Educating Our Confused 21st-Century Immune System
Wednesday, June 12, 2024
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In the last half-century, the prevalence of autoimmune disease — disorders in which the immune system attacks healthy tissue in the body — has increased sharply in the developed world. Our bodies are confused by this 21st-century world.An estimated one in 13 Americans has one of these often debilitating, generally lifelong conditions. Many, like Type 1 diabetes and celiac disease, are linked with specific gene variants of the immune system, suggesting a strong genetic component. But their prevalence has increased much faster — in two or three generations — than it's likely the human gene pool has changed.




Many researchers are interested in how the human microbiome — the community of microbes that live mostly in the gut and are thought to calibrate our immune systems — may have contributed to the rise of these disorders. Perhaps society-wide shifts in these microbial communities, driven by changes in what we eat and in the quantity and type of microbes we're exposed to in our daily lives, have increased our vulnerability.



To test this possibility, some years ago, a team of scientists began following 33 newborns who were genetically at risk of developing Type 1 diabetes, a condition in which the immune system destroys the insulin-producing cells of the pancreas. The children were mostly Finnish. Finland has the highest prevalence — nearly one in 200 under the age of 15 — of Type 1 diabetes in the world. (At about one in 300, the United States isn't far behind.) After three years, four of the children developed the condition. The scientists had periodically sampled the children's microbes, and when they looked back at this record, they discovered that the microbiome of children who developed the disease changed in predictable ways nearly a year before the disease appeared. Diversity declined and inflammatory microbes bloomed. It was as if a gradually maturing ecosystem had been struck by a blight and overgrown by weeds.

The study, published last year, was small. But for Ramnik Xavier, a molecular biologist at the Broad Institute in Cambridge, Mass., and a senior author on the study, the findings suggested for the first time that intervention might be possible. Maybe clinicians could catch and correct the microbial derangement in time to slow — or even prevent — the emergence of the disorder.




The question was how. The scientists turned to Russia for an answer. People living just over the border in Russian Karelia, as the region is known, have the same prevalence of genes linked to autoimmune disease. They also live at the same latitude and in the same climate. And yet they have a much lower vulnerability to autoimmune disease. Celiac disease and Type 1 diabetes occur about one-fifth and one-sixth as often, respectively, in Russian Karelia as in Finland. Hay fever and asthma, allergic diseases that also signal a tendency toward immune overreaction, are far less common.



So in a follow-up study, the results of which appeared last month in the journal Cell, Dr. Xavier and his colleagues followed 222 children who were genetically at risk of developing autoimmune diabetes. The newborns were equally divided among Finland, Russia and Estonia, where the prevalence of Type 1 diabetes is on the rise, but still well below Finland's.



Autoimmune diabetes can be predicted, to some degree, by the appearance of certain antibodies in the bloodstream that attack one's own tissues. After three years, 16 Finnish children and 14 Estonian children had these antibodies; only four Russian children did. And when the scientists compared the children's microbiomes in the three countries, they found stark differences. A group of microbes called bacteroides dominated in Finnish and Estonian infants. But in Russia, bifidobacteria and E. coli held sway. The scientists focused on a microbial byproduct called endotoxin, which usually spurs white blood cells into action. Both communities of microbes produced endotoxin, but not, it turned out, of equal potency. Endotoxin from Russian microbes strongly stimulated human immune cells. And when given to diabetes-prone mice early in life, it lowered their chances of developing the condition. But the Finnish endotoxin was comparatively inert. White blood cells didn't register its presence, and it failed to protect mice from developing autoimmune diabetes.



These findings are very preliminary, but they support a decades-old (and unfortunately named) idea called the hygiene hypothesis. In order to develop properly, the hypothesis holds — to avoid the hyper-reactive tendencies that underlie autoimmune and allergic disease — the immune system needs a certain type of stimulation early in life. It needs an education. The Russian kids evidently received this education courtesy of their distinct microbiomes. The Finns and Estonians seemingly did not. Why was the Russian microbiome so different? The scientists aren't sure. They controlled for diet, so it probably wasn't food — although the Finns generally eat more packaged foods than the Russians. Differences in breast-feeding couldn't explain it either. If anything, Finnish mothers nursed longer than Russians.  But Mikael Knip, a professor of pediatrics at the University of Helsinki and a senior author on the study, describes Russian Karelia as resembling Finland before World War II. It's relatively poor. Many families in the study drink untreated well water. Russian kids have more fecal oral infections, such as hepatitis A, suggesting more sharing not only of pathogens, but of microbes that may benefit health. And previous studies have found that Russian homes harbor a richer and more diverse community of microbes than Finnish ones.


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The hygiene hypothesis is sometimes misinterpreted as being about personal cleanliness. But it describes a much more complicated relationship with the microbial world, one that doesn't necessarily correlate with showers or disinfectant. Lifestyle seems to be the major determinant — how the way you live guarantees (or doesn't) exposure to a rich variety of microbes that favorably sculpt the immune system. It's worth noting that at 66.6 years, life expectancy in Russian Karelia is 13 years less than in Finland. Modern Nordic civilization does have its advantages. But Dr. Knip's hunch is that children growing up in Russian Karelia early on encounter microbes that are absent in Finland. The takeaway, in his view, is this: The human immune system most likely anticipates a microbiome that more closely resembles Russia's because, for most of human evolution, the world was, microbiologically speaking, more like Russian Karelia than modern Finland. When we don't encounter the attendant stimulation early in life, the immune system can become unsteady. Thus, in the past half-century, as Finland became a modern state, the incidence of autoimmune diabetes more than quintupled.


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There may also be other, stranger interactions at work. Scientists think, for example, that certain infections can bring on autoimmune diseases like Type 1 diabetes, which has been linked to a common family of viruses called enteroviruses. And yet, the Russian kids probably encounter more enterovirus infections than the Finns, but develop Type 1 diabetes less often. What gives? One possibility is that toughening the immune system early in life alters how we respond to hits later, making those viral infections less likely to provoke autoimmunity. Another is that the kind of microbiome you have when the virus arrives determines how you respond. And yet another is that when you first encounter viral infections determines how dangerous they are. If they arrive when infants are protected by their mothers' antibodies, as they probably do in Russian Karelia, no problem. But if they arrive after that protection has waned, they can push you toward autoimmunity.




Scientists have borrowed this theoretical framework from polio. One popular theory holds that if the poliovirus arrives in infancy, it produces mild if any symptoms. But if it arrives in childhood or adulthood, it can cause the feared paralysis. In retrospect, the polio epidemics that began striking Europe in the 19th century probably signaled improving conditions, not a new pandemic. Children were imbibing less human waste, and encountering the poliovirus later and later. This same dynamic may apply to another disease many consider autoimmune: multiple sclerosis. In M.S., the immune system is thought to strip the insulation, called myelin, off neurons, leading to progressive disability. The condition is linked to a herpes virus called Epstein-Barr, which establishes a lifelong, though generally asymptomatic, infection. M.S. hardly seems to occur without Epstein-Barr infection happening first. And yet nearly everyone has the virus by their late 30s. What determines who gets M.S.?