[PMC free article] [PubMed] [Google Scholar]Hamada H, Hiroi T, Nishiyama Y, Takahashi H, Masunaga Y, Hachimura S, Kaminogawa S, Takahashi-Iwanaga H, Iwanaga T, Kiyono H, et al. approximately 103C105 organisms per gram of luminal contents, at least in mice. Higher bacterial densities of 108 organisms per gram can be found in the ileum, which is the distal portion of the small intestine. In the large intestine or colon, bacteria can reach a density of 1010C1012 organisms per gram and comprise more than 1000 species, including obligate anaerobes, such as gene, which is involved in the formation of a productive type III secretion system, neither enter Peyers patches nor induce formation of fecal-antigen-specific IgA. However, these strains can still enter the lamina propria, presumably via a DC-mediated mechanism, and then reach the mesenteric lymph node and the spleen, where they induce IgG production (Martinoli et al., 2007). Notably, mice vaccinated with strains of Salmonella unable to elicit a fecal IgA response become infected if challenged with virulent Salmonella through the oral route, suggesting that antigen-specific IgA antibodies exert a protective role in the intestinal mucosa. Together, these data tell us that protective IgA responses to pathogens are predominantly initiated in Peyers patches. A similar scenario has been described for commensal bacteria. injected intragastrically in wild-type mice can be detected in DCs from Peyers patches and mesenteric lymph nodes (Macpherson and Uhr, 2004). This localization is associated with induction of commensal-specific IgA responses. However, bacteria cannot be recovered from the spleen, suggesting that mesenteric lymph nodes are important to exclude commensals from the systemic immune system. It remains to be established how noninvasive commensal species gain access to Peyers Rabbit Polyclonal to SLC33A1 patches. One possibility is that commensal bacteria first become opsonized by natural polyreactive IgA antibodies and then undergo IgA-mediated apical-to-basal transepithelial migration across FMK 9a M cells (Kadaoui and Corthesy, 2007; Mantis et al., 2002). Interestingly, IgA responses in mesenteric lymph nodes could also occur in response to transcutaneous immunization, suggesting the existence of a functional link between the skin and mucosal sites (Chang et al., 2008). Payers Patches as the Major Site for the Induction of Antigen-Specific Responses IgA CSR can also take place in isolated lymphoid follicular structures that are characterized by a cellular composition similar FMK 9a to that of Peyers patches (Hamada et al., 2002; Moghaddami et al., 1998). These isolated lymphoid follicles are lined by a specialized epithelium containing M cells and FMK 9a thus should mount IgA responses through pathways similar to those utilized by Peyers patches. Mice treated postnatally with LTR-Ig, a fusion protein of lymphotoxin- receptor (LTR) and IgG Fc, showed reduced size and numbers of Peyers patches and lacked isolated lymphoid follicles but were still able to generate antigen-specific mucosal IgA responses after oral immunization, although to a lesser extent than control mice (Yamamoto et al., 2004). Mice treated in utero with both TNF receptor (TNF-R) of 55 kDa-Ig and LTR-Ig lacked Peyers patches and mesenteric lymph nodes but retained intact isolated lymphoid follicles (Yamamoto et al., 2004). These mice failed to induce antigen-specific IgA responses after oral immunization, although having unaltered intestinal IgA antibodies. Together, these findings demonstrate that Peyers patches play a key role in the induction of specific IgA responses to orally administered antigens. They also indicate that isolated lymphoid follicles have a marginal role in these responses. Remarkably, Peyers patches do not absolutely require germinal centers to initiate antigen-specific antibody responses. Indeed, mice lacking CD28, a B7-binding T cell costimulatory molecule necessary for germinal-center formation, not only FMK 9a retain IgA-producing plasma cells in the intestinal lamina propria but can also mount high-affinity IgA antibodies to FMK 9a an orally administered T cell-dependent antigen (Gardby et al., 2003). In contrast, CD28-deficient mice cannot mount specific antibody responses when challenged with a T cell-dependent antigen through a systemic route (Gardby et al., 2003). This evidence indicates that Peyers patches can generate high-affinity IgA antibodies in the absence of canonical cognate T-DC or T-B cell interactions in the germinal center. The unique nature of Peyers patches is further emphasized by studies showing that Peyers patch B cells do.