A genetic variation that may have increased medieval Europeans' resistance to the Black Death centuries ago may have had a minor, but a significant, role in modern inflammatory diseases. Researchers were able to identify the imprints that the bubonic plague during the Black Death left on Europeans' immune systems using DNA taken from centuries-old remains. Researchers reported on October 19 in Nature that this deadly wave of disease tended to spare those who had a variant of a gene known as ERAP2, making it more common. Scientists already know that variant slightly increases the risk of developing Crohn's disease, a condition in which the digestive system is harmed by errant inflammation. Since Mihai Netea, a specialist in infectious diseases at Radboud University Medical Center in Nijmegen, the Netherlands, was not involved with the study, the findings demonstrate how ancient DNA studies can aid in the understanding of diseases. Additionally, the trade-off is crystal clear. Yersinia pestis, which causes the plague, once caused 60 percent of those infected to die. The Black Death, which is frequently dated from 1346 to 1350 and is thought to have killed at least 25 million people—more than a third of the population of Europe—was the most devastating of the waves of misery it brought upon the ancient world. Pathogens like Y. pestis have influenced the evolution of the human immune system by sparing people whose immune systems display particular traits. Researchers are trying to determine how the widespread winnowing of the plague changed the immune-related genetics of Europeans. Luis Barreiro, a population geneticist at the University of Chicago, and his team took DNA samples from the corpses of 516 people who died between 1000 and 1800 in London and Denmark, including those who were buried during the Black Death. The researchers looked at DNA stretches for immune-related genes and regions linked to autoimmune and inflammatory diseases. Four places on chromosomes within those regions showed convincing evidence of genetic changes that appeared to have been sparked by the Black Death, according to the researchers. One change was noticeable in the follow-up work: an increase in the frequency of an ERAP2 variant. Immune cells from Y. pestis-infected individuals with this variant of ERAP2 killed the bacteria more efficiently than immune cells lacking the variant. That particular variant has been linked to Crohn's disease in studies of contemporary populations. Even though the researchers estimate that the ERAP2 variant increases one's chances of surviving the Black Death by as much as 40%, Barreiro claimed that it only slightly raises the risk of developing Crohn's disease. The number of genetic variants needed to significantly increase your risk for complex diseases like Crohn's is probably in the hundreds or even thousands. For some time, theorists in the field have held that adaptations that strengthened our ancestors' immune systems against infectious diseases may also be responsible for the overactive, harmful immune activity. This idea is supported by earlier research on the plague. The ERAP2 variant and other changes that appear to be protective against the plague have been linked to inflammatory and autoimmune diseases, according to genetic studies that looked for signs of historical disease in contemporary Europeans. Similar to previous genetic changes that boosted the human immune system in the past, enabling it to more effectively fight off ancient infections, Barreiro said that this most recent discovery suggests that these genetic changes can be costly. When the heat is turned up too high, illness results.