Unexpected immune activation illustrated in the cold

February 19, 2018 by Science Report, Utrecht University Faculty of Science
Combining CryoEM and CryoET lets researchers see the C1 complex in 3D (coloured model) bound to antibodies in a native state (background) Credit: Thom Sharp/Leiden University Medical Center

Researchers at Utrecht University and Leiden University Medical Center, the Netherlands, have imaged an important immune system on-switch. Their novel technical approach has led to the discovery of two ways in which the immune system can be activated. This is important for designing better therapies for infections or cancer, according to team leaders Piet Gros and Thom Sharp. Their findings are published in Science.

When the immune system detects invading microbes, viruses and tumours, antibodies engage in an immediate defence strategy, alerting the body's immune system of a security breach. This is the entry cue for several molecules, together called the C1 complex, that stick to the surface of the rogue cell and eliminate it. Until recently, it was not known exactly how invaders were recognized, or how this C1 complex was activated.

Studying the C1 complex is 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.

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, (CryoEM) and cryo electron tomography (CryoET). "These technologies are exploding in the field," says Thom Sharp. "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.

CryoEM basically entails scattering thousands of copies of the same convoluted complex 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 in any orientation. 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, the images are then reconstructed into a 3-D representation of the complex.

The researchers were surprised to find 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 fit properly. 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.

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

Explore further: Researchers discover new approach to stimulate an immune response against tumor cells

More information: 'Structures of C1-IgG1 provide insights into how danger pattern recognition activates complement' Science, 16 February 2018, DOI: 10.1126/science.aao4988

Related Stories

Researchers discover new approach to stimulate an immune response against tumor cells

January 30, 2018
New drugs that activate the immune system to target cancer cells have improved the lives of many patients with cancer. However, immunotherapies are not effective in all patients, and the success of these therapies depends ...

Modulating immune responses

December 13, 2017
The protein Roquin plays a key role in the regulation of immune reactions. LMU researchers have now uncovered details of the mechanism by which it controls the function of regulatory T cells in the adaptive arm of the immune ...

Study unveils T cell signaling process central to immune response

May 16, 2017
The immune system cells known as T cells play a central role in the body's ability to fight infections and cancer. For decades, however, details of the molecular signaling process that leads to T cell activation have remained ...

Thorough analysis reveals immune system dynamics after immunotherapy

August 29, 2017
By combining new system-biological analyses and advanced data analysis, researchers at Karolinska Institutet have been able to monitor the maturation process of the immune system of leukaemia patients who have undergone stem ...

Clustering for health

August 15, 2017
When functioning appropriately, the immune system protects against multiple threats such as pathogens, disease-causing microbes, and tumors. However, when the immune system is inappropriately activated, it attacks the body, ...

Recommended for you

Obesity and health problems: New research on a safeguard mechanism

March 16, 2018
Obesity and its negative impacts on health - including metabolic syndrome, type-2 diabetes mellitus and cardiovascular complications - are a global pandemic (Taubes, 2009). The worldwide incidence of obesity has more than ...

Immune system 'double agent' could be new ally in cancer fight

March 16, 2018
St. Jude Children's Research Hospital scientists have discovered that an enzyme called TAK1 functions like a "double agent" in the innate immune response, serving as an unexpected regulator of inflammation and cell death. ...

Artificial sweetener Splenda could intensify symptoms in those with Crohn's disease

March 15, 2018
In a study that has implications for humans with inflammatory diseases, researchers from Case Western Reserve University School of Medicine and colleagues have found that, given over a six-week period, the artificial sweetener ...

Researchers identify common biological features of different types of asthma

March 14, 2018
A team of researchers from the NIHR Leicester Biomedical Research Centre - a partnership between Leicester's Hospitals, the University of Leicester and Loughborough University - has identified biological variations in lung ...

Scientists discover treatment target for sepsis

March 14, 2018
In a study published in Nature Communications, Northwestern Medicine scientists demonstrated the key role a molecule called oxPAPC plays in regulating the inflammatory response—findings which could inform the development ...

Researcher creates 'Instagram' of immune system, blending science, technology

March 10, 2018
Being on the cutting edge of science and technology excites Hollings Cancer Center (HCC) researcher Carsten Krieg, Ph.D. Each day, he walks into his lab that houses a mass cytometry machine aptly labeled Helios. Krieg explains ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.