Fig 12.23 The microbiota tune local and systemic immune responses. The microbiota has local and distant effects on immune function, although only a few individual organisms and mechanisms have been identified. Segmented filamentous bacteria (SFB) potently induce SFB‑specific TH17 cells, perhaps by inducing epithelial cells to produce serum amyloid A (SAA) protein that may act on dendritic cells. Bacterial flagellin favors TH17 and IgA responses by stimulating TLR‑5 on mucosal CD11b‑expressing dendritic cells. The microbiota is also needed for the presence of isolated lymphoid follicles and ILCs, especially ILC3 cells, but inhibits the accumulation of invariant NKT cells (iNKTs). Besides providing energy to colonic enterocytes, butyrate and other SCFAs may also act to drive the generation of FoxP3+ Tregs, although the molecular mechanism is still unclear. Clostridia also induce production of TGF‑β by epithelial cells. The polysaccharide antigen (PSA) from Bacteroides fragilis stimulates the preferential generation of regulatory T cells, possibly by binding to TLR‑2 on CD4+ T cells. Unidentified members of the microbiota are needed to maintain the production of TSLP, IL‑25, IL‑33, and RA.
12-22 Full immune responses to commensal bacteria provoke intestinal disease.
Elegant experiments in the 1990s led to the now generally accepted idea that potentially aggressive T cells that can respond to commensal bacteria are present in normal animals but are usually kept in check by active regulation (Fig. 12.24). If these regulatory mechanisms fail, unrestricted immune responses to commensal bacteria can lead to inflammatory bowel diseases such as Crohn’s disease. Many genes that are associated with susceptibility to Crohn’s disease in humans encode proteins that regulate innate immunity. When these regulatory processes fail, systemic immune responses are generated against antigens from commensal bacterial, such as flagellin. T-cell responses are also generated in the mucosa, leading to severe intestinal damage. IL-23 is important in this process, promoting differentiation of TH17 effector cells. IL-23 and IL-12 in concert can also induce inflammatory TH1 responses in the intestine, with some CD4 effector T cells found to produce both IFN-γ and IL-17 under these circumstances. These experimental results are consistent with clinical evidence for a linkage between polymorphisms in the IL-23 receptor and Crohn’s disease in humans. In all experimental models, the intestinal damage depends on the presence of commensal bacteria, can be prevented by treatment with antibiotics, and does not occur in germ-free animals.
Patients with Crohn’s disease and the related disorder ulcerative colitis exhibit dysbiosis and harbor unusual populations of intestinal microbiota. However, with the exception of enteroadherent Escherichia coli mentioned above, no individual species of commensal bacteria have yet been proven to be responsible for causing the damage. There is also experimental evidence that local responses to certain pathogenic viruses or parasites such as Toxoplasma gondii may trigger bystander activation of effector T cells specific to commensal organisms and produce persistent inflammation.
Summary.