Tuberculosis is a perplexing disease. It is the largest cause of mortality from infectious disease worldwide, however, it is believed that such deaths account for just around 5 per cent of Mycobacterium tuberculosis (Mtb) infections. Antibiotics can be credited with saving the lives of some Mtb patients, but there is still a gap between the prevalence of infection and the intended severity of its effects. An increasing body of research implies that genetic susceptibility to tuberculosis accounts for the disparity.
Discovery at The Rockefeller University
Researchers at The Rockefeller University have discovered another unusual mutation that makes its carriers far more likely to develop tuberculosis–but not other infectious diseases. This finding, which was recently published in Nature, has the potential to challenge long-held beliefs about the immune system.
Genetic Cause of TNF Deficiency
It’s long been known that an acquired deficiency of a pro-inflammatory cytokine called TNF is linked to an increased risk of developing TB. The current study, led by Rockefeller’s Stephanie Boisson-Dupuis and Jean-Laurent Casanova, revealed a genetic cause of TNF deficiency, as well as the underlying mechanism: a lack of TNF incapacitates a specific immune process in the lungs, leading to severe–but surprisingly targeted–illness.
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Implications for TNF’s Role in Immunity
The findings suggest that TNF, long considered a key galvanizer of the immune response, might actually play a much narrower role–a discovery with far-reaching clinical implications. “The past 40 years of scientific literature have attributed a wide variety of pro-inflammatory functions to TNF,” 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.”
Research Methodology
Casanova’s lab has been studying the genetic causes of TB for more than two decades through field work in several countries and a wide network of collaborating physicians across the world. They maintain an ever-growing database of whole-exome sequences from a global pool of patients–more than 25,000 people to date. Of those, some 2,000 have had TB.
Findings on Specific Genetic Mutations
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.
Study on Colombian Patients
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.
Genetic Analysis and Discovery
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.
Mutation in TNF Gene
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.
Impact on Immune Response
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.
Implications of the Findings
“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.”
Reassessment of TNF’s Role
The discovery also solves a long-standing mystery about why TNF inhibitors, which are used to treat autoimmune and inflammatory diseases, raise the chances of contracting TB. Without TNF, a key part of the defense against it is defunct. The findings may lead to a radical reassessment of TNF’s role in immune function–and new treatment possibilities. “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.”
(Except for the headline, this story has not been edited by Newsx staff and is published from a syndicated feed.)
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