New TB Findings Could Transform Inflammatory Disorder Treatment

The disease known as tuberculosis (TB) is perplexing. Although it is the world’s most common cause of infectious disease-related mortality, only around 5% of tuberculosis infections are thought to be caused by it (Mtb). Some people with MTB can thank antibiotics for saving their lives, but there is still a gap between the actual severity of the virus and its prevalence. This gap is particularly significant when considering Inflammatory Disorder Treatment, as understanding the underlying mechanisms of TB could lead to breakthroughs in treating these disorders. A rising amount of data points to genetic susceptibilities to tuberculosis as the cause of that disparity.

The Rockefeller University researchers have now discovered a second unusual mutation that significantly increases the risk of tuberculosis infection among carriers—but oddly, not for other infectious diseases. This discovery, which was just published in Nature, might challenge long-held beliefs about the immune system.

It has long been established that a heightened risk of tuberculosis (TB) is associated with an acquired deficit of TNF, a pro-inflammatory cytokine. Led by Stéphanie Boisson-Dupuis and Jean-Laurent Casanova of Rockefeller, the present study identified a hereditary etiology for TNF deficiency and its underlying mechanism: a shortage in TNF impairs a particular immunological function in the lungs, resulting in a severe but surprisingly focused sickness.

The results imply that TNF, which has long been thought to be a crucial immune response stimulant, may really have a considerably smaller function. This finding has significant therapeutic ramifications.

“A wide range of pro-inflammatory functions have been attributed to TNF in the past 40 years of scientific literature,” says Casanova, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases. “But beyond protecting the lungs against TB, it may have a limited role in inflammation and immunity.”

Uncommon Risk
For over twenty years, Casanova’s team has worked with a global network of cooperating clinicians to conduct fieldwork in multiple countries while investigating the genetic underpinnings of tuberculosis. They have amassed more than 25,000 whole-exome sequencing from patients worldwide in an ever-expanding database. About 2,000 of them have had tuberculosis.

Numerous uncommon genetic variants that make some persons susceptible to tuberculosis have been found over the years. For instance, changes in the CYBB gene can prevent the respiratory burst, an immunological mechanism that releases molecules known as reactive oxygen species (ROS). The respiratory burst occurs in immune cells across the body, despite its name suggesting the lungs.

ROS assist phagocytes—the Greek word for “eating”—white blood cells that consume pathogens and aid in their destruction of the intruders they have consumed. In the absence of ROS, such pathogens may proliferate unchecked and cause crippling consequences. Carriers of this CYBB mutation are therefore susceptible to a wide range of infectious diseases in addition to tuberculosis.

For the current investigation, the researchers hypothesized that two individuals in Colombia—a 28-year-old lady and her 32-year-old cousin—who had been hospitalized multiple times with serious lung diseases would have had severe, recurrent TB infections due to a similar inborn defect of immunity. They responded well to anti-TB medications at first in each cycle, but a year later they fell ill again.

Strangely enough, their long-term medical records revealed that they were otherwise in good condition and that their immune systems were operating regularly.

A glaring shortcoming
Together with whole-exome sequencing on the two, the researchers also analyzed the parents’ and relatives’ genetic makeup to determine why they were more susceptible to tuberculosis.

The TNF gene, which codes for proteins involved in the control of numerous biological processes, was mutated in the two individuals, making them the sole members of their extended family affected. TNF, which stands for “tumor necrosis factor,” is also linked to a number of diseases and disorders, such as cancer, rheumatoid arthritis, septic shock, and cachexia, which is dangerously low weight loss.

The majority of the protein is secreted by macrophages, a kind of phagocyte that uses the reactive oxygen species (ROS) produced by the respiratory burst to eliminate infections that it has eaten.

Because the TNF gene was dysfunctional in these two patients, there was no respiratory burst and no production of ROS molecules. The patients’ lungs’ alveolar macrophages became infected with Mtb as a result.

“We knew that the respiratory burst was important for protecting people against various types of mycobacteria, but now we know that TNF is actually regulating the process,” says Boisson-Dupuis. “And when it’s missing in alveolar macrophages, people will be susceptible to airborne TB.”

She adds, “It’s very surprising that the people we studied are adults who have never been sick with other infectious diseases, despite being repeatedly exposed to their microbes. They are apparently selectively at risk for TB.”

Potential for treatment
The finding also provides an explanation for the long-standing enigma of why TNF inhibitors, which are prescribed to treat inflammatory and autoimmune disorders, increase the risk of tuberculosis. One of the main lines of defense against it is rendered useless without TNF.

The results might force a thorough reevaluation of TNF’s involvement in immune response, opening up new avenues for treatment.

“TNF is required for immunity against Mtb, but it seems to be redundant for immunity against many other pathogens,” Casanova says. “So the question is, what other pro-inflammatory cytokines are doing the jobs we thought TNF was doing? If we can discover that, we may be able to block these cytokines rather than TNF to treat diseases where inflammation plays a role.”

For more information: Tuberculosis in otherwise healthy adults with inherited TNF deficiency, Nature, https://dx.doi.org/10.1038/s41586-024-07866-3