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

本项目旨在了解类风湿性关节炎相关间质性肺病（RA-ILD）的发展。这是一种使人衰弱的肺部疾病，在英国影响7- 100，000人，预后不良（中位生存期8.2年）。这种疾病的主要挑战之一是诊断，据信RA-ILD严重报告不足。我们正在寻求解决这个问题。我们已经能够将我们对癌症的知识，特别是40年来对一种常见癌症相关蛋白质变化的研究带入这一领域。我们和许多其他人已经注意到，慢性炎症性疾病和癌症中观察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MUC 1的粘蛋白，它通常存在于细胞表面，这些细胞排列在我们内部器官的导管上，形成内部“皮肤”，以保护器官免受伤害。在健康状态下，MUC 1的大部分结构上都有长的分支糖链，这有助于它结合并清除细菌和病毒，并保持水分。然而，在慢性炎症性疾病和癌症中，MUC 1发生变化，使其携带短糖链。这种结构的最常见形式称为MUC 1-ST，其中“ST”指的是短糖。MUC 1-ST常见的慢性炎性疾病的一个例子是间质性肺病（ILD），实际上，在许多国家，它被用于诊断和证实这些疾病。有趣的是，当我们对肺组织进行MUC 1-ST染色时，我们发现，是的，它在特发性肺纤维化（一种ILD）患者中升高，但它也存在于健康的肺中。去年，在类风湿关节炎（RA）研究领域出现了一些有趣的报告。他们都使用不同的方法表明，MUC 1在RA患者的关节细胞中表达。这是出乎意料的，然而，它使我们的一些旧数据变得有意义，我们在RA患者血液中测量了MUC 1和MUC 1-ST，发现RA患者的增加。在某些个体中，MUC 1-ST和其他形式的MUC 1携带短糖，被免疫系统识别为外来物，并产生抗体和T细胞对这种结构的反应。这在癌症中是积极的，其中这些免疫应答与改善的结果相关，但是我们考虑了这些应答在不同情况下是否可能是消极的。因此，该项目旨在a）观察RA患者关节中的MUC 1-ST是否可以触发对MUC 1-ST的免疫（抗体）应答（我们的初步数据显示9%的RA患者确实产生这些应答）和B）观察这些抗体是否与肺结合并触发自身免疫反应，其中身体将携带MUC 1-ST的肺细胞视为外来物。如果这是真的，我们将寻求开发一种检测MUC 1-ST和MUC 1-ST抗体的测试，作为帮助早期诊断和预后的临床工具。最后，因为我们相信RA关节是驱动自身免疫的MUC 1-ST的来源，我们将研究使用GSK的药物阻断这些过程。这将有望通过消除源头来阻止或减缓疾病。

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.