New study shows role of protein in rheumatoid arthritis susceptibility
A new study conducted by researchers in the Faculty and funded by Arthritis UK has shed light on how a genetic mutation in the protein that affects T cell responsiveness (PTPN22) could play a key role in the development of rheumatoid arthritis.
The study, undertaken at the Centre for Inflammation Biology and Cancer Immunology (CICBI) at King's and published in the journal Science Signaling, could provide a key insight into the function of the mutation, potentially opening the door for innovative new therapies to be created in future.
Rheumatoid arthritis is the second most common form of arthritis in the UK and causes joint pain and swelling, stiffness, fatigue and anaemia among other symptoms. It affects around 400,000 people in the UK, mostly between the ages of 40 and 50. For one in five of those with the condition, it can develop rapidly and cause severe pain and swelling that impacts daily life.
This new research aimed to build on existing understanding that a certain mutation in the gene that encodes for the protein PTPN22 is one of the strongest risk factors for rheumatoid arthritis, lupus and type 1 diabetes, influencing the way that certain receptors signal in immune cells.
This mutation is known to cause a subtle change in the PTPN22 protein, but prior to this it was not clear exactly how this change might alter the protein's function. In this study, advanced super-resolution microscopy techniques were used to visualise how the protein behaved at the nanoscale level.
By analysing how proteins and mutations affect the behaviour of immune cells, it becomes easier for scientists to understand how they then go on to cause inflammatory diseases, which are characterised by overactive immune responses doing damage to healthy tissue.
In normal circumstances, the protein was shown to be found in large clusters in T lymphocytes, breaking down into smaller clusters when the cells were activated, and allowing the phosphatase to inactivate its substrates. This function allows the phosphatase to switch off signals emanating from antigen receptors and adhesion molecules, such as interns. However, the specific gene mutation prevents the phosphatase from targeting its substrates, resulting in cells that become more adherent, and potentially exacerbating inflammatory functions.
Professor Andrew Cope, who led the study, said: ‘The ability to visualise where these proteins are located in the cells as they move has provided us with key insights into how the mutant phosphatase might be contributing to abnormal cellular functions. We believe that a susceptible host, with more sticky cells may result in an increased capacity for these cells to migrate to peripheral tissues, where they are retained and contribute to immune and inflammatory responses.’
Efforts will now be made to see how this molecular change affects cells, tissues and the body as a whole, in order to see how the mutation ultimately provokes the onset of disease. By laying bare this process, it could be possible to develop innovative therapies in the future that interrupt these irregular behaviours before they can cause damage.
Natalie Carter, Head of Research Liaison and Evaluation at Arthritis Research UK, said: ‘We have known for some time that there is a major genetic component to rheumatoid arthritis, and this unique study has given us further insight into the mechanisms of this. We hope that identifying how the PTPN22 protein behaves differently in people with rheumatoid arthritis will enable further research to better understand how the condition develops. This insight could lead to better treatments for people living with the painful condition, and opens up possibilities of finding an effective method of prevention.’