Immunity to the Black Death came at a cost to modern health.

A genetic variant that increases the risk of Crohn's disease may have helped people survive the bubonic plague.

Researchers looked for evidence of how the Black Death pushed the immune system to evolve by using DNA from the excavated remains of plague victims, including those buried in a London cemetery from 1348-1349, as well as people who died earlier and later.  MUSEUM OF LONDON ARCHAEOLOGY COURTESY
Researchers looked for evidence of how the Black Death pushed the immune system to evolve by using DNA from the excavated remains of plague victims, including those buried in a London cemetery from 1348-1349, as well as people who died earlier and later. MUSEUM OF LONDON ARCHAEOLOGY COURTESY


A genetic variant that appears to have boosted medieval Europeans' ability to survive the Black Death centuries ago may have contributed – albeit in a minor way – to an inflammatory disease that people are currently suffering from.


Researchers used DNA from centuries-old remains to decipher the imprints that bubonic plague left on European immune systems during the Black Death. Researchers report in Nature on October 19 that this devastating wave of disease tended to spare those who possessed a variant of a gene known as ERAP2, causing it to become more common. Scientists already know that that variant increases the risk of developing Crohn's disease, a condition in which erroneous inflammation harms the digestive system.

According to Mihai Netea, an infectious diseases specialist at Radboud University Medical Center in Nijmegen, Netherlands, who was not involved in the study, the findings show "how these studies on ancient DNA can actually help actually understand diseases even now." "And the trade-off is also obvious."


Bubonic plague, caused by the bacterium Yersinia pestis, once killed 60% of those infected (SN: 6/15/22). It caused successive waves of misery in the ancient world, the most devastating of which was the Black Death, often dated from 1346 to 1350, an episode thought to have wiped out at least 25 million people — roughly a third or more of Europe's population.


Pathogens such as Y. pestis have shaped the evolution of the human immune system by sparing individuals whose immune systems exhibit certain characteristics. Studies are being conducted to determine how the massive eradication of the plague altered Europeans' immune-related genetics.


In this most recent study, population geneticist Luis Barreiro of the University of Chicago and colleagues collected DNA samples from the remains of 516 people who died between 1000 and 1800 in London and Denmark, including those buried during the Black Death. 

The researchers looked for immune-related genes and areas associated with autoimmune and inflammatory diseases in stretches of DNA.

DNA samples were collected from burial sites in London, including the East Smithfield plague pits (shown here), and Denmark. ARCHAEOLOGY MUSEUM OF LONDON
DNA samples were collected from burial sites in London, including the East Smithfield plague pits (shown here), and Denmark. ARCHAEOLOGY MUSEUM OF LONDON


Within those regions, the researchers discovered four chromosomal locations with strong evidence of genetic changes that appeared to be caused by the Black Death. In subsequent research, one change stood out: an increase in the frequency of an ERAP2 variant. 

When infected with Y. pestis, immune cells from people with this version of ERAP2 killed the bacteria more effectively than cells without the variant. That same variant has been linked to Crohn's disease in studies of modern populations.  

While the researchers estimate that the ERAP2 variant increased the likelihood of surviving the Black Death by up to 40%, it only slightly increases the risk of Crohn's disease. "You probably need hundreds, if not thousands, of genetic variants to actually increase your risk in a significant way," Barreiro says of complex disorders like Crohn's.  

For a long time, researchers in the field have hypothesized that adaptations that helped our forefathers fortify their immune systems against infectious diseases can contribute to excessive, harmful immune activity. Previous plague research lends credence to this theory. 

A genetic analysis looking for traces of historical disease in modern Europeans, as well as a study of DNA from the remains of 16th-century German plague victims, both revealed what appear to be protective changes against the plague, which, like the ERAP2 variant, are linked to inflammatory and autoimmune conditions.  

Similarly, this latest discovery suggests that genetic changes that have previously boosted the human immune response, allowing it to better fight off ancient infections, can come at a cost. "If you turn the heat up too high, it causes disease," Barreiro says. CITATIONS J. Klunk et al. Immune gene evolution is linked to the Black Death. doi: 10.1038/s41586-022-05349-x. Published online October 19, 2022.

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