狼疮抗原和 HLA-DR 中 T 细胞表位的性质决定了自身抗体的起始和多样化。
Nature of T cell epitopes in lupus antigens and HLA-DR determines autoantibody initiation and diversification.
机构信息
Division of Rheumatology, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia, USA.
出版信息
Ann Rheum Dis. 2019 Mar;78(3):380-390. doi: 10.1136/annrheumdis-2018-214125. Epub 2018 Sep 25.
OBJECTIVES
The generation of systemic lupus erythematosus (SLE)-related autoantibodies have been shown to be T cell dependent and antigen driven with HLA-DR restriction. In this study, the initiating antigen(s) and the mechanism of autoantibody diversification were investigated.
METHODS
T cell epitopes (T-epitopes) of SmD1 (SmD) were mapped by T-T hybridomas generated from DR3AE mice immunised with SmD and with SmD overlapping peptides. TCRs from the reactive hybridomas were sequenced. The core epitopes were determined. Bacterial mimics were identified by bioinformatics. Sera from DR3AE mice immunised with SmD peptides and their mimics were analysed for their reactivity by ELISA and immunohistochemistry. Samples of blood donors were analysed for HLA-DR and autoantibody specificities.
RESULTS
Multiple HLA-DR3 restricted T-epitopes within SmD were identified. Many T-T hybridomas reacted with more than one epitope. Some of them were cross-reactive with other snRNP peptides and with proteins in the Ro60/La/Ro52 complex. The reactive hybridomas used unique TCRs. Multiple T-epitope mimics were identified in commensal and environmental bacteria. Certain bacterial mimics shared both T and B cell epitopes with the related SmD peptide. Bacterial mimics induced autoantibodies to lupus-related antigens and to different tissues. HLA-DR3 blood donors made significantly more SLE-related autoantibodies.
CONCLUSIONS
The unique antigenic structures of the lupus-related autoantigens provide the basis for being targeted and for T and B cell epitope spreading and autoantibody diversification with unique patterns. SLE-related autoantibodies are likely generated from responses to commensal and/or environmental microbes due to incomplete negative selection for autoreactive T cells. The production of SLE-related antibodies is inevitable in normal individuals. The findings in this investigation have significant implications in autoimmunity in general.
目的
已显示系统性红斑狼疮 (SLE) 相关自身抗体的产生依赖于 T 细胞且受 HLA-DR 限制，由抗原驱动。在这项研究中，我们研究了起始抗原和自身抗体多样化的机制。
方法
通过用 SmD 重叠肽免疫 DR3AE 小鼠产生的 DR3AE 小鼠 T-T 杂交瘤，对 SmD1（SmD）的 T 细胞表位 (T-epitopes) 进行了作图。对反应性杂交瘤的 TCR 进行了测序。确定了核心表位。通过生物信息学鉴定了细菌模拟物。通过 ELISA 和免疫组织化学分析用 SmD 肽及其模拟物免疫的 DR3AE 小鼠血清的反应性。分析了献血者样本的 HLA-DR 和自身抗体特异性。
结果
鉴定出 SmD 内多个 HLA-DR3 受限的 T-epitopes。许多 T-T 杂交瘤与一个以上的表位反应。其中一些与其他 snRNP 肽和 Ro60/La/Ro52 复合物中的蛋白质发生交叉反应。反应性杂交瘤使用独特的 TCR。在共生菌和环境细菌中鉴定出多个 T-epitope 模拟物。某些细菌模拟物与相关的 SmD 肽共享 T 和 B 细胞表位。细菌模拟物诱导针对狼疮相关抗原和不同组织的自身抗体。DR3 献血者产生的 SLE 相关自身抗体明显更多。
结论
狼疮相关自身抗原的独特抗原结构为靶向治疗以及 T 和 B 细胞表位扩展和自身抗体多样化提供了基础，且具有独特的模式。由于对自身反应性 T 细胞的不完全阴性选择，SLE 相关自身抗体可能是由对共生体和/或环境微生物的反应产生的。在正常个体中，SLE 相关抗体的产生是不可避免的。本研究中的发现对一般自身免疫具有重要意义。
Zotero 插件