Ancient DNA samples have been used to map the history of the immune system of European humans for the first time. Major changes occurred mainly during the young Stone Age, when people switched from an existence as hunters and gatherers to a life on a permanent site with agriculture and cattle breeding. Higher exposure to pathogens caused adaptations in immune responses, such as inflammation and tolerance. This is shown in a large study by the Radboudumc together with researchers from Groningen, Germany, Sweden, Spain and South Africa. The results have been published in eLIFE.
The history of mankind has been shaped by infectious diseases. To gain more insight into this, the researchers exposed the blood cells of hundreds of people to various pathogens and then determined the amount of cytokines produced, the drivers of the immune response. This information was then linked to the DNA of the blood cells, creating genetic profiles. The researchers then linked the profiles to more than 800 ancient DNA samples, from people who lived from 35,000 years ago to the present.
The analysis shows that the immune system changed especially significantly during the Neolithic period, from about 8,500 to 3,900 years BC. Last author and Professor of Internal Medicine at the Radboudumc Mihai Netea says: "People were actually already 'socially distancing' themselves before the Neolithic: they lived in small groups and were always outside. These people were hunters and gatherers. Only in the Neolithic do we see that people start living together much more. They built houses, developed agriculture and cattle breeding. By then, the villages were much larger than you would expect, often thousands of people together."
Because people started living so close together, diseases could spread much more easily. In addition, animal husbandry introduced more infections through animals, so-called zoonoses. Jorge Dominguez, researcher and first author of the study, explains: "Higher exposure to pathogens caused major changes in the control of immune responses such as inflammation and tolerance. With tolerance, the immune system actually stops responding to an invader. A new balance was created. This history of the immune system is what we see for the first time in our study." That balance between inflammation and tolerance was determined primarily by the historical period, the aggressiveness of the pathogens, and their spread.
In addition to genetic changes in the response to pathogens, changes in susceptibility to autoimmune diseases also occur. Mihai: "If we were to let someone from before the Neolithic live in what is now Nijmegen and adopt a modern lifestyle, that person would develop rheumatoid arthritis or multiple sclerosis much earlier than modern humans. We have become more insensitive to these diseases. On the other hand, our susceptibility to intestinal inflammation is actually increased compared to primordial humans. For example, Crohn's disease and gluten intolerance are much more common today because of changed lifestyles."
What does history teach us about relatively new viruses, such as COVID-19? Mihai: "The changes in the immune system in the Neolithic make a cytokine storm less likely now than in the past. So you see a balance in cytokines in the vast majority of patients with COVID -19. Only a few percent develop a cytokine storm, an overreaction of the immune system to a pathogen, which can be life-threatening. Humans used to be unaccustomed to viruses from the northern side of the world, such as influenza and coronaviruses, and probably overreacted to these infections. Our immune system had to adapt over thousands of years to provide proper protection. Looking at history, we have become who we are through exposure to different combinations of pathogens."
About the publication
The results of this study were published in eLIFE. Evolution of cytokine production capacity in ancient and modern European populations. Jorge Domínguez-Andrés, Yunus Kuijpers, Olivier B Bakker, Martin Jaeger, Cheng-Jian Xu, Jos WM Van der Meer, Mattias Jakobsson, Jaume Bertranpetit, Leo AB Joosten, Yang Li, Mihai G Netea.
An opinion piece also appeared in Science.
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