Bad antibodies made good: The immune system's secret weapon uncovered

[Indigophoton]

In a world first, scientists from Sydney's Garvan Institute of Medical Research have revealed how a population of 'bad' antibodies in the immune system - which are usually 'silenced' because they can harm the body - can provide crucial protection against invading microbes. The research was carried out in mice.

The 'bad' antibodies are known to react against the body's own tissues and can cause autoimmune disease. For this reason, it was once thought that they were discarded by the immune system or that they were made inactive in the long term. However, the new findings show for the first time that 'bad' antibodies go through a rapid 'redemption' process and are activated when the body is faced with a disease threat that other antibodies cannot tackle.

As a result, the 'redeemed' antibodies no longer threaten the body, but instead become powerful weapons to fight disease - and particularly diseases that evade the immune system by disguising themselves to look like normal body tissue.

Professor Chris Goodnow, who co-led the new research with A/Prof Daniel Christ (both Immunology Division, Garvan), says the new findings will fundamentally change thinking about how the immune system protects us.

"We once thought that harmful antibodies were discarded by the body - like a few bad apples in the barrel - and no one had any idea that you could start with a 'bad' antibody and make it good.

Carrying out the immune system's toughest task

The new research appears to solve an enduring mystery that has puzzled scientists for decades: How does the immune system attack invading microbes that look almost identical to the body's own molecules, without mounting an attack on the body at the same time?...

To understand how the immune system recognises these 'wolves in sheep's clothing', scientists from the Garvan Institute zeroed in on a mysterious army of immune cells in the bloodstream.

'Bad' antibodies are hiding inside silenced B cells

The silenced cell army contains millions of immune cells known as B cells - which produce antibodies to fight diseases. Unlike other B cells, though, the cells of this army pose a danger to the body. This is because they can make 'bad' antibodies, which can attack 'self' and cause autoimmune disease. For this reason, they are kept in a long-term silenced state (known as anergy).

Professor Chris Goodnow discovered the silenced cells 30 years ago - and has been working to understand their function ever since.

Towards better vaccines

Our findings indicate that theres a whole class of B cells out there - the silenced B cells - that might be accessible for vaccine development, and that we have so far largely ignored, A/Prof Christ says.

Dr Burnett adds, "We're hoping that, instead of ignoring this population of silenced B cells, researchers will in the future consider targeting these cells when they're developing vaccines, particularly against targets such as HIV, which disguise themselves as 'self'."

The article, https://medicalxpress.com/news/2018-04-bad-antibodies-good-immune-secret.amp

The paper, http://science.sciencemag.org/content/360/6385/223

Abstract
Antibodies have the specificity to differentiate foreign antigens that mimic self antigens, but it remains unclear how such specificity is acquired. In a mouse model, we generated B cells displaying an antibody that cross-reacts with two related protein antigens expressed on self versus foreign cells. B cell anergy was imposed by self antigen but reversed upon challenge with high-density foreign antigen, leading to germinal center recruitment and antibody gene hypermutation. Single-cell analysis detected rapid selection for mutations that decrease self affinity and slower selection for epistatic mutations that specifically increase foreign affinity. Crystal structures revealed that these mutations exploited subtle topological differences to achieve 5000-fold preferential binding to foreign over self epitopes. Resolution of antigenic mimicry drove the optimal affinity maturation trajectory, highlighting the value of retaining self-reactive clones as substrates for protective antibody responses.