Study Uncovers How TNF Deficiency Increases Tuberculosis Risk

Researchers have discovered how a protein produced by immune cells, known as tumor necrosis factor (TNF), which is commonly used in treating autoimmune and inflammatory diseases, increases the risk of tuberculosis (TB). TB, caused by ‘Mycobacterium tuberculosis’ (Mtb), is the leading cause of death from infectious diseases globally, though it affects only about 5% of those infected. Traditionally, a deficiency in TNF was known to raise TB risk, but new research published in Nature challenges earlier beliefs about the immune system’s role.

The study, led by Jean-Laurent Casanova from Rockefeller University, reveals that TNF is crucial for protecting the lungs against TB by maintaining specific immune processes. A lack of TNF, however, debilitates this defense mechanism, leading to severe illness. This was highlighted through the cases of two individuals in Colombia, a 28-year-old woman and her 32-year-old cousin, who suffered from recurrent TB despite initially responding to antibiotics. Genetic analysis showed they were the only family members with a TNF gene mutation that impaired TNF function, resulting in Mtb overwhelming their lung macrophages.

The findings clarify why TNF inhibitors, used for treating autoimmune diseases, increase TB susceptibility: without TNF, a critical component of the immune defense against TB is compromised.