Sydney scientists have solved an important mystery about our immune response, a finding that among other things could be used to help improve the body's reaction to vaccination.

As soon as we are infected with a virus or other microbe, we start generating antibodies. The cells that make antibodies, our B cells, are quickly faced with a choice about the direction they will take in life. Some will take the high road, making high quality antibodies over a period of several weeks. Others will take the low road, churning out low quality antibodies, sacrificing quality for speed.

Until now, no-one has understood what drives B cells to make that choice.

Drs Dominique Gatto and Robert Brink from the Garvan Institute of Medical Research have demonstrated in mice that the presence or absence of a cell surface receptor, EBI2, is the determining factor. Their findings are published online today in the prestigious international journal Immunity, ahead of the 21 August print issue.

"We have billions of B cells in our bodies, each with the ability to make antibodies against different microbes," said project leader Dr Brink. "However, only a very small fraction of B cells are going to be useful against any single infection, as only a few will have antibodies that roughly match it."

"Essentially, a race goes on between the replication of a microbe and the speed at which we can make antibodies. B cells start to proliferate as soon as they can and some start churning out antibody within three or four days."

Early in life all B cells are the same. They lie dormant in our bodies, with an antibody on the cell surface. If the antibody sticks onto an invading molecule, the B cell gets activated and starts to divide, resulting in thousands of clones.

Roughly half of those clones become short-lived 'plasma cells', which change from having copies of the antibody on their surface to making large amounts of secreted antibodies, which disperse through the body, labelling invaders for destruction. While these 'low affinity' antibodies are far from perfect, they can hold many infections at bay.

The other B cell clones migrate to areas known as 'germinal centres', specialised microenvironments where B cells start incorporating random mutations into their antibody genes, trying to create a new antibody that will more exactly match the invader. This process takes time, with thousands of rejects created before a few rare cells are selected to survive. These cells eventually produce the high affinity antibodies that can attack and eliminate invading microbes with great potency.  They also turn into 'memory B cells', that have long lives and provide immunity against a similar infection in the future.

"As B cell biologists, it is very important for us to understand why these cells behave as they do," said Brink. "There was evidence to suggest that when B cells went to germinal centres to make high affinity antibodies, they lost their EBI2 receptor."

"We tested the hypothesis that the receptor was driving the cells one way or another by creating mice without the EBI2 receptor. In those mice, 85% of the B cells went straight to germinal centres, while only 15% turned into plasma cells. In normal mice, it's an even split."

"We further proved the hypothesis with the inverse of the knockout experiment. By injecting normal B cells with an extra copy of the EBI2 gene, the extra gene remained even after B cells had shut down their own copy of EBI2. This made it impossible for B cells to go to the germinal centre, and the mice had a huge plasma cell response."

"We can now see that having this molecule switched on is important for short-term protection. Having it switched off is important for our long-term response."

These findings may be relevant to improving the efficacy of vaccinations. For example, devising strategies that inhibit EBI2 activity in B cells may enhance the long-term antibody responses that are the ultimate aim of vaccination.

ABOUT GARVAN
The Garvan Institute of Medical Research was founded in 1963.  Initially a research department of St Vincent's Hospital in Sydney, it is now one of Australia's largest medical research institutions with nearly 500 scientists, students and support staff. Garvan's main research programs are: Cancer, Diabetes & Obesity, Immunology and Inflammation, Osteoporosis and Bone Biology, and Neuroscience. The Garvan's mission is to make significant contributions to medical science that will change the directions of science and medicine and have major impacts on human health. The outcome of Garvan's discoveries is the development of better methods of diagnosis, treatment, and ultimately, prevention of disease.

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