Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis.
Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis.
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DOI：
10.1136/annrheumdis-2017-211300
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发表时间：
2017-11
影响因子：
27.4
通讯作者：
Thomas R
中科院分区：
文献类型：
--
作者：
Scally SW;Law SC;Ting YT;Heemst JV;Sokolove J;Deutsch AJ;Bridie Clemens E;Moustakas AK;Papadopoulos GK;van der Woude D;Smolik I;Hitchon CA;Robinson DB;Ferucci ED;Bernstein CN;Meng X;Anaparti V;Huizinga T;Kedzierska K;Reid HH;Raychaudhuri S;Toes RE;Rossjohn J;El-Gabalawy H;Thomas R
HLA-DRB 1等位基因与抗瓜氨酸肽抗体（ACPA）阳性类风湿关节炎（RA）相关的发病机制尚不完全清楚。RA高危HLA-DRB1等位基因有一个共同的基序，即“共享易感性表位”。在这里，HLA-DRB 1的正电性P4口袋容纳含有瓜氨酸但不含精氨酸的自身肽残基。HLA-DRB1 His/Phe13 β多态性与ACPA阳性RA分层，His13 β Ser多态性与ACPA阴性RA分层，与RA保护性分层。土著北美（INA）人群具有早发ACPA阳性RA的高风险，其中HLA-DRB1 * 04：04和HLA-DRB1 * 14：02被认为是INA中RA的危险因素。然而，HLA-DRB1 * 14：02具有His13 β Ser多态性。因此，我们旨在验证这种关联并确定其分子机制。对344例INA RA患者和352例对照者进行HLA基因型比较。使用X射线晶体学解析加载有波形蛋白-64Arg59 - 71、波形蛋白-64Cit59 - 71和纤维蛋白原β − 74Cit69 - 81的HLA-DRB1 * 1402-II类的结构。波形蛋白-64Cit59-71特异性和波形蛋白59 - 71特异性CD4 + T细胞通过使用肽组织相容性白细胞抗原（pHLA）四聚体的流式细胞术表征。分选抗原特异性T细胞后，使用多重巢式PCR和测序分析TCR α和β链。INA患者ACPA + RA与HLA-DRB1 * 14：02独立相关。与HLA-DRB 1 * 14：02的His13 β Ser多态性和P4口袋改变一致，瓜氨酸和精氨酸以相反的方向调节。在HLA-DRB 1 * 14：02 + RA患者和高危ACPA −一级亲属中观察到与瓜氨酸和精氨酸形式的波形蛋白59 - 71反应的寡克隆自身反应性CD4+效应T细胞。HLA-DRB1 * 14：02-波形蛋白59 - 71特异性和HLA-DRB1 * 14：02-波形蛋白-64Cit59 - 71特异性CD4+记忆T细胞是表型不同的群体。HLA-DRB1 * 14：02扩大瓜氨酸化和天然自身肽呈递和T细胞扩增的能力，增加ACPA + RA的风险。
The pathogenetic mechanisms by which HLA-DRB1 alleles are associated with anticitrullinated peptide antibody (ACPA)-positive rheumatoid arthritis (RA) are incompletely understood. RA high-risk HLA-DRB1 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-DRB1*04:04 and HLA-DRB1*14:02 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-64Arg59–71, vimentin-64Cit59–71 and fibrinogen β−74Cit69–81 were solved using X-ray crystallography. Vimentin-64Cit59–71-specific and vimentin59–71-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 HLA-DRB1*14:02. Consequent to the His13βSer polymorphism and altered P4 pocket of HLA-DRB1*14:02, both citrulline and arginine were accommodated in opposite orientations. Oligoclonal autoreactive CD4+ effector T cells reactive with both citrulline and arginine forms of vimentin59–71 were observed in patients with HLA-DRB1*14:02+ RA and at-risk ACPA− first-degree relatives. HLA-DRB1*14:02-vimentin59–71-specific and HLA-DRB1*14:02-vimentin-64Cit59–71-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.
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DOI：
10.1084/jem.20011194
发表时间：
2002-03-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hennecke J;Wiley DC
通讯作者：
Wiley DC
影响因子：
1.3
作者：
Foote EM;Singleton RJ;Holman RC;Seeman SM;Steiner CA;Bartholomew M;Hennessy TW
通讯作者：
Hennessy TW
DOI：
10.1002/art.39226
发表时间：
2015-09
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
--
作者：
Quirke AM;Perry E;Cartwright A;Kelly C;De Soyza A;Eggleton P;Hutchinson D;Venables PJ
通讯作者：
Venables PJ
影响因子：
2.3
作者：
Fisher BA;Cartwright AJ;Quirke AM;de Pablo P;Romaguera D;Panico S;Mattiello A;Gavrila D;Navarro C;Sacerdote C;Vineis P;Tumino R;Lappin DF;Apatzidou D;Culshaw S;Potempa J;Michaud DS;Riboli E;Venables PJ
通讯作者：
Venables PJ
影响因子：
--
作者：
James, Eddie A.;Moustakas, Antonis K.;Bui, John;Papadopoulos, George K.;Bondinas, George;Buckner, Jane H.;Kwok, William W.
通讯作者：
Kwok, William W.