The research sheds light on why therapies for numerous autoimmune and inflammatory conditions increase the likelihood of developing tuberculosis (TB), while also challenging established beliefs regarding the triggers of immune responses.
Tuberculosis remains a perplexing threat, standing as the foremost cause of death from infectious diseases worldwide. However, it is estimated that around 5% of individuals infected with Mycobacterium tuberculosis (Mtb) actually succumb to the disease. While antibiotics have played a role in saving some lives, a significant gap still exists between the number of infections and the severity of their outcomes. An increasing amount of research indicates that genetic factors may partly explain this discrepancy.
A team from The Rockefeller University has identified another rare genetic mutation that greatly increases the likelihood of developing TB in its carriers, yet intriguingly, they remain unaffected by other infections. This finding, recently published in Nature, might overturn long-standing views concerning the immune system.
It has been known for some time that a deficiency in a pro-inflammatory cytokine known as TNF raises the risk of TB. The current study, led by Stéphanie Boisson-Dupuis and Jean-Laurent Casanova from Rockefeller, uncovered a genetic basis for this TNF deficiency, along with the accompanying mechanism: a shortage of TNF disrupts a specific immune response in the lungs, resulting in severe yet surprisingly focused illnesses.
These results imply that TNF, once deemed essential for stimulating immune responses, may actually have a more limited role, a revelation that holds significant clinical relevance.
“Over the past four decades, scientific research has attributed a wide array of pro-inflammatory functions to TNF,” states Casanova, the head of the St. Giles Laboratory of Human Genetics of Infectious Diseases. “Beyond its role in protecting the lungs against TB, it may not significantly impact inflammation and immunity.”
Rare risk factors
For more than 20 years, Casanova’s laboratory has been investigating the genetic causes of TB through extensive field research and collaboration with physicians worldwide. They maintain an expanding database of whole-exome sequences from over 25,000 patients globally, including around 2,000 individuals who have experienced TB.
They have identified several rare genetic mutations that increase susceptibility to TB. For instance, mutations in the CYBB gene can compromise an immune process known as the respiratory burst, which produces reactive oxygen species (ROS). Despite its respiratory context, the respiratory burst occurs in immune cells throughout the body.
ROS play a crucial role in assisting phagocytes, the pathogen-eating white blood cells, in eliminating the bacteria they engulf. Without ROS, these pathogens can proliferate unchecked, leading to severe health complications. Consequently, individuals with the CYBB mutation become susceptible not only to TB but also to various other infectious diseases.
In the current investigation, the researchers suspected that a similar inherited immune deficiency might be responsible for the severe, recurring TB infections in two Colombian individuals—a 28-year-old woman and her 32-year-old cousin—who had faced multiple hospitalizations due to serious lung issues. Although they initially responded well to anti-TB medications, they fell ill again within a year.
Surprisingly, their extensive health records indicated normal immune system function, and they otherwise appeared healthy.
A significant deficiency
To investigate their heightened susceptibility to TB, the researchers conducted whole-exome sequencing on the two individuals, along with genetic assessments of their familial lineage.
The two were the only ones in their extended family to carry a mutation in the TNF gene, which is crucial for regulating various biological processes. Known as tumor necrosis factor, increased TNF levels are also linked to numerous health conditions, including septic shock, cancer, rheumatoid arthritis, and cachexia, which leads to severe weight loss.
This protein is primarily produced by a type of phagocyte known as a macrophage, which depends on ROS generated by the respiratory burst to dismantle the pathogens it has engulfed.
In these two patients, the TNF gene was nonfunctional, preventing the respiratory burst and the production of ROS. Consequently, their alveolar macrophages in the lungs became overwhelmed with Mtb.
“We previously recognized the respiratory burst as vital for protection against various mycobacterial infections, but now we’ve learned that TNF regulates this process,” notes Boisson-Dupuis. “When TNF is absent in alveolar macrophages, individuals become vulnerable to airborne TB.”
She further remarks, “It’s quite astonishing that these individuals are adults who have remained healthy against other infectious diseases despite repeated exposure. They are uniquely at risk for TB.”
Treatment implications
This revelation also clarifies a longstanding question regarding why TNF inhibitors, used for treating autoimmune and inflammatory diseases, increase the risk of tuberculosis. Without TNF, a crucial aspect of immune defense becomes ineffective.
The outcomes of this study may prompt a significant reevaluation of TNF’s function in the immune system and create new therapeutic opportunities. “TNF is essential for immunity against Mtb, but seems redundant for fighting many other pathogens,” says Casanova. “The real question becomes which other pro-inflammatory cytokines are fulfilling roles previously attributed to TNF? Discovering this could enable us to target these alternative cytokines instead of TNF for treating inflammatory diseases.”
