15 February 2018

Science Report:

Unexpected immune activation illustrated in the cold

Het C1-complex in 3D (in kleur) zoals het in de natuurlijke omgeving is gebonden aan de antilichamen, vastgelegd met CryoEM en CryoET

Researchers at Utrecht University and Leiden University Medical Center, the Netherlands, have for the first time made a picture of an important on-switch of our immune system. Their novel technical approach already led to the discovery of not one, but two ways in which the immune system can be activated. This kind of new insights are important for designing better therapies against infections or cancer, according to team leaders Piet Gros and Thom Sharp. Their findings are published on February 16, 2018 in the journal Science.

When invading microbes, viruses and tumours are detected in our bodies, our antibodies engage in an immediate defence strategy. They quickly raise warning signs on these aberrant surfaces that alert our body’s immune system of a security breach. This is the entry cue of several molecules, together called the C1 complex, that stick to the surface of the rogue cell and eliminate it from our body. Until recently, it was unknown how exactly invaders were recognized, and how this C1 complex was activated.

Challenging

Prof. Piet Gros
Prof. Piet Gros, Utrecht University

Studying the C1 complex has been challenging since its components often clump together when taken out of their natural environment into a lab setting. Together with the international biotech company Genmab A/S, researchers from Utrecht University and Leiden University Medical Center have now developed a unique technical approach to studying it in a more natural environment - and discovered more than expected.

Life-like detailed picture

In order to capture the binding and interaction of the complex, Piet Gros, Utrecht University and Thom Sharp, Leiden University Medical Center, combined two imaging techniques, cryo electron microscopy (CryoEM) and cryo electron tomography (CryoET). “These technologies are exploding in the field,” describes Thom Sharp, “and each method gives us different but complementary information on the same complex.” When combined, these methods provide a more life-like detailed picture of the system.

Reconstruction into a 3D representation

Het C1-complex in 3D (in kleur) zoals het in de natuurlijke omgeving is gebonden aan de antilichamen, vastgelegd met CryoEM en CryoET
Combining CryoEM and CryoET lets researchers see the C1 complex in 3D (coloured model) bound to antibodies in a native state (background)

For CryoEM, think of taking thousands of copies of the same convoluted complex and scattering them onto the sticky side of a piece of tape. The camera is in a fixed position and takes pictures of these particles, which may have landed right-side-up, on its side, on a point. CryoET, on the other hand, can image the complex in a more natural environment, as it is bound to the cell surface. It takes images from different angles of the complex, similar to a CT scan, where the particle rotates within the instrument. For both techniques, images are then reconstructed into a 3D representation of the complex.

Very different mechanisms identified

The researchers were surprised to find not one, but two ways in which the immune system can be activated: by physical distortion and by cross-activation. In some cases, the configuration of danger signals on a cell’s surface is sparse, and when antibodies bind, the entire complex must physically adjust or distort itself to properly fit. This adjustment of a single complex can set off an immune response. In other situations, where the danger signals are dense, multiple C1 complexes can help activate each other, like a neighbourhood watch system.

First report

This is the first report of two independent ways by which our immune system can be activated. In addition, the combination of CryoEM and CryoET enabled the visualization of details of these interactions that may enable researchers to create more specific therapeutics that can activate, slow down or stop the cascade of signals within our immune system.

Image

Combining CryoEM and CryoET lets researchers see the C1 complex in 3D (coloured model) bound to antibodies in a native state (background).

Publication

'Structures of C1-IgG1 provide insights into how danger pattern recognition activates complement'
Deniz Ugurlar, Stuart C. Howes, Bart-Jan de Kreuk, Roman I. Koning, Rob N. de Jong, Frank J. Beurskens, Janine Schuurman, Abraham J. Koster, Thomas H. Sharp, Paul W. H. I. Parren, Piet Gros
Science, 16 February 2018, DOI 10.1126/science.aao4988

Life Sciences

This research is part of the interdisciplinary research programme Life Sciences from Utrecht University, and particularly of Science for Life.