## 4 The Gastrointestinal System
### GI Host Defense
In FAE, antigens from the lumen are met by dendritic cells (DCs) and macrophages in the inductive sites of Peyer's patches, also coined as the subepithelial dome site, along with B cells and CD4\({}^{+}\) T cells, to present in germinal centers to undergo class-switching and somatic hypermutation of IgA\({}^{+}\) memory B cells and IgA-secreting plasma cells. The differentiation of B cells into IgA-secreting plasma cells is in part due to the crosstalk with gut microbiota, B cells, and the intestinal epithelium [69]. Immunoglobulin class switching occurs in the mesenteric lymph nodes, Peyer's patches, ILFs, and lamina propria [84]. The intestinal immune system is a dynamic, multifactorial process which has the ability to confer adaptive and innate immunity, combat pathogenic antigens, as well as maintain synergy with commensal organisms. The host GI immune system works in harmony with the commensal resident intestinal microbiota which largely contributes to mucosal IgA production and protection and is summarized in Figure 2[84]. In a study published by [PERSON] et al., specific intestinal microbiota were found to influence the production and protection of the gut by increasing expression of transforming growth factor beta-1 (TGF-B1) and therefore mediating mucosal IgA levels [84]. TGF-B1 is a cytokine involved in intestinal immune homeostasis, preventing overreaction of pro-inflammatory cytokine production and Th1 and Th2 cell differentiation while encouraging T cell polarization of Tregs [84]. [PERSON] et al., used fecal microbiota transplantation (FMT) to transplant stool from high-IgA producing BALB/c mice and low-IgA producing eosinophil knockout mice (AdblGATA-1) into specific pathogen free (SPF) BALB/c mice. Results indicated that SPF mice which received the high-IgA FMT had significantly higher levels of serum and fecal IgA levels as well as an approximately two-fold higher absolute count of CD45\({}^{+}\)IgA\({}^{+}\) B plasma cells in the small intestinal lamina propria [84]. These results show that specific populations of the gut microbiota, namely _Anareoplasma_ and _Erysipelotrichaceae incrtae sedis_, are capable of promoting IgA expression despite lack of eosinophil help, contrary to popular belief [84] and emancipates the microbiota, showing independent control over immune responses. In IEC, antigens from the lumen are also capable of being taken up by DCs through epithelial cells such as goblet cells [63], and other subepithelial mononuclear phagocytes such as macrophages [84], in the lamina propria which are then presented to T cells for B cell IgA class switching. T cells, macrophages, and other antigen presenting cells are also able to sample and respond [69; 79; 84; 85] by conferring specific immunity with IgA [81]. Antigen-specific mucosal effector cells such as memory B cells, CD4\({}^{+}\) Th1, CD4\({}^{+}\) Th2, and plasma cells producing IgA all reside within mucosal effector sites [59; 84]. Once specialized immunoglobulins are made by mucosal plasma cells in the lamina propria, they are transported across the epithelial barrier. First, the pentameric IgA (pIgA) and J chain complex are secreted and bind to the basolateral membrane of IECs by the polymeric immunoglobulin receptor (plgR). Next, these complexes are transcytosed into the intestinal mucus layers, driven by cleavage of pIgR, yielding secretory (sIgA) [86] which further confers mucosal surface protection. sIgA's innate ability to distinguish commensal organisms from overt pathogens has been debated and discussed in detail [86]; it has been suggested that sIgA antibodies may have greater affinity in the detection of pathogens due to various opportunistic and established virulence mechanisms of the pathogens [86].