Rare autoinflammatory disease: Scientists uncovered its biology and treatment

Scientists were able to target the condition directly and effectively with TNF inhibitors.


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Autoinflammatory syndrome, formerly known as periodic fever syndrome, is a heterogeneous and ever-increasing group of rare inflammatory disorders that manifest with recurrent fevers and/or inflammatory episodes. The condition is caused by the absence of a protein called TBK1 (TANK-binding kinase 1) that activates the body’s antiviral defenses.

A new study by Mount Sinai has found that this autoinflammatory condition can be treated with an FDA-approved class of drugs known as TNF (tumor necrosis factor) inhibitors.

Scientists dubbed this condition TBK1 deficiency. Scientists already knew about the condition, but the biology and treatment behind this remain elusive. Scientists from Mount Sinai Health System, in this study, have identified the cause and treatment for the first time.

The protein called TBK1 renders cells vulnerable to a jarring form of programmed cell death in response to TNF. Scientists found that this genetic effect can be effectively and quickly addressed by therapeutic agents that block the source of the inflammation.

Homozygous mutations in TBK1, which occur when both parents pass on copies of the aberrant gene encoding the protein, are sporadic. Scientists assumed that these mutations would leave individuals susceptible to a wide range of viral infections based on past studies in mouse models and human cell cultures.

Instead, they found that none of the four people in the cohort they studied, ages 7 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 essential protein involved in controlling inflammation and cell death.

Lead author Justin Taft, Ph.D., an investigator in the Department of Microbiology, the Precision Immunology Institute, and the Center for Inborn Errors of Immunity at the Icahn School of Medicine at Mount Sinai, said, “TBK1 signaling activates the body’s antiviral mechanisms to fight off infection and block different stages of viral replication, as well as control TNF-mediated inflammation. But if a mutation prevents the expression of the TBK1 gene or disrupts its function, 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 inflame surrounding tissue and fuels the inflammation.”

Scientists treated TBK1-deficient individuals with anti-TNF therapeutics. They confirmed their suspicions about the underlying biology of the genetically driven condition.

Dusan Bogunovic, Ph.D., Director of the Center for Inborn Errors of Immunity, said, “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.”

“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.”

Dr. Taft said“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. 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.”

Journal Reference:
  1. Justin Taft et al., Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death, Cell (2021). DOI: 10.1016/j.cell.2021.07.026


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