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NOT JUST BRUTE FORCE:
Innate immunity kicks in the moment a foreign substance invades // Kills generic physical structures // But also employs what it was never thought to have: a memory

Immunity: Our Innate Defense

By Rachael Moeller Gorman // Illustrations by Micah Lidberg // Summer 2012
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immunity

Micah Lidberg

When a leaf of poison ivy brushes someone’s skin for the first time, it leaves no visible trace. There’s no rash, and the skin doesn’t itch. But inside the body, the lick of urushiol oil from the plant’s sap awakens the immune system, causing T cells, a type of immune cell, to surface on the skin and form a deep immunological memory of the oil. The next time that person encounters poison ivy, the immune system recognizes it quickly, and within 24 hours the skin erupts in a rash and bursting pustules. In this case, the response is an allergic overreaction to the urushiol oil and the skin proteins it altered as it penetrated the skin, which the immune system cells then recognize as foreign and work to eliminate. The same kind of reaction, in other circumstances, could ward off a dangerous infection.

For years, scientists have understood that the body’s adaptive immune system engineers this intense response the second (or perhaps third or fourth) time a foreign substance is encountered. Conventional wisdom has held that only adaptive immunity, armed with T cells and B cells, possessed the complex biological machinery to remember a particular foreign molecule or microbe and to mount a vigorous immune response. Vaccines are predicated on this notion.

A second, more primal mode of infection fighting—the innate immune system—differs in that it begins working the moment a foreign substance enters the body. It is the body’s brutish first line of defense, recognizing common features that distinguish microbes from ourselves, and it quickly kills the invaders. But innate immunity works on generalizations, with its cells—including natural killer (NK) cells and phagocytes—and proteins systematically making their way through the body on the hunt for generic physical structures typical of microbes but not of humans. Still, these crude search-and-destroy missions can’t eliminate every type of virus or bacteria, as some have evolved to avoid attack; Staphylococcus bacteria, for example, produce an enzyme that breaks down the chemicals phagocytes use to kill those germs. Nor is the innate immune system powerful enough to kill every invader. But the biggest difference between innate and adaptive immunity was always thought to be the innate immune system’s inability to remember—and thus to attack with immediate, precisely targeted power—a microbe it has encountered before.

Because of all those apparent deficiencies, the innate immune system has never gotten much respect or attention as a vehicle for disease treatment or drug development. Innate immunity’s perceived shortcomings were also why the results of the experiments Ulrich von Andrian began conducting in 2002 were so shocking. Von Andrian, Mallinckrodt Professor of Immunopathology at Harvard Medical School, was looking at contact hypersensitivity (a laboratory version of a brush with poison ivy) in the bladders of mice. In a standard control experiment, von Andrian’s team used animals called RAG2-deficient mice, which lacked T cells and B cells—in other words, they had no adaptive immune system. They were protected only by blunt-edged, slash-and-burn innate immunity, which shouldn’t have been able to remember a thing.

But when the team re-exposed these RAG2-deficient mice to a foreign invader, a chemical they had encountered before, the altered mice responded with just as much infection-fighting inflammation as mice whose adaptive immune systems were intact. “It was an experiment that initially seemed to have gone awfully wrong,” says von Andrian, who assumed the team had made mistakes. “Certainly it was not explainable with any of the expert knowledge broadly accepted at the time.” Yet after years of additional work, von Andrian published a paper in 2006 reporting that the innate immune system—in particular, a subset of its NK cells—can indeed remember.

Many immunologists didn’t believe it, especially because von Andrian couldn’t explain how NK cells, with none of the adaptive immune system’s T cells and B cells, could possibly remember an attacker. Other scientists were astonished; in one news report, a researcher was quoted as saying “it’s like Christopher Columbus bumping into a new continent.” But along with other recent discoveries about innate immunity, von Andrian’s work is helping change the way science looks at the innate immune system, suggesting that it may be fighting more battles than anyone had imagined—and that it could be uniquely useful in efforts to attack HIV/AIDS, asthma and other diseases.

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1. “T Cell– and B Cell–Independent Adaptive Immunity Mediated by Natural Killer Cells,” by Jacqueline O’Leary et al., Nature Immunology, May 2006. The controversial study in which immunologist Ulrich von Andrian demonstrates that at least one component of the innate immune system, natural killer cells from the liver, can remember foreign substances they previously encountered—overturning a fundamental rule of immunology.

2. “HIV-1 Adaptation to NK-Cell-Mediated Immune Pressure,” by Galit Alter et al., Nature, Aug. 4, 2011. A demonstration of the fact that natural killer cells play a powerful role in fighting HIV, which, taken together with von Andrian’s paper, allows scientists to theorize that vaccines might be developed that target NK cells in addition to the traditional cells of adaptive immunity.

3. “Approaching the Asymptote? Evolution and Revolution in Immunology,” by Charles Janeway Jr., Cold Spring Harbor Symposia on Quantitative Biology, 1989. Janeway’s theories on innate immunity, presented here, marked the first time the innate immune system was recognized as a powerful defensive system in its own right; all of Janeway’s theories eventually proved true.

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