The Black Death caused by Yersinia pestis is the single largest human mortality event in recorded history. That pandemic killed up to 30-50% of the Afro-Eurasia population. As such, it is predicted to have had selective effects for immune response genes that could help protect against fatal outcomes. Similarly, many autoimmune diseases, including type 1 diabetes (at least before modern medicine), were under strong selective pressure because of their fatal outcomes. This study used ancient DNA extracts from two different populations before, during, and after Black Death to pinpoint immune loci that appeared to have been under positive selection. Four of those were found in both cohorts. One of those is associated with production of full length ERAP2 transcripts and the ability to produce cytokines and control intracellular levels of Yersinia pestis in macrophages. Several of the genes that appeared to have been positively selected by the pandemic are also associated with autoimmune/autoinflammatory diseases in present-day populations. This provides data and potential mechanisms for how a genetic variation that may increase risk of fatal outcomes from one immune-related disease can be “viable” long-term in that same population because it protects against fatal outcomes of another disease.