How immune cell ‘anti-heroes’ are locked-down

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Antibodies are Y-shaped proteins used by the immune system to defend against foreign invaders such as microbes. Stopping the immune system from attacking the body’s cells, though, is a delicate balancing act.
Credit: Science Picture Co / Getty Images

In the Hollywood blockbuster Suicide Squad, supervillains are kept locked away until they’re needed to stop an army of evil invaders, becoming anti-heroes that save the day. 

Something similar happens in our body every day, except the supervillains are self-reactive antibody-producing immune cells that, when re-educated and let loose, attack the new invaders threatening our health.

Zahra Sabouri and Samuel Perotti from Australian National University and colleagues from Australia and Turkey discovered how these potentially dangerous self-reacting cells are placed on “lockdown” – kept alive but unresponsive until they recognise a foreign pathogen and kick-start a protective immune response.

As these self-reacting immune cells are also seen in blood cancers such as leukaemia and lymphoma, this discovery may help to further understand how these cancers arise.

The work was published in Nature Communications.

Currently, more than five million people worldwide suffer from the autoimmune disorder lupus, where the immune system mistakenly attacks normal, healthy tissues such as small blood vessels in the kidneys, producing inflammation, pain and organ failure.

But our immune system must have developed ways to deal with cells that produce these self-reactive antibodies – otherwise, the number of people suffering autoimmune diseases would be much higher.

The new study shows how a type of antibody called immunoglobulin D (IgD), which hangs off the surface of antibody-producing immune cells called B cells, manages this.

Using mice, Sabouri, Perotti and their crew examined genes activated in locked down B cells, with and without IgD on their surface.

They found 220 genes were specifically activated in these cells, with IgD controlling around a third – boosting expression of some but dialling down others.

Intriguingly, IgD on the surface of self-reacting B cells helped them survive and multiply when locked away in immune tissues called germinal centres.

“We think that the large-scale lockdown of B cells is the immune system’s way of avoiding ‘holes’ in its defensive line, so that it is ready to respond to any conceivable invasion,” study co-author Christopher Goodnow, also at Australian National University, says.

“If every B cell capable of producing autoantibodies was removed, rather than kept in lockdown, we would severely limit the number of foreign invaders that our immune system could recognise.

“By locking down B cells, and keeping them alive, IgD strikes a delicate balance between protection from invaders and avoiding an immune attack on the body’s own tissues.”

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