Identification of HLA-B*27 bound peptides involved in the pathogenesis of Ankylosing Spondylitis and Reactive Arthritis

强直性脊柱炎和反应性关节炎发病机制中涉及的 HLA-B*27 结合肽的鉴定

• 批准号: MR/M019837/1
• 负责人: Geraldine Gillespie
• 金额: $ 57.28万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM019837%2F1
• 关键词: Identification; HLA; 27; bound; peptides

HLA-B*27 is found in over 90% of patients with Ankylosing Spondylitis and Reactive Arthritis, two of the most common inflammatory arthritic diseases. Yet this immune protein is present in only 5-7% of people without these diseases. HLA-B*27, like other HLA types, is present on almost all cells of the body. The normal function of HLA-B*27 is to bind to foreign peptides that come from infecting microbes, and to stimulate T cells to eliminate the infection. One hypothesis is that sometimes T cells that are stimulated by foreign microbes also react to peptides bound to HLA-B*27 that come from normal, uninfected cells. This is a theory we want to test. In this study, we will take T cells from the joints of patients with inflammatory arthritis and use a powerful, new method to identify all the peptides they respond to. The technique involves putting HLA-B*27 onto yeast cells, each of which can place a different peptide onto the HLA-B*27 protein. We can make 100 million yeast cells, each with a different peptide. Then we will make the receptor proteins, namely the T cell receptors (TCRs), that normally react with HLA-B*27 plus peptide, from the patient's T cells, to select the yeast cells that bind. Finally, we will analyse the HLA-B*27 bound peptides that the TCRs recognise and compare them to all the peptides in the human and microbe databases. The latter have been accumulated from the Human Genome Project and the Microbe Genome Project over the last 10 years. This will allow us to identify both the microbe peptides that first stimulated the T cells, and the peptides from normal cells that they potentially attack to cause arthritis. The ultimate aim of this study is to identify if peptides that bind to HLA-B*27 cause disease. If we are successful we, and others, should be able to make candidate treatments that interfere with that process. This approach to therapy will be highly specific to this type of arthritis and far less likely to cause serious side effects than current treatments.

HLA-B*27存在于超过90%的强直性脊柱炎和反应性关节炎患者中，这两种最常见的炎性关节炎疾病。然而，这种免疫蛋白只存在于5-7%没有这些疾病的人中。HLA-B*27与其他HLA类型一样，几乎存在于身体的所有细胞上。HLA-B*27的正常功能是与来自感染微生物的外源肽结合，并刺激T细胞消除感染。一种假设是，有时候，被外来微生物刺激的T细胞也会对来自正常未感染细胞的与HLA-B*27结合的肽产生反应。这是一个我们想要测试的理论。在这项研究中，我们将从炎症性关节炎患者的关节中提取T细胞，并使用一种强大的新方法来识别它们所响应的所有肽。该技术涉及将HLA-B*27置于酵母细胞上，每个酵母细胞可以将不同的肽置于HLA-B*27蛋白上。我们可以制造1亿个酵母细胞，每个细胞都有不同的肽。然后，我们将从患者的T细胞中制备受体蛋白，即T细胞受体（TCR），通常与HLA-B*27加上肽反应，以选择结合的酵母细胞。最后，我们将分析TCR识别的HLA-B*27结合肽，并将其与人类和微生物数据库中的所有肽进行比较。后者是过去10年来人类基因组计划和微生物基因组计划积累的。这将使我们能够识别首先刺激T细胞的微生物肽，以及它们可能攻击导致关节炎的正常细胞的肽。这项研究的最终目的是确定与HLA-B*27结合的肽是否会导致疾病。如果我们成功了，我们和其他人应该能够做出干扰这一过程的候选治疗方法。这种治疗方法对这种类型的关节炎具有高度特异性，并且比当前的治疗方法引起严重副作用的可能性要小得多。

项目成果

Interrogating the recognition landscape of a conserved HIV-specific TCR reveals distinct bacterial peptide cross-reactivity.

询问保守的 HIV 特异性 TCR 的识别图谱揭示了独特的细菌肽交叉反应性。

• DOI: 10.7554/elife.58128
• 发表时间: 2020
• 期刊: eLife
• 影响因子: 7.7
• 作者: Mendoza JL

Discovery of HLA-E-Presented Epitopes: MHC-E/Peptide Binding and T-Cell Recognition.

• DOI: 10.1007/978-1-0716-2712-9_2
• 发表时间: 2022
• 期刊: Methods in molecular biology (Clifton, N.J.)

HLA-E restricted, HIV-1 suppressing, Gag specific CD8+ T cells offer universal vaccine opportunities

HLA-E 限制性、HIV-1 抑制性、Gag 特异性 CD8 T 细胞提供通用疫苗机会

• DOI: 10.1101/2020.12.01.406066
• 发表时间: 2020
• 作者: Yang H

High-throughput characterization of HLA-E-presented CD94/NKG2x ligands reveals peptides which modulate NK cell activation.

• DOI: 10.1038/s41467-023-40220-1
• 发表时间: 2023-08-09
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Huisman, Brooke D. D.;Guan, Ning;Rueckert, Timo;Garner, Lee;Singh, Nishant K. K.;McMichael, Andrew J. J.;Gillespie, Geraldine M. M.;Romagnani, Chiara;Birnbaum, Michael E. E.
• 通讯作者: Birnbaum, Michael E. E.

Detailed and atypical HLA-E peptide binding motifs revealed by a novel peptide exchange binding assay.

新型肽交换结合测定揭示了详细且非典型的 HLA-E 肽结合基序。

• DOI: 10.1002/eji.202048719
• 发表时间: 2020
• 期刊: European journal of immunology
• 影响因子: 5.4
• 作者: Walters LC