OX40L, A New Susceptibility Gene for SLE
The Daily Mail, 3rd December 2007 reported that scientists have pinpointed a key gene behind lupus and we are pleased to have received the following submission on this topic
Professor Timothy Vyse, Dr Deborah Cunninghame Graham and Dr Andrew Wong. Imperial College, Hammersmith Hospital, London, W12 0NN
A note to the people who have donated blood
First of all, let me say a big thank you to all of the readers who have so generously contributed their blood to our study. It would not be possible to find these new genes without you!
Background
When someone gets a cold, the immune system produces proteins which cause inflammation and other proteins called antibodies which help to clear away the virus and any bacterial infection. However, in a lupus patient, things are a bit different. The patient's immune system produces antibodies against part of their own bodies (auto-antibodies) rather than against a virus or bacterial infection, as well as the proteins that cause inflammation. Depending on which part of the body is affected, the patient may have joint pains, kidney problems and skin rashes.
What is OX40L and how does it work?
There are several different types of immune cells which are involved in the production of these auto-antibodies and inflammatory proteins, including T and B cells. These cells do not work in isolation, but communicate with each other using chemical signals, usually when one protein on B cells binds to another protein on T cells. We have been looking at two of these signalling molecules, called OX40 and OX40L. OX40 is found on T cells and OX40L is found on B cells, and a strong message is sent between T cells and B cells after OX40L binds to OX40. This message acts to "rev" up the immune system!
The question that we were trying to answer was whether there were any variations, in the OX40L and OX40 genes which are found more often in lupus patients than in people who do not have lupus and whether these variations affect the amount of OX40 or OX40L that is made.
We chose a series of variants, called single nucleotide polymorphisms (SNPs) in OX40L and OX40. SNPs are differences in the DNA code for that gene, so some people have one DNA code and a few people have a different DNA code. Some of these different codes will increase the risk of getting lupus and others will protect against getting lupus. We are looking for "risk" codes that are more common in SLE patients than in the general population and "protective" codes that are found less frequently. There are also groups of these DNA codes found close together in the gene which will be inherited together. We designed genotyping experiments to look at each sample from our SLE family collection to discover which DNA codes they had for each SNP across the two genes.
Results
We identified a group of "risk" codes, at the start of OX40L (the promoter), which are more common in lupus patients than in the rest of the population and a "protective" group of codes, which were found less frequently. Finding this "risk" group in OX40L was important, because the promoter controls how active that gene is and therefore may determine how much OX40L is made and how strong the signal to the immune system is. We found the same "risk" group of codes in some US SLE families. In genetic studies, it is important to replicate results in different populations, because it means that the results are more likely to be true.
The next thing we discovered was that B cells from individuals with the "risk" codes had 6.7 times more OX40L on the cell surface compared to those samples which carried the "protective" codes. We think that this increased level of OX40L on B cells means that the signal between T cells and B cells will be stronger leading to increased activity of the immune system and increased production of autoantibodies and inflammatory proteins.
Next step
In the next couple of months we will be starting some experiments to try and understand in more detail how these "risk" codes in OX40L cause lupus. Some other exciting news is the publication of genome-wide association study in lupus from the SLEGEN consortium, of which Professor Vyse is a member. This work will provide a valuable source of novel candidate genes some of which may interact with OX40L, as part of a common pathway in causing lupus.
This project needs YOU!
We are very keen to collect more samples for our study, because the more we have, the easier it will be to find new genes. So if you are not currently part of our study and either want to take part yourself, or know someone else who would like to take part, please give our Research Coordinator, Dr. Andrew Wong a call, on 020-8383-2337. We would love to hear from you.
BACK TO INDEX
BACK TO TOP |
