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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

Decisions, Decisions

Upon encountering a novel antigen, the immune system must decide whether the antigen is pathogenic (meriting a so-called productive immune reaction, which tries to eliminate the antigen) or harmless (leading to a suppressed response). If commensal bacteria have in the past modulated APCs (macrophages and dendritic cells) via their pattern-recognition receptors, then these cells are more likely to express co-stimulatory molecules and secrete the types of cytokines that encourage Treg cell development and, therefore, tolerance.

In a healthy gut, the APCs are continuously exposed to components of the normal gut microbiota. Like a sleepy sheriff in a peaceful town, a dendritic cell raises only a negligible alarm of proinflammatory cytokines on getting a whiff of microbial LPS. In this quiescent state, the dendritic cells carry antigens from the gut to nearby lymph nodes, where, in a normal maturation process, the cells become further conditioned for tolerance and drive the expansion of Treg cells. Some of the Treg cells travel through lymphatic and blood vessels back to the gut mucosa to maintain homeostasis.

Altogether, the body avoids unnecessary hyperactivation of its immunological sentinels (along with potentially harmful inflammation) in two ways: initially, with the restrained alarm, and also later when the activated Treg cells migrate to the mucosa to exert homeostatic control. At the same time, the macrophage deputies in town, which retain their ability to engulf and kill microbial invaders, continue to do the work of getting rid of commensal bacteria that sneak past the gut lining.

Figure 6. According to the extended hygiene hypothesis...Click to Enlarge Image

In the gut-associated lymph nodes, conditioning for oral tolerance depends on the menu of microbial components that the dendritic cells receive. Tolerance to food proteins is more likely to develop in the presence of telltale components from certain commensal bacteria as well as from harmless bacteria native to soil and from surface water or parasites such as flatworms or flukes. (It's nice to know these pests are good for something.) This evidence supports the extended hygiene hypothesis, which argues that a too-hygienic lifestyle in industrialized countries can prevent the mucosal immune system from maturing, leading to inadequate secretory immunity and fewer Treg cells. In a way, you could say that our immune system has lost its stimulating "old friends." Supporters of the hypothesis speculate that this inadequacy could help explain the increasing incidence of allergy and other immune-mediated inflammatory disorders in Westernized society.

Several clinical studies have tested the hygiene hypothesis by evaluating the effect of probiotic preparations, which deliver to the gut new colonists—certain strains of commensal bacteria or intestinal parasites from other species. (Eggs from the pig whipworm Trichuris suis, which don't pose an infection risk to humans, are the stimulants of choice in the latter experiments.) Reports from studies in humans and animals indicate that lactobacilli and bifidobacteria enhance the production of SIgA, apparently in a T cell-dependent manner. In a double-blind study of infants with a family history of atopy, babies who received a daily dose of a probiotic (Lactobacillus GG strain) for the first six months of life had 50 percent less atopic dermatitis at age two than did babies who received a placebo. Allergy prevalence still differed between study groups four years later. It's unclear whether this remarkable result is the product of reinforced barrier function from SIgA, enhanced oral tolerance or both. 




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