An immunity gene evolved in Southeast Asia to protect against leprosy

May 16, 2017, Cell Press
M. leprae, one of the causative agents of leprosy: As an acid-fast bacterium, M. leprae appears red when a Ziehl-Neelsen stain is used. Credit: Public Domain

A mutation in an immune system gene rapidly rose in frequency in Southeast Asia approximately 50,000 years ago because it likely conferred protection against leprosy, which spread to the region from Africa around the same time. The findings, published May 16th in Cell Reports, show that the gene variant, called HLA-B*46:01, encodes a protein that binds to molecules derived from the bacterium that causes leprosy—a chronic infection of the skin and peripheral nerves. This HLS protein then presents these foreign molecules to the immune system, which destroys the infected cells.

"Our study suggests that HLA-B*46:01 may provide protection against severe leprosy because it is better adapted to present pathogen-derived peptide antigens for immunosurveillance by the immune system," says lead author Hugo Hilton of Stanford University School of Medicine. "The findings may explain why HLA-B*46:01 evolved 50,000 years ago and spread to become one of the most prevalent immunity gene variants in Southeast Asia."

Population expansion, cultural changes, and migration during the last 100,000 years exposed humans to pathogens against which they had not evolved effective resistance. Due to strong selective pressure, human leukocyte antigen (HLA) have evolved to provide immunity against diverse and rapidly evolving pathogens. "New HLA gene variants, or alleles, are thought to arise in human populations during episodes of Darwinian selection, but there is little direct evidence for the nature of this process," says senior study author Peter Parham of Stanford University School of Medicine.

One compelling example of such an episode is the HLA-B*46:01 allele, which is now carried by approximately 110 million individuals of Southeast Asian descent. This HLA-B gene variant formed through genetic recombination between its two parent alleles: HLA-B*15:01 and HLA-C*01:02. "HLA-B*46:01 has since become the most common HLA-B allele in Southeast Asia, suggesting that it fills an immunological niche not afforded by either parent or any other HLA variant found in the region," Hilton says.

In the new study, Hilton and Parham set out to determine why HLA-B*46:01 rapidly rose in frequency in Southeast Asia over a relatively short period. To do so, the researchers used high-resolution mass spectrometry to compare the peptide sequences presented by the HLA-B*46:01 protein with those presented by its parent alleles. They found that HLA-B*46:01 binds a small, distinct, and less diverse set of peptides compared with its most closely related parent, suggesting that the HLA molecule is specialized to protect against one or a small number of closely related pathogens. Moreover, 21% of HLA-B*46:01 peptides strongly bind to a natural killer cell receptor called KIR2DL3, allowing the HLA molecule to trigger an effective immune response.

Using an algorithm that predicts binding affinities of HLA molecules to peptides, the researchers found that HLA-B*46:01 is predicted to bind a significantly higher number of peptides derived from Mycobacterium leprae—the pathogen that causes leprosy—compared with its most closely related parent. But surprisingly, HLA-B*46:01 is predicted to bind equal or lower numbers of derived from Salmonella Enteritidis, HIV-1, or H1N1-influenza as compared to its parents.

The new findings are consistent with epidemiological studies showing that HLA-B*46:01 carriers are protected against a severe, life-threatening form of leprosy but are more susceptible to other infectious diseases, such as malaria, HIV, and SARS coronavirus. Moreover, this predisposes individuals to autoimmune disorders such as myasthenia gravis and Grave's disease, in addition to a rare type of head and neck cancer.

"Taken together, these observations support the notion that HLA-B*46:01 poses an immunological trade-off between protection against leprosy and protection against other diseases," Hilton says. "This suggests that the selective pressure exerted by in Southeast Asia must have been a stronger force over the past tens of thousands of years compared with the collective fitness detriment imposed by many other serious diseases in the region."

Explore further: Immune suppressant ineffective in treating leprosy inflammation

More information: Cell Reports, Hilton et al.: "The Intergenic Recombinant HLA-B*46:01 Has a Distinctive Peptidome that Includes KIR2DL3 Ligands" http://www.cell.com/cell-reports/fulltext/S2211-1247(17)30570-3 , DOI: 10.1016/j.celrep.2017.04.059

Related Stories

Immune suppressant ineffective in treating leprosy inflammation

March 30, 2017
Throughout the course of a leprosy infection, patients often have episodes of painful inflammation affecting their skin and nerves. Researchers have continuously struggled with finding effective drugs to treat these so-called ...

New vaccine shows promise as stronger weapon against both tuberculosis and leprosy

August 19, 2014
In many parts of the world, leprosy and tuberculosis live side-by-side. Worldwide there are approximately 233,000 new cases of leprosy per year, with nearly all of them occurring where tuberculosis is endemic.

'Immune Camouflage' may explain H7N9 influenza vaccine failure

September 25, 2015
The avian influenza A (H7N9) virus has been a major concern since the first outbreak in China in 2013. Due to its high rate of lethality and pandemic potential, H7N9 vaccine development has become a priority for public health ...

Leprosy strain genotyped from medieval pilgrim at UK burial site

January 26, 2017
Leprosy is a bacterial infection caused by Mycobacterium leprae or Mycobacterium lepromatosis. It has afflicted humans for thousands of years, reaching epidemic levels during the Middle Ages, and people continue to be affected ...

Recommended for you

New blood test to detect liver damage in under an hour

May 24, 2018
A quick and robust blood test that can detect liver damage before symptoms appear has been designed and verified using clinical samples by a team from UCL and University of Massachusetts.

Gut bacteria play key role in anti-seizure effects of ketogenic diet

May 24, 2018
UCLA scientists have identified specific gut bacteria that play an essential role in the anti-seizure effects of the high-fat, low-carbohydrate ketogenic diet. The study, published today in the journal Cell, is the first ...

Selective neural connections can be reestablished in retina after injury, study finds

May 24, 2018
The brain's ability to form new neural connections, called neuroplasticity, is crucial to recovery from some types of brain injury, but this process is hard to study and remains poorly understood. A new study of neural circuit ...

Space-like gravity weakens biochemical signals in muscle formation

May 23, 2018
Astronauts go through many physiological changes during their time in spaceflight, including lower muscle mass and slower muscle development. Similar symptoms can occur in the muscles of people on Earth's surface, too. In ...

Eating at night, sleeping by day swiftly alters key blood proteins

May 21, 2018
Staying awake all night and sleeping all day for just a few days can disrupt levels and time of day patterns of more than 100 proteins in the blood, including those that influence blood sugar, energy metabolism, and immune ...

Hotter bodies fight infections and tumours better—researchers show how

May 21, 2018
The hotter our body temperature, the more our bodies speed up a key defence system that fights against tumours, wounds or infections, new research by a multidisciplinary team of mathematicians and biologists from the Universities ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.