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by Matthew Eckwahl, PhD
Postdoctoral fellow in the Department of Biochemistry & Molecular Biology

Take a look at the people around you: besides identical twins, you’ll likely see an array of differences, from height to hair color. Humans vary extensively, not only in appearance but also in less tangible traits. Not surprisingly, these differences often have at least some genetic basis. The immune system is no exception. Individuals differ considerably in their ability to fight off infections and their risk of autoimmune diseases, like type 1 diabetes and inflammatory bowel disease. What’s more, the human immune response has been shaped over time by evolution.

Luis Barreiro, an associate professor at the University of Chicago, seeks to understand how natural selection influences the evolution of our species; in particular, he’s interested in how past evolutionary events affect the immune response. By identifying the genetic factors contributing to infectious disease susceptibility, Barreiro aims to uncover new genes and pathways linked to disease, opening the door to fresh research approaches and novel therapeutic targets.

In an influential 2016 report, Barreiro, then at the University of Montreal, helped shed light on differing disease rates between Americans of African and European descent. His team’s findings are particularly important given some troubling health disparities in autoimmune disorders such as multiple sclerosis and lupus. Young women of African ancestry, for example, are three times more likely than women of European descent to be affected by lupus, a chronic disease in which the body’s immune system attacks its own healthy tissues.

While factors such as environment and socioeconomic status undoubtedly play a role in these health discrepancies, Barreiro’s group showed that the immune response itself differs unexpectedly between people of African and European ancestry. How did they do this?

They first collected blood samples from both groups and isolated their macrophages, immune cells that “eat” bacteria and other parasites. Next, they infected these immune cells with bacterial pathogens—either Salmonella or Listeria, both common culprits of food poisoning—and used leading-edge genomic sequencing techniques to see how infection altered gene activity. Remarkably, they discovered that about one-third of genes active in macrophages showed different activity in people of European versus African descent.

It turns out that many of these genes are involved in activating the immune system: people of African ancestry showed much higher expression of genes associated with inflammation compared to those of European origin. While some of these are linked to known immune diseases like celiac and Crohn’s disease, they also provided at least one advantage: macrophages from African Americans were far better at devouring bacterial invaders and eliminating infection.

Incredibly, interbreeding with another human species—Neanderthals—also plays a role in this story. Although Neanderthals went extinct around 40,000 years ago, they left an indelible mark on the human genome, contributing to about 2 percent or less of human ancestry. Barreiro’s team identified immune variants that were preferentially passed on from Neanderthals to people of European—but not African—ancestry. Notably, these DNA variants are associated with reduced inflammation. (In a complementary report, the Barreiro lab explored a specific immunity gene that protects against viral infection and also appears to have been obtained from Neanderthal interbreeding.)

One mystery remains: what evolutionary pressures gave rise to these divergent immune responses? One possibility is that humans who migrated out of Africa experienced fewer exposures to potentially dangerous microbes, making a robust inflammatory response less valuable or even harmful. In contrast, Africa’s tropical environment may have favored a stronger immune response to combat more frequent pathogen exposure.

Regardless of the ultimate cause, each population seems to have ended at a different “balance point.” The immune system operates somewhat like a smoke alarm, keeping us safe from possible disaster. And like a smoke alarm, the system should respond proportionally to the threat at hand: not sensitive enough, and you risk being unaware as fire engulfs your house. But too sensitive, and the alarm shrieks at the first hint of burnt toast. There’s always a tradeoff. While an overactive immune system is better at fending off parasites, it may also lead to higher risk of autoinflammatory and autoimmune diseases.

Carl Sagan, a famous astronomer and science popularizer, once said, “You have to know the past to understand the present.” By highlighting how long-ago evolutionary events affect our genome, Barreiro’s findings expose a key influence that human ancestry has on immunity. Further, his research underscores the necessity of expanding racial diversity in clinical trials, where commonly more than 80 percent of participants are white. Together, by helping us better understand the evolutionary forces shaping our species, the work of Barreiro and others may contribute to the eventual dream of precision medicine.