Chain reaction in the human immune system trapped in crystals

A research team from Aarhus University has revealed details of how a chain reaction in the human immune system starts. With these results, the researchers hope to promote the development of strategies aimed at alleviating suffering caused by unintentional activation of the immune system.
The complement system is part of the innate immune system and is composed of about 40 different proteins that work together to defend the body against disease-causing microorganisms. It perceives danger signals in the body by recognising characteristic molecular patterns presented by pathogenic microorganisms or some of our own sick or dying cells that must be eliminated.

The complement system can be found in the blood, but also in the fluid surrounding the cells in tissues. Complement serves as the first line of defence against many pathogenic organisms, and the recognition of danger signals is handled by specialised proteins in the complement system.

For more than 20 years, Professor Steffen Thiel at the Department of Biomedicine, Aarhus University, has been a world leader in studies of MBL and MASP-2, which are two key proteins in the complement system.

When MBL recognises the danger signal, MASP-2 is converted into an active enzyme that can now cleave the protein C4, a third important protein in the complement system. This cleavage is the first step in a chain reaction that ends with the elimination of pathogenic bacteria and dying cells.

A research team led by Associate Professor Gregers R. Andersen at the Department of Molecular Biology and Genetics, Aarhus University, has now – in collaboration with Professor Thiel – succeeded in determining in atomic detail how the active enzyme MASP-2 recognises the substrate C4.

Potential impact on drug development

In many situations, an undesirable activation of the complement system takes place, which can damage our own tissues. Several pharmaceutical companies are currently working on developing drugs that can attenuate such damage.

“The very detailed understanding that we now have concerning parts of the complement system will undoubtedly lead to more intelligent ways of developing new drugs,” says Thiel.

“Of course, we won’t stop our studies here, as we’ll continue the very detailed studies of other proteins and molecular mechanisms within the immune system.”
The new results from Aarhus University have just been published in the journal Proceedings of the National Academy of Sciences (PNAS).

Read the full story on the website of Aarhus University.

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