Engineering: Scientists discover trigger behind body’s immune response

Immunologists have uncovered one of the molecular mechanisms which alerts the body to a new infection.

Proteins known as toll-like receptors have earned themselves the nickname of ‘immune system guard dogs’, sniffing out bacteria and viruses.

Once these pathogens have been detected, the toll-like receptors sound the alarm and activate the body’s immune system for an attack on the invaders.

Research led by Brown University immunologist Wen-Ming Chu has uncovered one of the molecular mechanisms alerting toll-like receptors – high-mobility group box 1 protein (HMGB1), a protein released when infection occurs, when cells are damaged or when tissue is injured.

Because of their ability to trigger an immune response, toll-like receptors have recently attracted the interest of pharmaceutical companies.

One of the proteins in this class, toll-like receptor 9 (TLR9), can pick up a very specific scent – a snippet of DNA common in bacteria and viruses.

The idea for drug makers is to create DNA-based drugs containing these snippets, called CpG DNA. The drugs would get the guard dogs barking, which, in turn, would prompt a fast immune response.

This would cause the body to attack cancerous tumours or, if used as an ingredient in vaccines, bolster the assault on infectious diseases such as hepatitis B and C. CpG DNA could even be used to treat immune system disorders such as asthma and allergies.

Understanding the body's alert system

In order to develop such drugs, researchers need to know what it is that alerts toll-like receptors to infection.

Chu and his team found a direct interaction between HMGB1, the protein released during infection, and TLR9.

When the invader’s DNA is present, researchers found that TLR9 merges with HMGB1. The combination occurs inside tiny cellular cargo boxes, known as endoplasmic reticulum-Golgi intermediate compartments (ERGIC).

In these boxes, the proteins bind to form a complex. Formation of this complex sets off a biochemical cascade that triggers the body’s immune response.

Researchers found that when HMGB1 is absent from cells, the body’s immune response is significantly delayed.

"We found out that HMGB1 acts an accelerator, quickly activating the body’s defences," Chu said.

"What’s exciting is that drug makers might be able to use this knowledge to treat disease. CpG DNA and HMGB1 could be used together in a vaccine."

Results of the research were published in the June issue of the journal Blood then highlighted in the July issue of Nature Reviews Immunology.

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