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.
Now, 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.
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.
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."
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.
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.
ROS help
pathogen-consuming white blood cells called phagocytes (from the Greek for
"eating") to destroy the invaders they've devoured. If ROS aren't
produced, those pathogens can thrive unchecked, leading to debilitating
complications. As a result, carriers of this CYBB mutation become vulnerable to
not just TB but to a wide variety of infectious diseases.
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.
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."
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."
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."
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