Whole-exome sequencing identified a frameshift variant in the TNF gene common to both patients, suggesting a genetic cause for their TB.

These findings raise questions about the traditional understanding of TNF's importance in immunity, particularly its link to tuberculosis susceptibility.

The research clarifies why TNF inhibitors, commonly used to treat autoimmune diseases, increase the risk of TB by compromising the immune defense against it.

Ultimately, the study suggests a reevaluation of TNF's role in immunity, which could lead to new treatment strategies focusing on other cytokines responsible for immune responses.

With around 25% of the global population infected with Mtb, genetic factors significantly influence the likelihood of developing TB, as only 5-10% of those infected will actually become ill.

A recent study published in Nature reveals that the immune-signaling protein TNF is critical for inflammatory responses in humans and plays a narrower role in immunity than previously thought.

Led by researchers Stépahnie Boisson-Dupuis and Jean-Laurent Casanova, the study emphasizes the genetic basis of recurrent TB linked to TNF deficiency, highlighting how genetic mutations affect immune responses and disease susceptibility.

Genetic analysis revealed that both patients had a mutation in the TNF gene, which is crucial for regulating immune responses and inflammation.

The absence of functional TNF led to an inability to produce reactive oxygen species (ROS), allowing Mycobacterium tuberculosis (Mtb) to proliferate unchecked in the patients' lungs.

This impaired ROS production in macrophages is critical for controlling Mtb, underscoring the importance of TNF signaling in macrophage function.

Tuberculosis (TB) remains the leading cause of death from infectious diseases worldwide, with only about 5% of infections resulting in death.

The research focused on two patients from a consanguineous Colombian family who experienced severe, recurring TB infections despite having otherwise normal immune systems.