New Genetic Mutation Uncovered Linked to Tuberculosis Risk

Researchers at The Rockefeller University have uncovered a groundbreaking genetic mutation that significantly increases susceptibility to tuberculosis (TB), but not to other infectious diseases.

This pivotal finding, recently published in Nature, challenges longstanding views on immune system function and the role of tumor necrosis factor (TNF) in disease resistance.

Historically, an acquired deficiency in TNF, a key pro-inflammatory cytokine, has been associated with a heightened risk of TB. The latest study, led by Stephanie Boisson-Dupuis and Jean-Laurent Casanova from Rockefeller University, has pinpointed a genetic cause for this deficiency and its specific impact on TB vulnerability.

The study reveals that a genetic mutation impairs TNF production, leading to a critical breakdown in a specific immune process in the lungs. This impairment leaves individuals highly susceptible to severe TB while leaving them relatively unaffected by other infections. This discovery provides new insight into the precise role of TNF, previously believed to be broadly involved in inflammation and immunity.

"The past 40 years of scientific literature have attributed various pro-inflammatory functions to TNF," explains Casanova, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases. "However, our findings suggest that TNF's role may be more specialized, primarily focused on protecting the lungs against TB."

The researchers' investigation began with two individuals from Colombia who experienced severe, recurring TB infections despite having otherwise normal immune systems. Genetic analysis revealed a mutation in the TNF gene that disrupted its function and, consequently, the respiratory burst mechanism essential for fighting TB.

This mechanism, involving the production of reactive oxygen species (ROS) by immune cells, was found to be defective in these patients, allowing Mycobacterium tuberculosis (Mtb) to proliferate unchecked in their lungs.

The discovery also sheds light on why TNF inhibitors, commonly used to treat autoimmune conditions, increase the risk of TB. Without TNF, a crucial line of defense against TB is compromised.

This research opens the door to re-evaluating TNF's role in immune defense and exploring alternative treatment options. "If TNF is less critical for immunity against other pathogens, identifying other pro-inflammatory cytokines involved in these processes could lead to new therapeutic approaches," Casanova adds.

The study, drawing on a global database of genetic sequences from over 25,000 individuals, continues to highlight the importance of genetic factors in disease susceptibility and immune function.

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