New TB discovery may change how we treat inflammatory disorders

New Delhi, Oct 16 (IANS) A team of US researchers on Wednesday said they have found a rare mutation that leaves its carriers much more likely to become ill with tuberculosis (TB) — but, curiously, not with other infectious diseases.

The research from The Rockefeller University in the US, published in the journal Nature, may upend long held assumptions about the immune system.

It has long been known that an acquired deficiency of a pro-inflammatory cytokine called TNF is linked to an increased risk of developing TB.

The current study, led by Rockefeller’s Stephanie Boisson-Dupuis and Jean-Laurent Casanova, revealed a genetic cause of TNF deficiency, as well as the underlying mechanism -- a lack of TNF incapacitates a specific immune process in the lungs, leading to severe — but surprisingly targeted — illness.

The findings suggest that TNF, long considered a key galvanizer of the immune response, might actually play a much narrower role—a discovery with far-reaching clinical implications.

“The past 40 years of scientific literature have attributed a wide variety of pro-inflammatory functions to TNF,” says Casanova. “But beyond protecting the lungs against TB, it may have a limited role in inflammation and immunity.”

Over the years, the team has identified several rare genetic mutations that render some people vulnerable to TB.

For example, mutations in a gene called CYBB can disable an immune mechanism called the respiratory burst, which produces chemicals called reactive oxygen species (ROS). Despite its pulmonary-sounding name, the respiratory burst takes place in immune cells throughout the body.

For the current study, the team suspected that a similar inborn error of immunity may lay behind the severe, recurring TB infections experienced by two people in Colombia — a 28-year-old woman and her 32-year-old cousin — who had been repeatedly hospitalised with significant lung conditions. In each cycle, they initially responded well to anti-TB antibiotics, but within a year, they were sick again.

In these two patients, the TNF gene failed to function, preventing the respiratory burst from occurring, and thus the creation of ROS molecules. As a result, the patients’ alveolar macrophages, located in their lungs, were overrun with Mtb (Mycobacterium tuberculosis).

“We knew that the respiratory burst was important for protecting people against various types of mycobacteria, but now we know that TNF is actually regulating the process,” said Boisson-Dupuis.

The discovery also solves a long-standing mystery about why TNF inhibitors, which are used to treat autoimmune and inflammatory diseases, raise the chances of contracting TB.

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