Alison Simmons: Crohn's disease
Crohn’s is an inflammatory bowel disease that results from a breakdown in the immune system’s ability to recognize the intestine microflora as ‘self’. Genetic factors that function in innate immune pathways predispose to developing Crohn’s disease. A better understanding at the molecular level might help us develop better immunotherapies.
Q: What is Crohn's disease?
AS: Crohn's is an inflammatory bowel disease that affects 1 in 1000 people in Western populations. It is thought to result from a breakdown in immune tolerance to intestinal microbes in people with a given genetic background. It leads to inflammatory lesions developing in the gastro intestinal mucosa, which results in symptoms of bloody diarrhoea, abdominal pain and weight loss. Some patients respond to conventional immunotherapies like steroids quite well and they go on to have a fairly trouble-free disease. Others have intractable problems and fail all the conventional immunotherapies. These patients often end up needing to have multiple operations so there is an unmet need there.
Q: What is the role of the innate immune system in Crohn's disease?
AS: Over the last ten years there has been a lot of genetic research which has unearthed various genetic variants that lead to development of the disease. Amongst the most strongly associated genes are genes that fall in to the category of innate immune system genes. The innate immune system is the most primitive arm of the human immune system. It is composed of a series of receptors that are known as pattern recognition receptors. These receptors recognise conserved molecular motifs on microbes and are the gatekeepers of the immune system – they recognise these conserved motifs and decide whether or not to mount a full-blown immune response. There is a particular innate immune receptor associated with Crohn's disease called NOD-2. We have worked on the function of NOD-2 and shown that its role normally is to get rid of intracellular bacteria and it does this by a process known as autophagy (the bacteria are engulfed in a membrane and then degraded). We've found that this pathway involves a number of other Crohn's susceptibility genes and that in Crohn's disease that this process goes wrong.
More recently we have mapped this signalling cascade in more detail. This has shown that not only does the signalling cascade involving NOD-2 control bacterial destruction, but other innate immune functions that are also defective in Crohn's patients. This adds weight to the idea that in some patients with Crohn's disease their problem is one of immunodeficiency rather than an autoimmune disease as such. At the moment we are trying to work on understanding specific molecules in that pathway that could be used for structure-based drug design.
Q: Can your research help us understand other diseases?
AS: The normal role of NOD-2 is in defence against intracellular bacteria such as the bacteria that cause tuberculosis, leprosy and salmonella disease. Understanding the wiring of NOD-2 signalling has relevance for understanding how these bacteria are cleared normally and how they may manipulate the immune system to give a more pathogenic disease when people are infected. Understanding this might provide us with avenues for better therapies for those diseases and also help us develop better vaccines. The types of techniques that we use to understand innate immune receptor function of other receptors apart from NOD-2 can be important in other diseases where these receptors have aberrant function; they have been linked to inflammation in other contexts such as inflammation-induced cancer, or inflammation-associated pathology associated with chronic viral infections. We use the same techniques to explore other immune functions as well as NOD-2.
Q: What are the most important lines of research that have developed in the past 5 to 10 years?
AS: Firstly for Crohn's disease it has really been uncovering the genetic basis of the disease through advances in sequencing technology. This has really revealed numerous Crohn's susceptibility genes. Secondly, the same advances in sequencing technology have enabled us to uncover the composition of the microbes of the gut that drive inflammation in people with given genetic defects. It's really early days at the moment but these technologies will unleash a whole load of information about this in the near future. I think the third thing that is really critical is that we've been able to build on these genetic advances to really understand the function of the genes that are dysregulated and how they drive inflammation. This is illustrated by our own work with NO-2, for example.
Q: Why does your line of research matter and why should we put money in to it?
AS: By defining in molecular detail the signalling cascade involving NOD-2 we can define targets for drug design for patients who have defects in that signalling cascade. This is really important for patients who have Crohn's where conventional immunotherapies may not work in a significant subset of patients. That information can also be used to stratify the disease. That means to identify subsets of patients where particular molecular defects exist that would be amenable for specific therapeutic approaches, so they would not have to have other immunotherapies that won't work needlessly.
Q: How does your research fit in to translational medicine within the department?
AS: We have a major programme of translational research in collaboration with members of the Target Discovery Institute, here in Oxford. This involves using their high-throughput platforms to define molecules that will be candidates for structure-based drug design. Through my clinical work in the Translational Gastroenterology Unit we have a number of clinical trials, initiated or about to be initiated, in collaboration with various pharmaceutical companies. We also have translational programmes of work exploring the function of various innate immune receptors, across various inflammatory contexts. This work involves collaborations with people at the Kennedy Institute of Rheumatology, the Wellcome Trust Centre for Human Genetics, the Human Immunology Unit, the Vaccine Centre and the International Centre for Translational Immunology.