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Workings of intestinal gateway known as “inner outside”

Posted May 15, 2017
This news or article is intended for readers with certain scientific or professional knowledge in the field.

A research group at the University of Tokyo has identified in a study with mice a protein directly linked to the M cells’ function to capture antigens around intestinal and other mucous membrane surfaces. Manipulating the protein, allograft inflammatory factor 1 (Aif1), holds promise of contributing to the development of more effective mucosal vaccines—immunizing agents, administered orally or through the nose, that enter the body via the mucous membrane—as an alternative to the conventional injectable type of vaccines.

Role of Aif1 in M cells in the intestines. In normal (wild-type) mice, Aif1 is expressed in M cells. Aif1 activates an enzyme (GTPase) typified by Rac in a calcium ion-dependent manner. Activated GTPase induces actin remodeling, transforming the shape of the cell membrane on the interior surface of the intestines and leading to antigen uptake. GTPase also activates a receptor (β1 integrin) that recognizes Yersinia enterocolitica, a bacterium that causes food poisoning, enabling its effective uptake. In Aif1-deficient mice, both the uptake of antigens and the invasion of pathogenic bacteria are diminished because they cannot activate GTPase. Image credit: Shintaro Sato.

Our body detects and rids itself of foreign substances through its immune response. On the other hand, our digestive tract, including the intestines, which digests the food we take in, is exposed to foreign substances such as ingested food and intestinal bacteria—in spite of it being inside the body. Therefore, a mucosal immune system that recognizes “good” and “bad” foreign substances and responds accordingly is at work on the mucous membranes of the digestive tract and other areas. The intestinal mucous membrane comprises trap-like structures for capturing foreign substances, or antigens, and M cells are thought to be the key player responsible for this function. Previous studies have shown that specialized proteins, called receptors, engaged in the effective uptake of microorganisms are expressed in M cells; however, the molecules directly involved in the M cells’ function of capturing and transporting antigens through the cell—a process known as transcytosis—had not yet been reported.

The research group led by Professor Hiroshi Kiyono of the Institute of Medical Science at the University of Tokyo and Specially-Appointed Associate Professor Shintaro Sato of the Research Institute for Microbial Diseases at Osaka University analyzed genes expressed in epithelial cells lining the inner surface of intestines in a group of normal mice and in another group made up of mice lacking M cells. From their analysis, the researchers found that Aif1 is a molecule expressed only in M cells. They then produced Aif1-deficient mice and discovered, through examining the protein’s function, a correlation suggesting that regulation of actin activity in M cells by Aifl was involved in transformation of the membrane during antigen uptake.

“Temporary control of Aif1 function and expression can contribute to the development of more effective mucosal vaccines by increasing their uptake of antigens,” says Kiyono. He continues, “On the other hand, it can also be applied toward preventing infections by blocking the invasion of disease-causing microorganisms considered ‘bad’ foreign substances.”

Source: University of Tokyo

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