Implications for Inflammatory Disease Management
The disease tuberculosis is complicated. Though it is thought to only contribute for around 5% of Mycobacterium tuberculosis infections, it is the leading cause of infectious disease-related mortality worldwide. Some Mtb patients have been given the gift of life by antibiotics, yet there is still a discrepancy between the actual severity of the infection and its frequency.
There is growing evidence that the difference can be attributed to a hereditary predisposition to tuberculosis. Currently, a different uncommon mutation that increases the carrier's risk of developing tuberculosis but not other infectious diseases has been found by researchers at The Rockefeller University. Recent publication of this discovery in Nature raises the possibility of challenging long-held notions on the immune system
Over the years they've identified several rare genetic mutations that render some people vulnerable to TB. For example, mutations in a gene called CYBB can disable an immune mechanism called the respiratory burst, which produces chemicals called reactive oxygen species (ROS). Despite its pulmonary-sounding name, the respiratory burst takes place in immune cells throughout the body.
For the current study, the team suspected that a similar inborn error of immunity may lay behind the severe, recurring TB infections experienced by two people in Colombia--a 28-year-old woman and her 32-year-old cousin--who had been repeatedly hospitalized with significant lung conditions. In each cycle, they initially responded well to anti-TB antibiotics, but within a year, they were sick again.
Puzzlingly, however, their long-term health records showed that their immune systems functioned normally, and that they were otherwise healthy.
To find out why they were particularly prone to getting TB, the researchers performed whole-exome sequencing on the two, as well as a genetic analysis of their respective parents and relatives.
The two were the only members of their extended family with a mutation in the TNF gene, which encodes for proteins linked to the regulation of a variety of biological processes. Short for "tumor necrosis factor", increased TNF production is also associated with a variety of conditions, including septic shock, cancer, rheumatoid arthritis, and cachexia, which causes dangerous weight loss.
Key Highlights:
1) Identification of a rare mutation in the TNF gene that significantly increases the risk of developing tuberculosis without affecting susceptibility to other infectious diseases.
2) The tumor necrosis factor is crucial for the respiratory burst mechanism in macrophages, which generates reactive oxygen species necessary for combating Mycobacterium tuberculosis.
3) The implications of these findings are profound for both TB treatment and the management of inflammatory diseases.
The protein is largely secreted by a type of phagocyte called a macrophage, which relies on the ROS molecules generated by the respiratory burst to finish off pathogens they've consumed.
In these two patients, the TNF gene failed to function, preventing the respiratory burst from occurring, and thus the creation of ROS molecules. As a result, the patients' alveolar macrophages, located in their lungs, were overrun with Mtb.
"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."
The finding also provides an explanation for the long-standing question 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 re evaluation 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."
Input from: ANI