Linking the Black Death with Crohn’s disease predisposition

Expert

Dr Luis Barreiro, University of Chicago, IL, USA

In a recent study published in the journal Nature, using exhumed corpses from Denmark and the UK, a team of researchers identified genetic variants which helped the immune system fight the 14^th century pandemic known as the Black Death [1]. The drastic and sudden bottleneck in population may be attributable for a positive selection in immune system evolution, which consequently may have had the side effect of increasing susceptibility to autoimmune diseases, including Crohn’s disease. Medicom Medical Publishers spoke with Dr Luis Barreiro, senior author of the paper.

The fourteenth-century bubonic plague pandemic, caused by the bacterium Yersinia pestis, is known as the Black Death. It killed almost half of the population in Europe, the Middle East, and North Africa from 1348 to 1349. This deadly disease has been hypothesised to have selected for genetic variants that protected against infection, and would be more present in the European population after the plague has died out. People with protective variants of certain genes would be more likely to survive and pass on those variants to future generations.

The team of researchers, led by Dr Hendrik Poinar at McMaster University in Canada and Dr Luis Barreiro at the University of Chicago (IL, USA), used ancient DNA samples to search for variants enhanced by the Black Death. The team sampled DNA from the remains of more than 500 people who died before, during, and after the Black Death. Most samples came from three cemeteries in London and from five locations throughout Denmark.

Dr Barreiro explained: “We focused on regions of the genome known to be related to the immune system and immune disorders. We looked for genetic variants that became much more or less common after the Black Death. We found 4 genetic variants to be strong candidates for further investigation. ”

“Of the 4 candidate variants, 1 stood out as being especially protective. Individuals carrying 2 copies of this variant were about 40% more likely to survive the Black Death than those without it. The variant was near the gene called ERAP2. ERAP2 encodes a protein that breaks pathogen proteins into smaller pieces to help the immune system detect infections. Human immune cells with the protective variant produced the full-length, functional protein. Those lacking this variant produced a shortened, non-functional protein. Cells possessing 2 copies of the protective variant produced more functional protein than those with just one copy.”

The team went on to test how the protective variant affected the function of human immune system, in particular the macrophages, using cell culture systems in the lab. They found that macrophages harbouring the protective variant of ERAP2 released an altered cytokine profile which was more effective at fighting infection with Y. pestis.

These results suggest that the Black Death influenced the evolution of the human immune system. “When a pandemic this extreme — killing 30 to 50% of the population — occurs, there is bound to be selection for protective alleles in humans,” Dr Barreiro added. “Even a slight advantage means the difference between surviving or dying. Of course, those survivors who are of reproductive age will pass on their genes. The result is that there is an enrichment for overactive immune genotypes. It follows that overactive immune genotypes will predispose to certain autoimmune conditions ”.

“Accordingly, the protection against plague conferred by ERAP2 variants appears to have come at a cost. The protective ERAP2 variant is a known risk factor for Crohn’s disease [2]. Another protective variant has been associated with an increased risk of two autoimmune diseases. Thus, the Black Death and other past pandemics may have shaped humans’ immune systems in ways both good and bad. While we acquired better protection against infections, we became more susceptible to autoimmune diseases.”

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