The mucosal immune system is often the first to tangle with microbial invaders. To better understand it, scientists should focus on the interplay between the mucosal immune system and friendly microbes.

The mucosal immune system, which stands like a military battalion protecting the nasal passages, intestinal lining, and other vulnerable surfaces of the human body, is often the first to tangle with microbial invaders. It’s also of considerable interest to researchers who hope to improve vaccines, treat diseases, and even quell allergies and asthma.

To boost their understanding of this key defense against disease, scientists should focus on the interplay between the mucosal immune system and friendly microbes, according to B. Brett Finlay, a Howard Hughes Medical Institute (HHMI) international research scholar at the University of British Columbia in Canada.

You cannot study the functioning of mucosal immune systems without considering the microbiota.

IB. Brett Finlay

Finlay has spent his career studying diarrhea-causing bacteria. In a commentary in the July 2010 issue of Nature Immunology, he and colleagues Navkiran Gill and Marta Wlodarska offer what he admits is an outsider’s take on the mucosal immune system. This defensive line includes the mucous membranes that line the respiratory system, the digestive tract, and other potential portals of entry for pathogens. But it also encompasses immune cells such as T cells and dendritic cells, signaling molecules, and other protective components that pitch in to guard the body’s boundaries.

Researchers have excelled at teasing out the workings of individual parts of the mucosal immune system, Finlay and his colleagues note. For example, they now know many details about how the gastrointestinal tract reacts to pathogens in your food and how the respiratory system mobilizes to fend off bacteria and viruses you inhale.

What researchers have largely overlooked, the authors contend, is how the boundary defenses in different parts of the body work as a unit, a single mucosal immune system—although scientists recognized this integration nearly 40 years ago. “What happens in the gut affects what happens in the respiratory system” and elsewhere in the body, Finlay says. For an example of these interconnections, consider the vaccine against genital infection by the herpes simplex virus type 2. It’s a nasal spray. Somehow, exposing mucous membranes in the nose to the vaccine triggers genital mucous membranes to produce defenses against the virus.

“If we can incorporate the single mucosal system concept [into the field], we will have a much deeper understanding of how this type of immunity works,” Finlay says. A key area of research, he adds, involves finding ways to tap into the lines of communication that allow mucosal defenses to share information.

Finlay and his colleagues argue that one particular part of the mucosal immune system requires more attention: our microbiota, the bacteria that swarm in the mouth, the gut, and other parts of the body. People host so many microbes—more than 500 species and trillions of individual cells in the intestine alone—that they qualify as an additional organ system, Finlay and colleagues write. “You cannot study the functioning of mucosal immune systems without considering the microbiota,” Finlay explains.

That’s because, as researchers are starting to recognize, our bacterial partners shape the development of our immune defenses. Two years ago, HHMI investigator Dan Littman at New York University teamed up with Finlay and his colleagues to discover a prime example. The researchers found that genetically identical mice purchased from different laboratory suppliers had different kinds of intestinal bacteria. Their immune systems were also different: if they harbored certain bacteria, they had Th17 cells, which incite inflammation. Without these bacteria, the rodents had more immune-dampening regulatory T cells. The balance between these two types of cells could determine whether the mice are susceptible to inflammatory bowel disease.

The results could also raise doubts about research that attributes immune differences among animals to genetic differences. “You say, ‘Uh oh, what is due to genetic differences and what is due to differences in composition of microbiota?’” Finlay says. He thinks researchers need to start looking for the answer.

Focusing on our microbiota could also bring medical benefits by clearing up several long-running medical mysteries. For example, Finlay says, it might explain why vaccines tested and produced in the developed world often don’t work as well in developing countries. Residents of different countries might host unique kinds of bacteria that cause their immune systems to react differently to the shots.

Scientists might also gain insight into the hygiene hypothesis, a controversial explanation for the rising prevalence of asthma and allergies in developed countries. The argument is that people in the developed world are, in Finlay’s words, “living in places that are way too clean” and thus avoid exposure to microbes necessary to fine-tune the immune system. Without this exposure, the immune system becomes prone to allergy or asthma. Although the hypothesis has been around for more than a two decades, researchers can now test whether the presence of particular types of bacteria in the intestines makes asthma and allergies more or less likely.

New technologies that enable researchers to delve into bacterial DNA, proteins, and metabolism make this a good time to start asking questions about our microbiota, Finlay says. Back when they worked under technical limitations, researchers asked, “What can I do?” he says. Now, with powerful techniques in genomics, proteomics, and metabolomics at their fingertips, they can ask, “What should I do?”

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