Restricting unwanted immune reactions

June 7, 2018, University of Münster
Binding model: The S100A8/S100A9 protein complex (grey/beige) binds to the TLR4 receptor (rainbow-coloured) and MD2 (red) and triggers immune reactions in cells. Blocking this interaction is a new therapeutic approach. Credit: Vogl et al./ J. Clin. Invest.

The immune system often initiates its response to pathogens by activating immune cells, so-called phagocytes, which migrate to sites of inflammation. There, the phagocytes release certain proteins, including the S100A8/S100A9 heterodimeric protein complex, which triggers or amplifies the inflammatory reaction at the site of the disease. However, if too many of these complexes are released, they can exacerbate the disease; for example, this happens in the case of autoimmune, rheumatic or dermatological diseases. Researchers at the Cells-in-Motion (CiM) Cluster of Excellence at the University of Münster (Germany) have now decoded how the activity of these proteins is regulated. The leading scientists of the study, immunologists Thomas Vogl and Johannes Roth, now want to use these novel fundamental insights to develop new treatment options to combat autoimmune diseases, arthritis, allergies or inflammatory diseases of the bowel, lungs or cardiovascular system. The study was published in the Journal of Clinical Investigation.

Many scientific publications have already described the tasks of the two proteins S100A8 and S100A9. But so far, it has not been clear to researchers whether these two proteins act alone or in conjunction with each other. The Münster researchers have now been able to show that the proteins always work as a heterodimeric complex composed of both S100A8 and S100A9. As soon as it is released, the heterodimer complex binds to a TLR4-expressing cell, triggering a suitable immune response via this receptor. Importantly, the S100A8/S100A9 heterodimer complex only has a short lifetime during which to spark this initial impulse. If it does not find a suitable target cell for activation, two individual heterodimers associate to form a heterotetramer; in this form, each heterodimer complex is inactive. This mechanism guarantees that the body will only trigger an where needed—in other words, the remains localized.

The researchers also showed that if this regulation is disturbed such that not all of the excess S100A8/S100A9 heterodimer complexes can form tetramers, the result is exacerbation of : "Too many heterodimers remain active, trigger a strong immune response, and act systemically in the entire body," explains Prof. Thomas Vogl, the lead author of the study. This is a process that is behind blood poisoning, for example—but it is also relevant for many autoimmune diseases, rheumatoid arthritis, allergies, and even cardiovascular diseases.

These findings by the Münster immunologists may lead to new approaches for treating many inflammatory diseases. Currently, new drugs are already being used to block the TLR4 receptor signaling pathway to inhibit misguided immune responses. However, one problem is that sometimes, the body has to combat bacteria at the same time. As the immune system is blocked, the TLR4 receptor can no longer fulfill this important function.

"This is why we're searching for antibodies which specifically only block the S100-TLR4 axis, while the receptor is untouched, respectively free on the bacterial side," says Thomas Vogl. "These antibodies should specifically block only the active heterodimers and weaken the immune only locally, at the site of inflammation. The TLR4 receptor, which is important for immune defense, remains untouched and can trigger the suitable immune response in the case of any bacterial danger." Drugs developed according to this new approach to treat conditions like autoinflammatory disorders would therefore have fewer side effects for patients than currently existing pharmaceuticals.

The next step for the researchers is to work with companies to find suitable antibodies and develop pharmaceuticals for treating diseases accompanied by overwhelming immune reactions. It will take years, however, before drugs are available to deactivate excess S100A8/S100A9 in the human body and thus prevent unwanted immune reactions.

Explore further: Igniting the rheumatoid arthritis flame through a cellular cascade

More information: Thomas Vogl et al, Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation, Journal of Clinical Investigation (2018). DOI: 10.1172/JCI89867

Related Stories

Igniting the rheumatoid arthritis flame through a cellular cascade

May 30, 2018
Chronic inflammatory disorders, including autoimmune diseases such as rheumatoid arthritis, involve the action of various inflammatory molecules (cytokines) produced by cells of the immune system. One such cytokine, IL-17, ...

New research reveals how cat dander triggers allergic responses

July 25, 2013
New research reveals how the most common cause of severe allergic reactions to cats, the Fel d 1 protein which is found in cat dander, triggers an allergic response.

Searching for targeted treatments for inflammatory diseases

February 6, 2018
Inflammatory diseases such as Crohn's disease and multiple sclerosis have been linked to faults in a critical immune pathway that enables inflammation to continue unchecked.

Novel role for spleen B cells in inflammatory response to bacterial toxins

May 9, 2016
The inability to adequately respond to infection can cause a whole-body state of inflammation known as sepsis. This can eventually lead to systemic inflammatory response syndrome (SIRS), and even death. White blood cells ...

Researchers discover the unexpected role of platelets in immune response

February 1, 2018
Platelets play a much more important role in our immune system than previously thought, according to a study published by researchers from Université Laval and Centre hospitalier universitaire (CHU) de Québec Research Centre. ...

Recommended for you

New study shows how gut immune cells are kept in control

June 22, 2018
Every day, the human gut works on a fine-tuned balance that ensures the retention of essential nutrients while preventing infection by potential armful microbes. Contributing to this surveillance system is a specialised group ...

Human immune 'trigger' map paves way for better treatments

June 21, 2018
A discovery about how human cells are 'triggered' to undergo an inflammatory type of cell death could have implications for treating cancer, stroke and tissue injury, and immune disorders.

Our intestinal microbiome influences metabolism—through the immune system

June 21, 2018
Research tells us that the commensal or "good" bacteria that inhabit our intestines help to regulate our metabolism. A new study in fruit flies, published June 21 in Cell Metabolism, shows one surprising way they do this.

Fetal T cells are first responders to infection in adults

June 20, 2018
Cornell University researchers have discovered there is a division of labor among immune cells that fight invading pathogens in the body.

How a thieving transcription factor dominates the genome

June 20, 2018
One powerful DNA-binding protein, the transcription factor PU.1, steals away other transcription factors and recruits them for its own purposes, effectively dominating gene regulation in developing immune cells, according ...

Severe stress may send immune system into overdrive

June 19, 2018
(HealthDay)—Trauma or intense stress may up your odds of developing an autoimmune disease, a new study suggests.

0 comments

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.