A recent study has revealed how a protein produced by immune cells, commonly used in treatments for autoimmune and inflammatory diseases, increases the risk of tuberculosis (TB). While TB remains the leading cause of death from infectious diseases globally, only 5% of people infected with Mycobacterium tuberculosis (Mtb) — the bacteria responsible for TB — actually die from it. Mtb primarily affects the lungs and is spread through the air.
The Role of TNF in TB
Scientists have long known that a deficiency in a protein called “tumour necrosis factor” (TNF) can elevate the risk of developing TB. However, new research has challenged previous beliefs about the immune system. Published in the journal *Nature*, the study reveals that a lack of TNF hinders a crucial immune process in the lungs, leading to severe TB infections.
Jean-Laurent Casanova from Rockefeller University in the US explained that TNF plays a protective role in the lungs against TB. However, he noted that otherwise, it has “a limited role in inflammation and immunity.”
The Study of Recurring TB Infections
The research focused on two individuals in Colombia — a 28-year-old woman and her 32-year-old cousin — who experienced recurring TB infections. Both patients were frequently hospitalized with severe lung conditions. Although they initially responded well to anti-TB antibiotics, they fell ill again within a year, despite their immune systems functioning normally.
Genetic Analysis and Key Findings
To understand why these patients kept getting TB, researchers conducted whole-exome sequencing and a genetic analysis of their parents and relatives. The analysis revealed that the two patients were the only members of their extended family with a mutation in the TNF gene, which caused the protein to fail to function properly.
As a result, the patients’ alveolar macrophages, immune cells located in the lungs, were overwhelmed with Mtb. The researchers concluded that the absence of TNF in these cells makes people more vulnerable to airborne TB.
This discovery answers a long-standing question about why TNF inhibitors, used to treat autoimmune and inflammatory diseases, increase the risk of TB. Without TNF, a critical part of the body’s defense against TB is compromised, leading to higher susceptibility to the disease.
