New Tuberculosis Breakthrough Could Revolutionize Treatment of Inflammatory Disorders

New Delhi: A team of US researchers has identified a rare genetic mutation that significantly increases the risk of tuberculosis (TB) in its carriers, but does not make them more susceptible to other infectious diseases. This groundbreaking discovery, published in the journal Nature by scientists from The Rockefeller University, challenges long-standing beliefs about the immune system’s role in fighting infections.

The study, led by Stephanie Boisson-Dupuis and Jean-Laurent Casanova, highlights a genetic deficiency linked to a lack of the pro-inflammatory cytokine TNF (tumor necrosis factor), a key molecule in immune responses. It has been previously established that acquired TNF deficiencies increase the risk of TB, but this research uncovered a genetic cause for this deficiency, and the precise mechanism by which it impacts the body. The lack of TNF disrupts a specific immune process in the lungs, resulting in severe TB but with little effect on other infections.

According to Casanova, this finding challenges the long-held belief that TNF is crucial for a broad range of immune functions. "For the past 40 years, TNF has been thought to perform a wide variety of pro-inflammatory roles," he explained. "But beyond protecting the lungs from TB, it appears to have a much more limited function in inflammation and immunity."

The research offers fresh insights into how the immune system operates, with potential clinical implications for treating TB and understanding inflammatory disorders. Over the years, Casanova’s team has discovered several rare mutations that make individuals more vulnerable to TB. One such mutation, affecting the CYBB gene, disrupts the immune system’s respiratory burst—a process that generates reactive oxygen species (ROS) in immune cells, which are crucial for combating infections, including TB.

In their latest study, Boisson-Dupuis and Casanova focused on two patients from Colombia, a 28-year-old woman and her 32-year-old cousin, who both experienced recurring, severe TB lung infections. Despite responding initially to anti-TB antibiotics, both patients fell ill again within a year of treatment. Genetic analysis revealed that the TNF gene in these patients was not functioning, preventing the respiratory burst from taking place, which in turn halted the production of ROS molecules. As a result, the patients' alveolar macrophages in the lungs became overwhelmed by Mycobacterium tuberculosis (Mtb), the bacterium responsible for TB.

Boisson-Dupuis emphasized that while the respiratory burst has been known to protect against various mycobacteria, this research confirms that TNF plays a crucial regulatory role in this immune process. The discovery also resolves a long-standing puzzle about why TNF inhibitors, used to treat autoimmune and inflammatory diseases, increase the risk of TB. By inhibiting TNF, these drugs inadvertently disrupt the body's ability to fight TB, making individuals more susceptible to the disease.