Professor Richard Cornall aims to understand the causes of autoimmune diseases. Autoimmunity occurs when the immune system which is normally designed to attack pathogens ends up attacking the body. Professor Cornall is also interested in how people differ in their inherited susceptibility and why these differences are sustained in human populations by natural selection.
Autoimmune diseases can lead to the loss of function of specific organs – such as rheumatoid arthritis and early on-set diabetes – or to systemic autoimmune diseases where the whole body is attacked. A better understanding of how the immune system is formed and regulated could help us design new treatments.
Ultimately, medical research must translate into improved treatments for patients. At the Nuffield Department of Medicine, our researchers collaborate to develop better health care, improved quality of life, and enhanced preventative measures for all patients. Our findings in the laboratory are translated into changes in clinical practice, from bench to bedside.
Q: What is autoimmunity?
RC: Autoimmunity is a situation when the immune system which is normally designed to attack pathogens attacks our own bodies – a sort of friendly fire situation. Autoimmune diseases are divided into those which effect specific organs, where you lose the functions of specific organs - examples of that would be early-onset diabetes where the insulin producing cells in the pancreas are destroyed or rheumatoid arthritis which attacks the joints - and then there are systemic ones where the whole body is attacked like systemic lupus, you have some generalised effects from those. It’s distinct from allergy which sometimes confuses people. Allergies are where you have an abnormal response against something outside the body, such as house dust mites, so it’s not the same as allergies it’s where the body attacks itself.
Q: How do autoimmune diseases develop?
RC: To understand that you have to understand that the immune system generates cells at random in order to fight pathogens and it needs to be able to do that at random so that it can adapt to any of the pathogens that might arise in the environment. Because it’s a random process there is a chance that you will develop cells that will also react against yourself just as they would against the pathogens. So there needs to be control mechanisms to prevent those cells from reacting against you. Autoimmune diseases occur typically when two things arise: one, you have to have the abnormal cell which will arise by chance, and then you have to have some defect in the normal control mechanisms which are there in all of us to prevent those cells from damaging us. That is the basic answer. In addition sometimes, in fighting off particular pathogens we get cross reactions between the pathogens and our cells. For example in rheumatic fever where you can have a bacterium causing a sore throat you can afterwards get an autoimmune disease effecting the heart due to a cross reactivity. The same is true for a disease called Guillain-Barré syndrome which causes paralysis, sometimes affects young people, quite a number of those people have had an infection in their gut from another bacteria then there is a cross-reaction between the pathogen and nerve cells.
Q: Where do people have different susceptibility to these diseases?
RC: Some people get susceptibility because of factors in the environment. Those would be things like the bacteria that I’ve mentioned and sometimes they would be other factors in the environment which would change our proteins to trick our immune system into thinking they were foreign. An example would be sunlight in patients with lupus which can trigger information, and smoking in some people can release proteins in the lungs that the immune system then thinks is foreign and triggers an autoimmune disease. So the environment’s one factor and then there is our inheritance, our genes. There is increasing recognition that our genetic make-up differs widely in terms of our ability to fight infections and that’s probably because natural selection is very strong. Historically, and still in many parts of the world infectious diseases are the major cause of death. Our immune systems have evolved in lots of different ways to fight infections. We’re all very different and some of those mechanisms which we think may enable us to fight infections better can also predispose us to getting autoimmune diseases. In addition to that there are random differences between us that which also probably affect the immune system because it’s very complicated.
Q: Can this research help us design better treatments?
RC: Yes definitely. If you understand the triggers to autoimmune disease then there is no reason why you shouldn’t be able to stop them. Of course you can also identify those people who are susceptible perhaps because of susceptible genes or environmental exposure then you can prevent it. If you can’t step in at an early stage you can still step in later. If you understand the downstream consequences then you can block the autoimmune process and of course the idea is to block it specifically so you prevent the reactivity against yourself but you still preserve that ability to fight foreign pathogens.
Q: What are the most important lines of research that have developed over the past 5 or 10 years?
RC: I think the most important thing must be the human genome project and access to the wealth of genetic information. That allows us to understand individual’s susceptibility, or it is beginning to at any rate. In the last 10 years it’s also allowed us to start to look in a lot more detail at how individual genes work and how the proteins work and that’s allowed us to dissect the pathways in much more detail so that’s the most important thing. Other things that are important are increasing ability to make new therapies, biological agents like the TNF therapy. And to conduct drug screening protocols with small molecules and so on.
Q: Why does your line of research matter, why should why put money into it?
RC: Most of what we’re doing in my lab is very basic research. It’s important because if you want to understand what goes wrong then you have to understand what the normal processes are. That’s important for understanding the flip-side of autoimmunity which is how we generate a good response against pathogens which is in a world-wide sense the most important thing to understand in immunology. It’s important for understanding how to make better vaccines and how to fight off infections and so on. In respect to the autoimmune diseases themselves they’re important because about 2% of the population have those diseases. Many of them are very long-term and quite debilitating. Although it’s only 2%, it figures large in medical practice. Many of them are also diseases that affect young people - like insulin-dependent diabetes, multiple sclerosis. And many of them are diseases of the elderly and also extremely debilitating - rheumatoid arthritis for example, so they’re very important diseases to try to get to grips with.
Q: How does your research fit into translational medicine within the department?RC: A lot of the basic research is identifying pathways that are involved in the immune response. That work is important for our lab but also for lots of the other labs around the department and the division. We also collaborate with lots of people working in genetics and we assist them by identifying the pathways that are defective. I’m also a Clinician; I work in the renal unit. A lot of the diseases I see there are autoimmune diseases and I collaborate with lots of the rheumatologists and other physicians around the hospital; that’s the clinical side of it. Then I have a programme with Professor Simon Davis at the Weatherall Institute. The two of us are trying to develop antibodies which will target the regulatory mechanisms in the immune system to try and turn on those things that would normally dampen down the immune response and control autoimmune diseases; that’s a sort of therapy side of things. It is lab, clinical, then finally trying to develop new treatments: that’s the translational medicine spectrum for me.