Crossing the Frontlines in Mucosal Immunity

WORKING IN CONCERT:

Courtesy Katherine L. Knight and Ki-Jong Rhee © 2004 American Association of ImmunologistsLeft is a section of appendix following introduction of Bacteroides fragilis; right is a section of appendix following introduction of B. fragilis plus Bacillus Subtilis. B. fragilis alone results in no gut-associated lymphoid tissue (GALT) development while the combination shows a B lymphocyte follicle (red dots).Commensal or nonpathogenic bacteria have established a mutually beneficial relationship with the host immune system that allows them to reside peacefully within the lumen of a healthy host's gut. Lumenal colonization by diverse commensal species is essential for host health, permitting processing of indigestible carbohydrates and preventing colonization by pathogenic bacteria. But it's a delicate balance. "How [does the gut] maintain the necessary bacterial concentration but not become inflamed?" asks Andrew Neish, a pathologist at Emory University School of Medicine in Atlanta.The way that bacteria cross the intestinal mucosa seems to play a key role in this. Katherine Knight's group at Loyola University Chicago, and Andrew Macpherson and Therese Uhr at UniversitätsSpital Zürich, show respectively that regulated uptake of commensal bacteria both enhances the host's immune system development,1 and enables low-level immunosurveillance that prevents bacterial penetration beyond the lumen.2Meanwhile, Jean Fioramonti and colleagues at the Institut National de la Recherche Agronomique in Toulouse demonstrate aberrant bacterial translocation beyond the intestinal mucosa in neonatally stressed adult rats, accompanied by physiological changes reminiscent of conditions such as irritable bowel syndrome.3 Knight's and Macpherson's studies are important in demonstrating the involvement of intestinal flora in establishing mucosal immunity, says Fioramonti, and his own group's work shows that stress during the neonatal period can compromise these processes, with dire consequences.Knight's group demonstrates in rabbits that gut-associated lymphoid tissue (GALT) development and repertoire diversification require regulated bacterial uptake from the gut lumen into underlying mucosal tissues, as well as bacterial expression of specific stress-response genes. They suggest that the gut's harsh environment may induce expression of these genes. But not every commensal species promotes GALT development: "We had to take combinations of organisms in general," says Knight, showing the importance of species diversity among intestinal flora.Knight concedes that not all host species develop their antibody repertoire like the rabbit, but she is convinced that commensals contribute more generally. "I think that usually what you find in one species ... something like it ends up occurring in other species as well," she says.Macpherson and Knight agree that they are probably looking at different aspects of the same process of bacterial uptake. Macpherson and Uhr focused on how the mucosal immune system then handles commensals. They found that bacteria are efficiently killed upon macrophage uptake, but are retained alive in mucosal dendritic cells. These cells migrate to the mesenteric lymph nodes and induce localized IgA responses that in turn limit bacterial penetration beyond the intestinal mucosa, yet support lumenal colonization.Macpherson says that while it is clear that exposure to commensals is a key factor in inflammatory bowel disease, particularly Crohn disease, it is unclear whether damage results from an overactive immune system in the GALT, or from excessive permeability through the remainder of the epithelial cell layer. "That is something that we need to find out," he says.Fioramonti's work begins to approach this issue. In adult rats separated regularly from their mothers before weaning, Fioramonti detected bacteria in mesenteric lymph nodes, liver, and spleen; mucosal mast-cell density was also increased, as was colonic susceptibility to inflammation. Fioramonti says his hypothesis, based on studies of acute stress in adult animals, is that bacterial translocation is secondary to increased epithelial permeability. Work in press, he says, offers more detail.Macpherson cautions that it is difficult to distinguish the different etiological factors behind Fioramonti's observations, because so much happens during early maternal separation. Nevertheless, he says that the work demonstrates the importance of maintaining a functional epithelial barrier. Knight adds, "It shows what a fundamental difference ... abusive care-giving can make [to] the well-being of the animal."Lora Hooper, a mucosal biologist at The University of Texas Southwestern Medical Center at Dallas, suggests that "developing mucosal immune cells are poised for interaction with commensal bacteria, and this is very important in shaping the development of the mucosal immune system." She says she anticipates profound changes in the perception of these beneficial microbial interactions and their importance in human health and development in the coming years.A. Nicola Schweitzer nschweitzer@mac.com is a freelance writer in Boston.

Crossing the Frontlines in Mucosal Immunity

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