Revealed: cause and treatment for rare autoinflammatory disease

A global research team, led by the Icahn School of Medicine at Mount Sinai, has discovered that the absence of a protein that activates the body’s antiviral defences can cause a rare, rheumatoid-like autoinflammatory condition, which is treatable with an FDA-approved class of drugs known as TNF (tumour necrosis factor) inhibitors.

The scientists reported that the absence of the protein, known as TBK1 (TANK-binding kinase 1), renders cells vulnerable to a jarring form of programmed cell death in response to TNF, but that this genetic defect can be effectively and quickly addressed by therapeutic agents that block the source of the inflammation. The condition, which is now termed TBK1 deficiency, was previously known to scientists but its name, cause and treatment have now been identified for the first time in the journal Cell.

Homozygous mutations in TBK1, which occur when copies of the aberrant gene encoding the protein are passed on by both parents, are extremely rare. Based on past studies in mouse models and human cell cultures, researchers assumed that these mutations would leave individuals susceptible to a wide range of viral infections. They found instead that none of the four people in the cohort they studied, ages seven to 32, showed signs of inadequate antiviral immunity. Rather, they all suffered from a systemic autoinflammatory condition that resulted from a dysregulated response to TNF, an important protein involved in controlling inflammation and cell death.

“TBK1 signalling activates the body’s antiviral mechanisms to fight off infection and block different stages of viral replication, as well as control TNF-mediated inflammation,” said Mount Sinai’s Dr Justin Taft, lead author of the study. “But if a mutation prevents expression of the TBK1 gene or disrupts its function, then cells become overly sensitive to TNF. And that can trigger a disproportionate amount of cell death, which sets off a violent cascade of debris from dying cells that inflames surrounding tissue and fuels the inflammation.”

By treating TBK1-deficient individuals with anti-TNF therapeutics, the research team confirmed their suspicions about the underlying biology of the genetically driven condition.

“We have essentially defined a new disease and its associated mechanisms of autoinflammation, which previously were managed with steroid treatments, non-steroidal anti-inflammatory drugs or other non-specific therapeutics clinicians deemed worth trying,” said senior author Dr Dusan Bogunovic, also from Mount Sinai. “We were able to target the condition directly and effectively with TNF inhibitors once we knew the causative factors of the inflammation. And the clinical improvement was quick and substantial.”

For Dr Taft, the work of the global research team underscores the power of the increasingly vital field of personalised medicine.

“We started with four individuals who were known to have a homozygous TBK1 mutation, and did extensive lab work to determine how the defect could induce this autoinflammatory reaction,” he said. “And from the genetics we uncovered not only a plausible mechanism of the disease and new information around TBK1 biology, but identified a disease-specific treatment that significantly improves the autoinflammatory condition.”

Image credit: ©stock.adobe.com/au/Gorodenkoff

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