Researchers uncover the biology and treatment behind a rare
autoinflammatory disease

Date:
August 19, 2021
Source:
The Mount Sinai Hospital / Mount Sinai School of Medicine
Summary:
The absence of a protein that activates the body's antiviral
defenses can cause a rare rheumatoid-like autoinflammatory condition
that is treatable with an FDA-approved class of drugs known as TNF
(tumor necrosis factor) inhibitors, researchers have found.



FULL STORY ==========================================================================
The absence of a protein that activates the body's antiviral defenses can
cause a rare rheumatoid-like autoinflammatory condition that is treatable
with an FDA-approved class of drugs known as TNF (tumor necrosis factor) inhibitors, a global research team led by Mount Sinai has found.


==========================================================================
The condition, which is now termed TBK1 deficiency, was previously known
to scientists but its name, cause and treatment were identified for the
first time in the study published August 6 in Cell.

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.

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 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 important protein involved in controlling inflammation and cell death.

"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," says lead author Justin Taft,
PhD, 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. "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 Mount Sinai-led
team confirmed its 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,"
says Dusan Bogunovic, PhD, Director of the Center for Inborn Errors of Immunity; Associate Professor of Oncological Sciences, Microbiology,
and Pediatrics; member of the Precision Immunology Institute and The
Mindich Child Health and Development Institute; and senior author
of the study. "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 team of researchers underscores
the power of the increasingly vital field of personalized 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," says Dr. Taft. "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."
In addition to Mount Sinai, the collaborative research effort included
Erasmus University Medical Center in the Netherlands, Mayo Clinic,
the National Human Genomic Research Institute, Imperial College London,
SRCC Children's Hospital and Jaslok and Breach Candy Hospitals in Mumbai, India, and Hacettepe University in Ankara, Turkey.

========================================================================== Story Source: Materials provided by The_Mount_Sinai_Hospital_/_Mount_Sinai_School_of Medicine. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Justin Taft, Michael Markson, Diana Legarda, Roosheel Patel,
Mark Chan,
Louise Malle, Ashley Richardson, Conor Gruber, Marta
Marti'n-Ferna'ndez, Grazia M.S. Mancini, Jan A.M. van Laar,
Philomine van Pelt, Sofija Buta, Beatrijs H.A. Wokke, Ira
K.D. Sabli, Vanessa Sancho-Shimizu, Pallavi Pimpale Chavan, Oskar
Schnappauf, Raju Khubchandani, Mu"şerref Kasap Cu"ceoğlu,
Seza O"zen, Daniel L. Kastner, Adrian T. Ting, Ivona Aksentijevich,
Iris H.I. M. Hollink, Dusan Bogunovic. Human TBK1 deficiency leads
to autoinflammation driven by TNF-induced cell death.

Cell, 2021; 184 (17): 4447 DOI: 10.1016/j.cell.2021.07.026 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210819125252.htm

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