Protein mutation found to cause autoimmune disease

An international team of scientists has identified a rare, mutated version of a protein called TNIP1 that causes a chronic autoimmune disease similar to Sjögren’s syndrome — a condition that leads to extreme dryness of the eyes and mouth that can cause blindness if left untreated. The mutation may also be responsible for more severe autoimmune diseases including lupus, which causes inflammation in organs and joints, skin rashes and fatigue, and can in extreme cases be fatal.

Published in the journal Nature Immunology, the study was conducted by researchers at The Australian National University (ANU), The Francis Crick Institute and Shanghai Jiao Tong University. Lead author Dr Arti Medhavy, who completed the work as part of her PhD at ANU, said this is the first time scientists have shown a variation of the TNIP1 protein is responsible for causing autoimmune disease in humans.

“TNIP1 essentially acts as a gatekeeper of the immune system by removing obsolete proteins and taking them to the cell’s degradation sites where they are broken down, recycled and repurposed,” Medhavy said.

“Importantly, TNIP1’s role in the waste management system includes the removal of damaged or leaky mitochondria, which helps maintain healthy cells.

“But the mutated version of the TNIP1 protein is less efficient at taking these waste proteins and mitochondria to be processed, leading to toxic build-up within cells. If this waste isn’t dealt with, these materials can become detrimental to the cell and trigger the immune system, which ultimately promotes the onset of autoimmune disease.”

The researchers identified the TNIP1 mutation in two unrelated patients — one from Australia and one from China. Despite both having the same TNIP1 mutation, one patient exhibited signs and symptoms of lupus, while the other seemed to display symptoms of Sjögren’s syndrome.

“The TNIP1 mutant protein is similar to the lupus-causing TLR7 mutation in that it affects the same biochemical pathway,” noted study co-author Dr Vicki Athanasopoulos, from ANU.

Using gene-editing technology, the researchers introduced the TNIP1 mutation into mice. They found that mice carrying the mutation developed a condition that mimicked the Sjögren’s disease-like symptoms seen in one of the human patients.

With no cure available for autoimmune disease, Athanasopoulos said there is a need to develop tailored treatments that specifically target the proteins and biochemical pathways that lead to the onset of the disease, rather than suppressing the entire immune system and thus making patients more susceptible to infection.

“There is work already underway by pharmaceutical companies to develop new drugs and tweak existing ones that inhibit the TLR7 pathway,” Athanasopoulos said. The team’s findings could thus lead to new and tailored treatments for Sjögren’s syndrome and lupus that is caused by TNIP1 variants.

Medhavy added that, although both patients with the TNIP1 mutation had slightly different forms of autoimmune disease, they both had abnormally high levels of IgG4 antibodies in their blood.

“The abnormally high presence of IgG4 in both patients is interesting because clinicians might be able to use IgG4 as a biomarker of TNIP1-driven autoimmune disease,” she said.

“By screening patients with autoimmune disease for high levels of igG4, clinicians might be able to test whether patients also possess the TNIP1 mutation, which would indicate that they may respond well to therapies targeting the same TLR7 pathway.”

Image credit: iStock.com/herraez