A fascinating article in Nature finds positive selection for several alleles that protected against Yersinia pestis during the plague of 1346-1350 in Europe; they also increase the risk of autoimmune disease. Klunk, J., et al. (2022). Evolution of immune genes is associated with the Black Death. Nature, 611(7935), 312–319.

The staggering selection pressures of infectious disease is underscored by the 30-50% death rate of the bubonic plague waves wreaking havoc in Afro-Eurasia in 1346-1350.

How strong, then, is the actual evidence that these recurrent epidemics have shaped our current genetics, and might that affect our current risks for chronic inflammatory diseases? Linking signatures of natural selection with the individual causative pathogens is notoriously difficult.

A heroic study published in Nature (October 19th, 2022) by Klunk et al. combines genetic sequencing of 206 human skeletal remains from two countries during and after the Black Death episode, with state of the art functional immunological wet-lab experiments.

The study yields plausible immunobiology, notably on a peptidase (ERAP2: endoplasmic reticulum amino peptidase) that affects inflammatory cytokines involved in protection against Yersinia pestis and control over its intracellular infection. Importantly, ERAP1 and 2 work jointly to trim pathogen peptides for presentation by MHC/HLA-I molecules to activate protective killer CD8-positive T cells.

Protective variants overlap with alleles that in the current age predispose to autoimmune disease, suggesting that the price for enhanced plague resistance is increased risk of chronic inflammatory disease.

This most elegant study will most likely become a landmark classic, which will productively find its way into teaching tools for a wide variety of audiences, from clinicians, geneticists and immunologists, to high school classrooms.

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