Do autoantibodies to aberrantly glycosylated MUC1 drive extra-articular rheumatoid arthritis, and can GSK assets prevent driver antigen formation?

针对异常糖基化 MUC1 的自身抗体是否会导致关节外类风湿性关节炎，GSK 资产能否阻止驱动抗原形成？

• 批准号: MR/Y022947/1
• 负责人: Joanna Porter
• 金额: $ 32.05万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY022947%2F1
• 关键词: Do; autoantibodies; aberrantly; glycosylated; MUC1

This project is looking to try to understand the development of rheumatoid arthritis associated interstitial lung disease (RA-ILD). This is a debilitating lung disease affecting 7-100,000 people in the UK, with a poor prognosis (median survival 8.2 years). One of the main challenges of this disease is diagnosis, with RA-ILD believed to be heavily under-reported. We are looking to address this issue.We have been able to bring across our knowledge of cancers, specifically 40 years of studying the changes to a common cancer-associated protein, into this field. We, and many others have noticed that the cellular and molecular changes seen in chronic inflammatory diseases and cancers are very similar. Our particular interest is a mucin called MUC1 which is normally found on the surface of cells which line the ducts of our internal organs forming an internal 'skin' to protect the organ from injury. In healthy states MUC1 has long branched sugar chains attached to much of its structure, which help it bind to and remove bacteria and viruses, and hold water. However, in chronic inflammatory diseases and cancers MUC1 changes so that it carries short sugar chains. The most common form of this structure is called MUC1-ST, where the 'ST' refers to the short sugars. One example of a chronic inflammatory disease where MUC1-ST is common is interstitial lung disease (ILD), indeed it is used to diagnose and prognosticate these conditions in many countries. Interestingly when we stained lung tissue for MUC1-ST we found that, yes, it was up in patients with idiopathic pulmonary fibrosis (a type of ILD) but it was also present in healthy lungs. Last year a couple of interesting reports came out in the field of rheumatoid arthritis (RA) research. They both showed, using different methods, that MUC1 was expressed by cells in the joint of RA patients. This was unexpected, however it made sense of some of our old data where we had measured MUC1, and MUC1-ST, in RA patient blood, finding an increase in RA patients. In some individuals, MUC1-ST and other forms of MUC1 carrying short sugars, are recognised as foreign by the immune system, and it generates antibody and T cell responses to this structure. This is positive in cancers where these immune responses are associated with improved outcomes, however we considered if these responses may be negative under different circumstances. This project is therefore designed to a) look at whether MUC1-ST in the joint of RA patients can trigger an immune (antibody) response to MUC1-ST (our preliminary data shows 9% of RA patients do indeed generate these responses) and b) see whether these antibodies bind to the lung and trigger an autoimmune reaction where the body sees the lung cells carrying MUC1-ST as foreign. If this is true, we will look to develop a test to detect both MUC1-ST and the antibodies to MUC1-ST as a clinical tool to help with early diagnosis and prognosis. Finally, because we believe the RA joint is the source of the MUC1-ST that drives the autoimmunity, we will look at blocking these processes using GSK's drugs. This would hopefully stop or slow down the disease by removing the source.

该项目试图尝试了解类风湿关节炎相关的间质性肺疾病（RA-ELD）的发展。这是一种令人衰弱的肺部疾病，影响了英国7-100,000人，预后不良（中位生存率为8.2岁）。该疾病的主要挑战之一是诊断，据信RA-ild被严重报道。我们正在寻求解决这个问题。我们已经能够使我们对癌症的了解，尤其是40年来研究与癌症相关蛋白质的变化的40年。我们和许多其他人注意到，慢性炎症性疾病和癌症中看到的细胞和分子变化非常相似。我们特别感兴趣的是一种称为MUC1的粘蛋白，通常在细胞表面上发现，该细胞表面排列着内部器官的管道，形成内部“皮肤”以保护器官免受损伤。在健康状态下，MUC1具有长长的分支糖链，这些糖链附着在其大部分结构上，这有助于其与细菌和病毒的结合并去除水，并保持水。但是，在慢性炎症性疾病和癌症中，MUC1会发生变化，从而带有短糖链。该结构的最常见形式称为MUC1-ST，其中“ ST”是指短糖。 MUC1-ST常见的慢性炎症性疾病的一个例子是间质肺疾病（ILD），实际上它用于诊断和预测许多国家的这些疾病。有趣的是，当我们为MUC1-ST染色的肺组织时，我们发现，是的，特发性肺纤维化患者（一种ILD），但它也存在于健康的肺中。去年，在类风湿关节炎（RA）研究领域发表了一些有趣的报道。他们都使用不同的方法表明MUC1是由RA患者关节中细胞表达的。这是出乎意料的，但是这是我们一些旧数据的理解，其中我们测量了MUC1和RA患者血液中的MUC1-ST，发现RA患者的增加。在某些个体中，MUC1-ST和其他形式的含短糖的MUC1被免疫系统识别为外来，并且会产生抗体和T细胞对该结构的反应。在这些免疫反应与改善结果相关的癌症中，这是积极的，但是我们认为，如果在不同情况下这些反应可能是负面的。因此，该项目的设计旨在a）查看RA患者关节中的MUC1-ST是否可以触发对MUC1-ST的免疫（抗体）反应（我们的初步数据显示，RA患者中有9％确实会产生这些反应）和B ）查看这些抗体是否与肺部结合并触发自身免疫反应，在该反应中，人体将带有MUC1-ST的肺细胞视为异物。如果这是真的，我们将寻求一项测试，以检测MUC1-ST和MUC1-ST的抗体，作为帮助早期诊断和预后的临床工具。最后，因为我们认为RA关节是驱动自身免疫性的MUC1-ST的来源，所以我们将考虑使用GSK的药物阻止这些过程。有望通过去除来源来阻止或减慢疾病。