Fungus-fighting protein's role in autoimmune disease and cancer

A protein in the immune system programmed to protect the body from fungal infections is also responsible for exacerbating the severity of autoimmune diseases such as irritable bowel disease (IBS), type 1 diabetes, eczema and other chronic disorders, according to research led by The Australian National University (ANU) and published in the journal Science Advances.

The scientists discovered a previously unknown function of the protein, known as DECTIN-1, which in its mutated state limits the production of T regulatory cells or so-called ‘guardian’ cells in the immune system. These guardian cells are crucial to preventing autoimmune disease because they suppress the effects of a hyperactive immune system, which can be extremely dangerous if not properly regulated, as it turns the body’s natural defences 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,” said lead author Dr Cynthia Turnbull, from ANU.

“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,” Turnbull said — potentially without the nasty side effects of existing autoimmune treatments.

The scientists believe they can control the immune system by turning the DECTIN-1 protein on and off, like a light switch. According to Professor Carola Vinuesa, from The Francis Crick Institute, “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.

“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. She explained, “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 defences.

“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.”

Current treatments for autoimmune disease aren’t very effective and have a lot of damaging side effects, because the majority of existing treatments suppress the entire immune system rather than targeting a specific area. Vinuesa explained, “That means it might not fix the exact problem behind the patient’s disease and could inadvertently make them vulnerable to infections. Many people on these kinds of treatments also get bacterial, fungal and viral infections which can make their autoimmunity worse.”

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,” said Dr Pablo Canete, from The University of Queensland (UQ). “The CTLA-4 mutation prevents guardian cells from working properly and is known to cause severe autoimmune disease in about 60–70% of people who carry it in their DNA.

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

“We discovered the family’s only child had both the DECTIN-1 mutation and the CTLA-4 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.”

Image caption: A 3D-printed stencil of the DECTIN-1 protein. Image credit: Tracey Nearmy/ANU.