Uncovering immunodeficiency genetics

How the immune system works, and the role of our genetic makeup in causing a range of inherited immune diseases including autoimmune conditions, allergy and increased cancer risks, have been revealed by a landmark study from researchers at Cambridge University. The team have read the complete genetic codes of over 1000 patients with these sorts of disorders to link the genes they carry with the diseases they develop. Chris Smith spoke to Ken Smith from the Cambridge Institute of Therapeutic Immunology & Infectious Disease...

Ken - We did this by studying a group of patients with defective immune systems, with conditions called primary immune deficiency. And these patients are susceptible to infections, often very severe infections: about a third develop inflammatory diseases, and about 10%, various sorts of cancer. And this is caused by genetic problems, but in the vast majority of patients with these conditions, the genetic cause is not found. So what we did was to recruit a very large number of these patients from over 27 centres across the UK; we ended up with more than a thousand patients, which is more than a third of patients with this condition in the country. And we sequenced their entire genome rather than the usual approach, which is to sequence just a small proportion of it. By doing that we could then discover new genetic causes.

Chris - I get that you got these patients, you know they have a condition that unites them, and that you read the DNA end to end. But if you read a book from end to end, you wouldn't necessarily know which chapters were the ones playing the role in the story that you're referring to. So how did you link the diseases these people had with what the genetic code was saying?

Ken - What we did was to look for mutations or variants that were present in patients with the disease, but were not present in a large number of healthy people. If a few of these very rare mutations were found in a gene in patients with immune deficiency and were not found in the normal population, that made us very suspicious that that gene was involved in causing immune dysfunction. What we then had to do was go to the laboratory to prove the association of that gene with immunodeficiency. What that did in this study was to allow us to find more than five new genetic causes of immune dysfunction, with many more, I think, still to come from the study.

Chris - Why was this missed before? It's pretty straightforward what you've done, in the sense of reading people's genomes. Why had no one thought to do it the way you did it?

Ken - I think they probably thought to do it, but it's only become affordable recently. Until recently it was impossible to sequence whole genomes at scale, as we've done. But through the national BioResource rare diseases programme, it's become possible to afford to sequence patients. The second thing is the statistical approaches, headed by Ernest Turro and others, that have allowed us to analyse such large numbers of genomes. So it's a technical advance rather than a philosophical one.

Chris - Obviously it's very useful for patients who have one of these conditions, because it means you can give them almost a more precise diagnosis. But is it true that when nature makes a mistake in this way, sometimes some of her other inner workings are revealed? That's kind of the old saying, isn't it. Have you learned more about how the immune system works in a healthy person by studying a less healthy person?

Ken - We have. We've found a number of genetic pathways involved in causing these problems with the immune system, that we have evidence are involved in much more common diseases as well. And by finding that information out, we can study more about the immune system in general. What we've also done for the patients who get the diagnosis is put them in a position to plan their lives better; understand the implications of their disease for their families, which is often not known until they have a genetic diagnosis; and in many cases, to allow specific treatments for the disease that wouldn't have been possible without a diagnosis.