TNIP1 gene mutation tied to Sjögren’s-like autoimmune disease: Study
Blocking TLR7 signaling could reverse these effects, a mouse study shows
A mutation in the TNIP1 gene resulted in a chronic autoimmune disease for two people, one of whom had symptoms similar to Sjögren’s disease, a study shows.
The other patient had symptoms of systemic lupus erythematosus (SLE), another type of autoimmune disease.
Experiments in mice with the mutation, which also developed Sjögren’s-like symptoms, revealed that blocking TLR7 signaling could reverse these damaging effects, making it a good therapeutic approach for people with TNIP1-associated autoimmunity.
“Our study established a causative role for TNIP1 variants in human autoimmunity,” wrote the researchers, who noted that identifying TNIP1-associated disease in people with apparent autoimmunity, “would pave the way for pathway-targeted treatments such as TLR7 … inhibitors.”
The study, “A TNIP1-driven systemic autoimmune disorder with elevated IgG4,” was published in Nature Immunology.
Autoimmune diseases arise when the immune system launches an attack against healthy tissue. In Sjögren’s disease, these attacks affect the moisture-producing glands, leading to dry eyes and mouth, along with other symptoms. SLE can affect virtually any organ and often leads to kidney problems.
Treatments for autoimmune conditions often seek to broadly suppress the immune system, but this can leave people immunocompromised and at risk of contracting serious infections or illnesses. More specific treatments that target underlying disease pathways are needed.
Effects of TNIP1 gene mutation
TNIP1, encoded by the TNIP1 gene, is a protein involved in the body’s waste management system, getting rid of unneeded proteins or other cellular components.
“Proteins are critical to our growth, development, and overall health, but they have a shelf life,” Arti Medhavy, PhD, the study’s first author, said in a university press release. Medhavy completed the work during her graduate studies at The Australian National University, and is now a researcher at Griffith University.
When proteins are no longer needed, they’re deactivated with the help of TNIP1, Medhavy said. The protein is also involved in removing damaged mitochondria, the organelle responsible for producing cellular energy.
“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.
If that waste removal process is disrupted, cellular debris can accumulate and send the immune system into overdrive, triggering autoimmune disease.
Here, the researchers identified the same TNIP1 mutation, called Q333P, in two unrelated people with autoimmune diseases, making it the first time the gene has been associated with autoimmunity in people.
One patient, an 8-year-old girl from Australia, had some symptoms resembling Sjögren’s disease, including dry eyes and mouth, called sicca, mouth ulcers, fatigue, and joint pain. The other patient, a 47-year-old woman from China, had symptoms more like SLE, including arthritis, proteins in the urine, which is a sign of kidney problems, and elevations in a range of autoimmunity-associated antibodies.
While their disease presentations differed, both had abnormally high levels of an antibody called IgG4 in their bloodstream.
Exploring TNIP1 mutation in mice
To learn more about the mutation, the researchers engineered it into mice, who then developed a disease that looked similar to Sjögren’s, with the presence of autoimmunity-associated antibodies, salivary gland inflammation, and immune cell alterations.
Genetic mutations in the gene encoding the TLR7 immune signaling protein are known to cause lupus. Interestingly, TLR7 and TNIP1 are involved in a shared signaling pathway. This autoimmune presentation was dependent on TLR7 signaling and blocking this pathway eased the disease, experiments indicated.
The Q333P mutation leads to autoimmunity by increasing TLR7 signaling, in turn impairing protein and mitochondria waste removal processes, the evidence suggested.
It’s possible then that TNIP1-mediated disease might be responsive to approaches that target TLR7. Scientists are already working on developing TLR7-targeted medications for treating lupus. A way to identify patients with TNIP1-related disease who may be responsive to this approach could be to measure IgG4 in the bloodstream.
“Clinicians might be able to use IgG4 as a biomarker of TNIP1-driven autoimmune disease,” Medhavy 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.”
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