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Jun 3, 2016

Educate Your Immune System: NYT | Opinion - June 3, 2016

Moises Velasquez-Manoff
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.
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.
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.?

Alberto Ascherio, an epidemiologist at Harvard, thinks that, even more so than with polio, when you’re exposed to Epstein-Barr influences your fate. Studies on migrants suggest that a childhood in the developing world, where infection with Epstein-Barr generally occurs early, lowers one’s risk of M.S. But acquiring Epstein-Barr in adolescence or adulthood, when it can cause mono — infectious mononucleosis, the “kissing disease,” as American teenagers call it — more than doubles the risk of M.S.
The implication is that, by delaying exposure to once-common infections, improvements in societal hygiene may increase the prevalence of autoimmune diseases. Paradoxically, until we have a vaccine that confers lifelong immunity to Epstein-Barr, the best way to reduce one’s risk of M.S., says Dr. Ascherio, may be deliberate exposure to the virus while young. That’s unlikely to happen, he concedes, but it jibes with an overarching theme of this research.
The world today is very different from the one our immune system evolved to anticipate — not just in what we encounter, but in when we first encounter it. Preventing autoimmune disorders may require emulating aspects of that “dirtier” world: safely bottling the kinds of microbes that protect the Russian kids, so we can give them to everyone and guide the “postmodern” immune system along a healthier path of development.