By Craig Lammert, M.D. AIHA Executive Director

The bubonic plague often conjures images of flea bites and grotesque swollen lymph nodes. But when people think of the Black Death, should they also think of autoimmune diseases?

As a race, humans have faced a number of infectious diseases over our history. In fact, these historical infections have likely shaped our immune systems to what they have become and have possibly even driven the risk for autoimmune conditions. For instance, the second pandemic of the bubonic plague (caused by the bacterium Yersinia pestis) reduced the population up to 50% in some areas of Europe. Those who survived likely had certain gene types that protected against dying from the plague, and they passed their genetic material to the next generation.

Recently, a collaborative effort between multiple academic medical centers sought to find genetic changes imposed by the bubonic plague in Europe. The published work studied and compared variation of DNA from people who died shortly before, during, or soon after the plague in London and across Denmark.
The authors found that several “immune system-related” gene forms from people who lived after the plague had substantial changes compared to those who lived before the plague. An interesting finding was a change to the gene ERAP2. The study team believes that the ERAP2 gene likely played a role in how the immune system handled Yersinia pestis infection. The authors estimated that individuals with the “plague-selected” form of ERAP2 were 40% more likely to survive Yersinia pestis infection compared to those who did not have this form of ERAP2.
We now know that ERAP2 is a gene that is responsive to a number of different infectious stimuli, and it likely regulates many inflammatory-related components of our immune system. Interestingly, the form of ERAP2 gene that gave protection against the plague also has been found to be a risk factor for Crohn’s disease. This is one way that natural selection resulting from the plague led to an increased risk of autoimmunity in current populations. The authors found another gene change during the plague in a gene called CTLA4. Today, this form of CTLA4 is associated with rheumatoid arthritis and lupus.
Our genomes (and genetic control of our immune systems) are dynamic and ever changing with our environment. Undoubtedly autoimmune conditions are increasing in prevalence, but it may be as a result of historical conditions and exposures.
The next time you wonder about how you or loved ones came to develop autoimmune diseases, it’s not such a far stretch to blame those plague-infected fleas in the 14th century. Read more in the published article.