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Understanding immune system memory -- in a roundabout way

While the principle of immune memory has been known for decades, the exact molecular mechanisms underpinning it have remained a mystery. Australian scientists have now unraveled part of that mystery, identifying the role of a gene called STAT3, which acts as a kind of roundabout, directing chemical messenger molecules to various destinations.

An infection, or a vaccination, 'primes' the immune system, so that when you next encounter the same invader, your body 'remembers' it and quickly makes large amounts of exactly the right antibodies to quash the infection.

Once a cell is primed, traffic on the STAT3 roundabout speeds up enormously, as if the road has been upgraded and the signage much improved.

Primed immune cells, known as 'memory B cells', behave very differently from 'nave B cells', which have never seen infection. Memory B cells act with great speed and efficiency, removing a pathogen so quickly that people frequently remain unaware they have been infected.

Patients with the rare immunodeficiency disorder, Hyper IgE Syndrome, caused by mutations in the STAT3 gene, have a 'functional antibody deficiency'. While you can detect antibodies in their blood, those antibodies are not very good at fighting specific diseases or infections.

Through studying the blood cells of Hyper IgE patients over time, Associate Professor Stuart Tangye, Dr Elissa Deenick and Danielle Avery, from Sydney's Garvan Institute of Medical Research, have gained considerable insight into the STAT3 gene. They recently observed that nave B cells in Hyper IgE patients barely respond to important signaling molecules, whereas their memory B cells behave in the same way as those of healthy people.

The lab members realised that nave B cells need a very strong chemical signal indeed targeting STAT3 to kick-start antibody production. Conversely, memory B cells only need faint signals to generate a huge antibody response. Even STAT3-compromised memory cells from Hyper IgE patients are functional. This breakthrough finding is published in the Journal of Experimental Medicine, now online.

"This study helped explain why patients who have mutations in STAT3 can't generate an effective secondary response to infection," said Associate Professor Tangye.

"STAT 3 directly affects the creation of memory cells, and so while these patients have a few, they are reduced tenfold."

"When people mount a normal primary or secondary immune response, various messenger molecules known as 'cytokines' bind to receptors on the cell surface and activate STAT3."

"Many structurally different cytokines, with complementary roles in antibody production, converge at STAT3 it's literally like a roundabout, showing cytokines which route to take next within the cell."

"This study has shown us that memory cells are much more sensitive to the cytokine signals they receive. They are more robust and efficient, and the magnitude of their response is much greater than that of nave cells."

"B cells fundamentally change their biology between the nave state and the memory state. STAT3 appears to be the key to this molecular rewiring because without it, memory cells cannot form properly."

"These findings explain a lot to me about how immunological memory works, and also throw more light on Hyper IgE Syndrome. They also tell us that if you want to improve antibody responses, there are certain pathways and cell types that can be targeted."

"We can see the future potential to amplify the potency of vaccines, as well as help Hyper IgE patients."


Contact: Alison Heather
Garvan Institute of Medical Research

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