Do autoantibodies to aberrantly glycosylated MUC1 drive extra-articular rheumatoid arthritis, and can GSK assets prevent driver antigen formation?
Lead Research Organisation:
University College London
Department Name: Medicine
Abstract
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.
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.
Technical Summary
Altered glycosylation is commonly seen in chronic inflammatory diseases, including cancers. A common inflammation-induced change in glycosylation, seen in RA, ILD and cancer, is an increase of expression of sialic acid (hypersialylation) often driven by an increase in sialyltransferase expression levels. Hypersialylation is commonly seen on O-linked glycans on mucins and mucin-like molecules, owing to the high number and high occupancy of glycosylation sites.
We have reported that 84% of breast cancers (BCs) express a particular hypersialylated form of MUC1, termed MUC1-ST (MUC1 carrying sialylated core 1 O-glycans: Sialic acid-galactose-N-acetylgalactosamine). MUC1 can be measured in the serum, with crude aberrant glycosylation being used as a serological proxy for disease in ILD and cancers (e.g. KL-6 and CA15-3). We have recently observed this same glycoform of MUC1 in ILD tissue, BAL and plasma (vs non-ILD lung disease), and surprisingly, at low levels in healthy lung.
Two recent publications have shown MUC1 to be present on fibroblasts in the RA synovium. These observations crystallised the data from an old unpublished project into this current application. The old project was designed to test the hypothesis that RA patients generated autoantibodies to MUC1-ST which gave them protection from BSc - as such we had data showing the presence of both the antigen (32% patients) and the autoantibodies (9% patients) in RA sera.
Given the recent reports we have repurposed the old data formulating the hypothesis that RA synovial fibroblasts express MUC1-ST, which then drives autoantibody formation, which (upon minor lung injury) induces ILD through binding MUC1-ST on Type II alveolar cells thereby triggering antibody-induced cell death. In testing this hypothesis we will also look to a) develop a test for the antigen and autoantibody for diagnostic/prognostic use and b) test GSK assets in their ability to prevent the production of MUC1-ST on fibroblasts.
We have reported that 84% of breast cancers (BCs) express a particular hypersialylated form of MUC1, termed MUC1-ST (MUC1 carrying sialylated core 1 O-glycans: Sialic acid-galactose-N-acetylgalactosamine). MUC1 can be measured in the serum, with crude aberrant glycosylation being used as a serological proxy for disease in ILD and cancers (e.g. KL-6 and CA15-3). We have recently observed this same glycoform of MUC1 in ILD tissue, BAL and plasma (vs non-ILD lung disease), and surprisingly, at low levels in healthy lung.
Two recent publications have shown MUC1 to be present on fibroblasts in the RA synovium. These observations crystallised the data from an old unpublished project into this current application. The old project was designed to test the hypothesis that RA patients generated autoantibodies to MUC1-ST which gave them protection from BSc - as such we had data showing the presence of both the antigen (32% patients) and the autoantibodies (9% patients) in RA sera.
Given the recent reports we have repurposed the old data formulating the hypothesis that RA synovial fibroblasts express MUC1-ST, which then drives autoantibody formation, which (upon minor lung injury) induces ILD through binding MUC1-ST on Type II alveolar cells thereby triggering antibody-induced cell death. In testing this hypothesis we will also look to a) develop a test for the antigen and autoantibody for diagnostic/prognostic use and b) test GSK assets in their ability to prevent the production of MUC1-ST on fibroblasts.
