The secret role of epigenetics in antibody production

Scientists from the UK’s Babraham Institute have discovered a set of epigenetic marks and proteins that behave like genetic switches, controlling which genes contribute to making antibodies. Published in the journal Frontiers in Immunology, their research explains how inappropriate use of these control switches may weaken our body’s defences against illness and could even contribute to leukaemia.

The immune system can fight almost any infection by creating customised antibodies, each of which is made by combining a few genes from a large selection of possible components in a process called V(D)J recombination. Like building blocks, each combination of genes creates a unique antibody. Some of these genetic building blocks are much more likely to be used by the immune system than others, though it is not clear why.

By combining genes in many different ways, the immune system creates antibodies with the precision needed to identify and fight any possible infection. However, some people have genetic conditions that mean their immune system cannot produce a large enough variety of antibodies, so they are less able to fight diseases. The immune system also weakens as we age. In both cases, changes to the newly discovered control mechanism could be partly responsible for these weaknesses.

“Our bodies are able to produce millions of different antibodies from just a few genes using V(D)J recombination, so it’s an incredibly complex system,” said Dr Louise Matheson, first author on the study. “We wanted to understand how this process is controlled as well as which epigenetic marks and proteins are involved. By understanding these systems we can learn how to better control the immune system and how to help it fight infections.”

Antibodies are made using several clusters of genes, called loci. The researchers focused on just one locus in mice, known as immunoglobulin kappa. In mice and humans, the kappa locus contains around 140 genes for making parts of an antibody. By using a method called VDJ-seq, a type of DNA sequencing, the researchers showed that the most commonly used antibody genes are labelled with specific histone methylations, a type of epigenetic mark. The team also found a link between the most active genes and two proteins called PU.1 and IKAROS.

“We have discovered some of the key factors that switch on the genes that make antibodies,” said research leader Dr Anne Corcoran. “This is a valuable insight into how the immune system protects our bodies, and what may be at fault when the immune system is weakened. This will ultimately help us to design diagnostic tests for people affected by recurrent infections and to devise therapies to boost the body’s response to infection.”

The team suggests that loss of the epigenetic marks and proteins highlighted by the study could contribute to weakening of the immune system in old age and in some genetic conditions. If their future research can prove this, it could lead to new treatments to strengthen the immune system and help more of us to stay healthy for longer into old age.

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