Cliff Rims, Hannes Uchtenhagen, Kadin Brooks, Bernard Ng, Sylvia E Posso, Jeffrey Carlin, William W Kwok, Jane H Buckner, Eddie A James
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引用次数: 0
Abstract
Rheumatoid arthritis (RA) is associated with high-risk HLA class II alleles known as the "RA shared epitope." Among prevalent shared epitope alleles, study of DRB1*04:04 has been limited. To define relevant epitopes, we identified citrullinated peptide sequences from synovial antigens that were predicted to bind to HLA-DRB1*04:04 and utilized a systematic approach to confirm their binding and assess their recognition by CD4 T cells. After confirming the immunogenicity of 13 peptides derived from aggrecan, cartilage intermediate layer protein (CILP), α-enolase, vimentin, and fibrinogen, we assessed their recognition by T cells from a synovial tissue sample, observing measurable responses to 8 of the 13 peptides. We then implemented a multicolor tetramer panel to evaluate the frequency and phenotype of antigen-specific CD4 T cells in individuals with anti-citrullinated protein antibody (ACPA)-positive RA and controls. In subjects with RA, CILP-specific T cell frequencies were significantly higher than those of other antigens. The surface phenotypes exhibited by antigen-specific T cells were heterogeneous, but Th1-like and Th2-like cells predominated. Stratifying based on disease status and activity, antigen-specific T cells were more frequent and most strongly polarized in RA subjects with high disease activity. In total, these findings identify novel citrullinated epitopes that can be used to interrogate antigen-specific CD4 T cells and show that antigen-specific T cell frequency is elevated in subjects with high disease activity.
类风湿性关节炎(RA)与被称为 "RA 共享表位 "的高风险 HLA II 类等位基因有关。在流行的共享表位等位基因中,对 DRB1*04:04 的研究还很有限。为了确定相关表位,我们从滑膜抗原中鉴定出了可与 HLA-DRB1*04:04 结合的瓜氨酸肽序列,并利用系统方法确认了它们的结合,评估了 CD4 T 细胞对它们的识别。在确认了从凝集素、软骨中间层蛋白(CILP)、α-烯醇化酶、波形蛋白和纤维蛋白原中提取的 13 种肽的免疫原性后,我们评估了滑膜组织样本中的 T 细胞对它们的识别能力,观察到了 13 种肽中 8 种肽的可测量反应。然后,我们采用多色四聚体面板来评估抗瓜氨酸蛋白抗体(ACPA)阳性 RA 患者和对照组中抗原特异性 CD4 T 细胞的频率和表型。在 RA 患者中,CILP 特异性 T 细胞的频率明显高于其他抗原。抗原特异性T细胞的表面表型各不相同,但以Th1样和Th2样细胞为主。根据疾病状态和活动性进行分层,抗原特异性 T 细胞在疾病活动性高的 RA 受试者中更为常见,极化程度也最强。总之,这些研究结果确定了可用于检测抗原特异性 CD4 T 细胞的新型瓜氨酸表位,并表明疾病活动度高的受试者体内抗原特异性 T 细胞频率升高。
期刊介绍:
Clinical & Experimental Immunology (established in 1966) is an authoritative international journal publishing high-quality research studies in translational and clinical immunology that have the potential to transform our understanding of the immunopathology of human disease and/or change clinical practice.
The journal is focused on translational and clinical immunology and is among the foremost journals in this field, attracting high-quality papers from across the world. Translation is viewed as a process of applying ideas, insights and discoveries generated through scientific studies to the treatment, prevention or diagnosis of human disease. Clinical immunology has evolved as a field to encompass the application of state-of-the-art technologies such as next-generation sequencing, metagenomics and high-dimensional phenotyping to understand mechanisms that govern the outcomes of clinical trials.