2024-08-28 18:07:00
Researchers at Rockefeller University have discovered another rare mutation that increases the likelihood that its carriers will develop tuberculosis, but, curiously, not other infectious diseases. This discovery could change everything that has been maintained for a long time about the immune system.
It is known that an acquired deficiency of a pro-inflammatory cytokine called TNF is related to an increased risk of developing cancer. Current research reveals the genetic cause of TNF deficiency, as well as the underlying mechanism: the lack of TNF impairs a specific immune system in the lungs, leading to a severe but surprisingly rare disease.
The findings suggest that TNF, long considered a key galvanizer of the immune response, may have a much more limited effect, a discovery with wide clinical implications.
Over the years, many rare genetic mutations have been identified that make some people more vulnerable to tuberculosis. For example, mutations in a gene called CYBB can suppress an immune system called oxygen burst, which produces chemicals called reactive oxygen species (ROS). Despite its name lungs, the lungs occur in immune cells throughout the body.
ROS help pathogen-receiving white blood cells called phagocytes destroy pathogens they have ingested. If ROS are not generated, these pathogens can proliferate indefinitely, leading to devastating complications. As a result, carriers of this CYBB mutation become vulnerable not only to tuberculosis, but to many infectious diseases.
For the current study, the team suspected that such a genetic error of the vaccine could be found after severe, recurrent tuberculosis infections suffered by two people in Colombia (a 28-year-old woman and her relative his relative 32 years 32) who has been repeatedly hospitalized for serious lung problems. In each stage, they initially responded well to anti-tuberculosis drugs, but within a year they were sick again.
Most surprisingly, however, long-term health records show that their immune systems are functioning normally and that they are otherwise healthy.
To find out why they get tuberculosis, the researchers did a general program on the two, with a genetic analysis of their parents and relatives.
Both are the only members of their extended family with a mutation in the TNF gene, which encodes proteins linked to the regulation of many biological processes. Increased production of TNF (short for “tumor necrosis factor”) is also associated with various conditions, including septic shock, cancer, rheumatoid arthritis, and cachexia, which causes dangerous weight loss.
The protein is largely secreted by a type of phagocyte called a macrophage, which relies on ROS molecules generated by oxygen respiration to kill pathogens that have been ingested. In these two patients, the TNF gene is inactive, preventing oxygen bursts from occurring and therefore the creation of ROS molecules. As a result, the patients’ alveolar macrophages, located in the lungs, were invaded by Mtb.
The discovery also solves a long-standing mystery about why TNF inhibitors, which are used to treat autoimmune and inflammatory diseases, increase the chances of tuberculosis. Without TNF, an important part of the defense against this disease does not work.
The findings may lead to a radical evaluation of TNF’s role in immune function and new treatment possibilities.
The study was recently published in the journal Nature.
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