and T cell expansion, increasing risk of ACPA+ RA.
等位基因与抗瓜氨酸化肽抗体（ACPA）阳性类风湿关节炎（RA）相关的致病机制尚未完全明确。已知RA高危等位基因具有一个共同基序，即“共享易感性表位（SE）”。在此，HLA - DRB1的正电P4口袋可容纳含有瓜氨酸而非精氨酸的自身肽残基。HLA - DRB1 His/Phe13β与ACPA阳性RA相关，而His13βSer多态性与ACPA阴性RA及RA易感性相关。北美原住民（INA）人群患早发性ACPA阳性RA的风险较高，其中HLA - DRB104:04和HLA - DRB114:02被认为是INA中RA的风险因素。然而，HLA - DRB1*14:02具有His13βSer多态性。因此，我们旨在验证这种关联并确定其分子机制。
比较了344例INA RA患者和352例对照的HLA基因型。使用X射线晶体学解析了负载波形蛋白 - 64Arg、波形蛋白 - 64Cit和纤维蛋白原β - 74Cit的HLA - DRB1*1402 - II类分子的结构。使用肽 - 组织相容性白细胞抗原（pHLA）四聚体通过流式细胞术对波形蛋白 - 64Cit特异性和波形蛋白特异性CD4 + T细胞进行表征。在分选抗原特异性T细胞后，使用多重巢式PCR和测序分析TCRα和β链。
INA中的ACPA RA与……独立相关。由于HLA - DRB114:02的His13βSer多态性和P4口袋改变，瓜氨酸和精氨酸以相反方向被容纳。在HLA - DRB114:02 RA患者和有风险的ACPA一级亲属中观察到与波形蛋白的瓜氨酸和精氨酸形式均反应的寡克隆自身反应性CD4 +效应T细胞。HLA - DRB114:02 - 波形蛋白特异性和HLA - DRB114:02 - 波形蛋白 - 64Cit特异性CD4 +记忆T细胞是表型不同的群体。
HLA - DRB1*14:02拓宽了瓜氨酸化和天然自身肽呈递以及T细胞扩增的能力，增加了ACPA + RA的风险。
