Nav: Home

An immunity gene evolved in Southeast Asia to protect against leprosy

May 16, 2017

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 (@Hilton_HG) 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) genes 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 peptides 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 gene variant 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 leprosy 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."
-end-
Major funding for this work was provided by the National Institutes of Health.

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

Cell Reports (@CellReports), published by Cell Press, is a weekly open-access journal that publishes high-quality papers across the entire life sciences spectrum. The journal features reports, articles, and resources that provide new biological insights, are thought-provoking, and/or are examples of cutting-edge research. Visit: http://www.cell.com/cell-reports. To receive Cell Press media alerts, contact press@cell.com.

Cell Press

Related Immune System Articles:

Using the immune system as a defence against cancer
Research published today in the British Journal of Cancer has found that a naturally occurring molecule and a component of the immune system that can successfully target and kill cancer cells, can also encourage immunity against cancer resurgence.
First impressions go a long way in the immune system
An algorithm that predicts the immune response to a pathogen could lead to early diagnosis for such diseases as tuberculosis
Filming how our immune system kill bacteria
To kill bacteria in the blood, our immune system relies on nanomachines that can open deadly holes in their targets.
Putting the break on our immune system's response
Researchers have discovered how a tiny molecule known as miR-132 acts as a 'handbrake' on our immune system -- helping us fight infection.
Decoding the human immune system
For the first time ever, researchers are comprehensively sequencing the human immune system, which is billions of times larger than the human genome.
Masterswitch discovered in body's immune system
Scientists have discovered a critical part of the body's immune system with potentially major implications for the treatment of some of the most devastating diseases affecting humans.
How a fungus can cripple the immune system
An international research team led by Professor Oliver Werz of Friedrich Schiller University, Jena, has now discovered how the fungus knocks out the immune defenses, enabling a potentially fatal fungal infection to develop.
How the immune system protects us against bowel cancer
Researchers from Charité - Universitätsmedizin Berlin have discovered a protective mechanism which is used by the body to protect intestinal stem cells from turning cancerous.
How herpesviruses shape the immune system
DZIF scientists at the Helmholtz Zentrum München have developed an analytic method that can very precisely detect viral infections using immune responses.
The immune system's fountain of youth
Helping the immune system clear away old cells in aging mice helped restore youthful characteristics.
More Immune System News and Immune System Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Rethinking Anger
Anger is universal and complex: it can be quiet, festering, justified, vengeful, and destructive. This hour, TED speakers explore the many sides of anger, why we need it, and who's allowed to feel it. Guests include psychologists Ryan Martin and Russell Kolts, writer Soraya Chemaly, former talk radio host Lisa Fritsch, and business professor Dan Moshavi.
Now Playing: Science for the People

#538 Nobels and Astrophysics
This week we start with this year's physics Nobel Prize awarded to Jim Peebles, Michel Mayor, and Didier Queloz and finish with a discussion of the Nobel Prizes as a way to award and highlight important science. Are they still relevant? When science breakthroughs are built on the backs of hundreds -- and sometimes thousands -- of people's hard work, how do you pick just three to highlight? Join host Rachelle Saunders and astrophysicist, author, and science communicator Ethan Siegel for their chat about astrophysics and Nobel Prizes.