Turning Mutated Protein on and off May Help against Cancer and Autoimmune Disease

New research from the Australian National University (ANU) has found that a protein called DECTIN-1, programmed to protect the body from fungal infections, is also responsible for exacerbating the severity of certain autoimmune diseases. The discovery could pave the way for more effective drugs and may help manage severe autoimmune conditions.

Their findings are published in Science Advances in an article titled, “DECTIN-1: A modifier protein in CTLA-4 haploinsufficiency.”

The scientists found DECTIN-1 in its mutated state limits the production of T regulatory cells. The immune system is designed to protect the body from infection, but in severe cases, it becomes overactivated and turns the body’s natural defenses against itself.

“When this happens, the immune system wrongly perceives healthy cells as a threat, causing it to attack the body and promote the onset of autoimmune disease,” lead author Cynthia Turnbull, PhD, from ANU, said.

“Although the DECTIN-1 protein helps to fight fungal infections, in its mutated state it’s also responsible for exacerbating severe autoimmune disease.

“Understanding how and why the mutated version of this protein causes autoimmunity in patients brings us a step closer to developing more effective drugs and offers new hope to more than one million Australians who suffer from some form of autoimmune disease.”

The scientists believe they can control the immune system by turning the DECTIN-1 protein on and off, like a light switch.

“Turning on the protein would lower the intensity of the immune system’s defensive response which would help to treat conditions such as autoimmune disease,” said Carola Vinuesa, MD, PhD, a professor from the Francis Crick Institute.

“On the other hand, turning off the protein could give the immune system a boost, sending its defensive mechanisms into overdrive and allowing the body to treat an entirely different set of diseases.

“The findings are exciting because there haven’t been many discoveries of so-called modifier proteins such as DECTIN-1, which can change the way the immune system behaves to the extent it can either cause a disease or prevent it.”

According to Turnbull, this means DECTIN-1 could play a key role in treating cancer.

“Cancer cells can disguise themselves by releasing certain proteins and chemicals into the body that essentially render them invisible from the immune system’s natural defenses,” she said.

“We think that by using drugs to turn off the DECTIN-1 protein, in combination with existing therapies, we can activate the immune system and help it identify and attack the cancerous cells.”

By examining the DNA of a Spanish family, the researchers discovered the DECTIN-1 mutation was responsible for exacerbating the severity of a chronic autoimmune disease suffered by the family’s only child.

“We found the family was also carrying a mutated version of another immune system protein known as CTLA-4. The CTLA-4 mutation prevents guardian cells from working properly and is known to cause severe autoimmune disease in about 60 to 70 percent of people who carry it in their DNA,” Pablo Canete, PhD, a research fellow at the University of Queensland, said.

“Strangely, the remaining 30 to 40 percent of the population who carry this mutated protein don’t develop the disease.

“We discovered the family’s only child had both the DECTIN-1 mutation and the CTLA4 mutation, while his parents had only one of each. This helped us identify why the child, who is now in his twenties, was the only person in the family to develop severe autoimmunity, ending a 20-year-long mystery behind the cause of his disease.

“By discovering the existence of mutated versions of modifier proteins such as DECTIN-1, we finally have an explanation for why some people develop severe autoimmune diseases while others don’t, even if they inherit gene mutations passed down from family members.”