FEATURE ARTICLE
Why We Develop Food Allergies
Coached by breast milk and good bacteria, the immune system strives to learn the difference between food and pathogens before the first morsel crosses our lips
Per Brandtzaeg
Immunity Patch
Immune cells are woven into the fabric of the gut rather than being restricted to one place, but there are also discrete structures for immune surveillance. Dotting the prairie of tiny villi that lines the gastrointestinal tract are swollen domes called Peyer's patches. These regions, part of a larger system of gut-associated lymphoid tissue or GALT, are covered by an epithelial-cell layer containing specialized M cells (the M stands for membrane or microfold), which constantly scan the stream of passing antigens and transport them to the principal cell types in the immune system—B cells (from the bone marrow), T cells (from the thymus) and antigen-presenting cells (APCs) such as macrophages and dendritic cells. It is here that mucosal immunity is induced and regulated.
What follows the identification of an antigen is a complicated ballet of cells, secreted signals and movement from one compartment of the body to another. The keys to the system are the APCs, the "decision makers" in the immune system, which link innate and adaptive immunity. APCs process chunks of antigen brought in by M cells and then show the pieces, along with a selection of co-stimulatory signals, to so-called naive T cells, which have never met their cognate antigens before. Those specific T cells whose antigen receptors match one of the pieces become primed or activated; they then release cytokines (hormone-like regulatory proteins) and growth factors that instruct B cells to proliferate, differentiate and begin producing IgA. Activated T and B cells migrate to nearby lymph nodes to receive additional biological signals; most of those cells then enter the bloodstream. Many will return to the lamina propria of the gut, the tissue layer beneath the surface epithelium, or to mammary glands in lactating mothers through a kind of chemical navigation system. There, depending on what antigen-induced "second signals" the B cells receive, they may undergo one last, or terminal, differentiation to become plasma cells, which produce antibodies in quantity (about 10,000 molecules per second).
The system works differently in newborns who have never encountered microbes. Very few IgA-producing B cells circulate in the blood of newborns, although this number is approximately 75 times higher after the first month of life, a period of continuous stimulation of GALT by microbial antigens.
In the GALT structures, APCs need to receive certain "danger signals"—fragments of commensal bacteria from the digestive tract—to provide the right mix of co-stimulatory signals that prime helper T (Th) cells to aid the B cells. Without this timely inoculation with bacteria, the IgA system fails to develop normally. Bacteria from the genus Bacteroides and certain strains of Escherichia coli seem to be particularly good at stimulating the mucosal immune system. Lactic-acid-producing bacteria (lactobacilliand bifidobacteria) also contribute. These microbes help establish and regulate the epithelial barrier as well.
At least in mice, many of the beneficial effects of the commensal microbiota come from the binding of bacterial components by pattern recognition receptors on the surface of or inside the epithelial cells. This binding starts a back-and-forth, homeostasis-enhancing exchange of signals between epithelial cells and cells in the underlying lamina propria, including macrophages and dendritic cells. Experiments in mice suggest that before birth, cells lining the gut can detect certain parts of chewed-up microbes—particularly the component of the bacterial cell wall known as endotoxin or lipopolysaccharide (LPS)—because the cells contain an intracellular receptor for this common bacterial signature. Exposure to LPS in the mother's vaginal tract during birth modulates the gut epithelium so that it becomes tolerant to microbial patterns after birth. In remarkable contrast, mice delivered by caesarean section do not show signs of epithelial tolerance. These observations may be relevant to humans: Children who have a genetic predisposition to produce excess IgE (as indicated by mothers who suffer from various allergic reactions—a condition called atopy) are at least eight times as likely to develop food allergy when delivered by caesarean section.
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