Various mechanisms are likely to account for oral tolerance to protein antigens, including anergy, deletion of antigen-specific T cells, and the generation of regulatory T cells induced in the mesenteric lymph node to become gut-homing, antigen-specific FoxP3-positive Treg cells via the production of retinoic acid and TGF-β by migratory dendritic cells (see Section 12-7). Although it is known that all these events are also essential for the suppression of systemic immune responses, the mechanisms responsible for this link between the mucosal and peripheral immune system are not yet understood. At times, oral tolerance can fail, as is believed to occur in celiac disease (discussed in more detail in Section 14-17) or peanut allergies (discussed in Sections 14-10 and 14-12).
The intestinal immune system generates protective immunity against antigens that are presented during infections by pathogenic organisms. IgA antibodies are produced locally, serum IgG and IgA are made, and the appropriate effector T cells are activated in the intestine and elsewhere. When the antigen is encountered again, there is effective memory, ensuring rapid protection. Antigens from food proteins induce tolerance locally and systemically, with little or no IgA antibody production. T cells are not activated, and subsequent responses to challenge are suppressed. In the case of commensal bacteria, there may be some local IgA production, but no primary systemic antibody responses, and effector T cells are not activated.
On day 7, the mice are injected with ovalbumin plus adjuvant to stimulate an effective immune response Mice are fed either ovalbumin or a control mixture
Fig. 12.19 Tolerance to antigens can be experimentally generated by oral administration. Mice are fed for 2 weeks with 25 mg of either ovalbumin, the experimental protein, or a second protein as a control. Seven days later, the mice are immunized subcutaneously with ovalbumin plus an adjuvant, and after 2 weeks, the serum antibodies and T‑cell function are measured. Mice that were fed ovalbumin have a lower ovalbumin‑specific systemic immune response than those fed the control protein.
Although mucosal tolerance can be used to avoid inflammatory disease in experimental animal models of type 1 diabetes mellitus, arthritis, and encephalomyelitis, clinical trials in humans have been less successful, and have been superseded by other therapies, such as monoclonal antibodies, that we will discuss in greater detail in Chapter 16.
12-19 The normal intestine contains large quantities of bacteria that are required for health.
The surfaces of the healthy body are colonized by large numbers of microorganisms, collectively referred to as the microbiota, or microbiome, composed mostly of bacteria, but also archaea, viruses, fungi, and protozoa . The intestine is the largest source of these organisms, although all the other mucosal tissues harbor their own, distinct populations of microbes. We each harbor more than 1000 species of commensal bacteria in our intestine, and they are present in greatest numbers in the colon and lower ileum. As many of the species cannot be grown in culture, their exact numbers and identities are only now being established by high-throughput sequencing techniques. In humans, there are several major phyla of bacteria, plus the archaea—in descending order, Firmicutes, Bacteroidetes, Proteobacteria, Actinobacteria, and Archaea. There are at least 1014 of these microorganisms that collectively weigh about 1 kg. The intestinal microbiota normally exists in a mutually beneficial, or symbiotic, relationship known as mutualism that has been established in humans over many millennia and has coevolved with vertebrates throughout their history. As a result, the populations of these microbes found in different groups of animals are distinctive and are highly adapted to their individual host species.