Study shows how WAVE2 protein maintains the immune system balance

Sinai Health researchers have reported that they have uncovered a new mechanism that regulates harmful overreactions in the body’s immune system, such as the deadly types of hyper-inflammation.

Study senior author, Dr. Kathy Siminovitch, senior investigator at the Lunenfeld-Tanenbaum Research Institute (LTRI) and Canada Research Chair in the Mechanisms Regulating Immunologic Disease, is seen here in this undated file photo. Image Credit: Sinai Health.

Researchers from the Lunenfeld-Tanenbaum Research Institute (LTRI) have described how a protein, called WAVE2 and expressed in all immune cells, plays a vital role in regulating the immune system balance. The study results were recently published in the Science journal.

As part of the analysis, the researchers turned off, or knocked out, the WAVE2 protein in a subset of immune cells in mice, which resulted in extreme inflammation and autoimmunity, and also an inability to mount an immune reaction to a viral infection.

According to Dr. Kathy Siminovitch, the senior author of the study, the team has also discovered that another protein, called mTOR, becomes excessively active in the absence of the WAVE2 protein, throwing the immune system into overdrive and causing the exhaustion of immune cells.

Much like Goldilocks, a proper immune response requires such a delicate balance. You have to get it just right. By developing a mouse strain in which T cells, key players in immunity, lack WAVE2, we have shown that this protein is absolutely required for balanced immune responses.”

Dr Kathy Siminovitch, Canada Research Chair, Mechanisms Regulating Immunologic Disease, Lunenfeld-Tanenbaum Research Institute

Dr Siminovitch is also the senior investigator of that study from the Lunenfeld-Tanenbaum Research Institute.

A major concern for medical experts is how to keep the immune system from going into overdrive, as they continue to deal with the devastating impacts of the COVID-19 pandemic, especially in the aged population.

Individuals over the age of 65 are more likely to experience severe COVID-19, partly because of a condition known as “cytokine storm” in which the immune system overreacts and impairs organs.

The pandemic has starkly illuminated the critical importance of immune balance and the severe consequences of disrupting such balance. It has also highlighted the importance of fundamental research, which has taken us where we are today in understanding the virus and having treatment and prevention strategies in hand.”

Dr Kathy Siminovitch, Canada Research Chair, Mechanisms Regulating Immunologic Disease, Lunenfeld-Tanenbaum Research Institute

Dr. Siminovitch has spent many years studying the molecular and genetic pathways that control and sustain the immune system balance. In a previous study, she helped in tracing the intricate molecular steps that convert a rare gene mutation into Wiskott-Aldrich syndrome, which affects boys’ immune systems and can lead to death at a younger age.

According to Dr. Siminovitch, they would like to broaden their research work to investigate how the WAVE2-mTOR pathway may play a role in certain inflammatory, autoimmune, and other conditions, like Alzheimer’s disease.

Understanding how to achieve this kind of control in immunity is really important. This research opens the door to new ways of restoring that balance through the development of new therapeutics that target the WAVE2- mTOR pathway.”

Dr Kathy Siminovitch, Canada Research Chair, Mechanisms Regulating Immunologic Disease, Lunenfeld-Tanenbaum Research Institute