Integration and regionalization

Lymphoid cells are located in three distinct compartments in the gut: organized gut-associated lymphoid tissue (GALT), the lamina propria and the surface epithelium. GALT comprises the Peyer's patches, the appendix and numerous solitary lymphoid follicles, especially in the large bowel (O'Leary and Sweeney, 1986). All these lymphoid structures are believed to represent inductive sites for intestinal immune responses (Brandtzaeg et al., 1999a). The lamina propria and epithelial compartment constitute effector sites but are nevertheless important in terms of cellular expansion and differentiation within the mucosal immune system. GALT and other MALT structures (see below) are covered by a characteristic follicle-associated epithelium (FAE), which contains membrane (M) cells (Figs 14.1 and 14.3). These specialized thin epithelial cells are particularly effective in the uptake of live and dead antigens from the gut lumen, especially when they are of a particulate nature (Hathaway and Kraehenbuhl, 2000). Many enteropathogenic infectious bacterial and viral agents use the M cells as portals of entry.

GALT structures resemble lymph nodes with B-cell follicles, intervening T-cell areas and a variety of antigen-presenting cell (APC) subsets, but there are no afferent lymphatics supplying antigens for immunological stimulation. Therefore, the exogenous stimuli must come directly from the gut lumen, probably in the main via the M cells. Among the T-cells, the CD4+ helper subset predominates, the ratio between CD4 and CD8 cells being similar to that of other peripheral T-cell populations (Brandtzaeg et al., 1999a). In addition, B-cells aggregate together with T-cells in the M cell pockets, which thus represent the first contact site between immune cells and luminal antigens (Brandtzaeg, 2001;Yamanaka et al., 2001). The B-cells may perform important antigen-presenting functions in this compartment, perhaps promoting antibody diversification and immunological memory or contributing to tolerance induction (Brandtzaeg et al., 1999b). Other types of professional APCs, macrophages and dendritic cells (DCs), are located below the FAE and between the follicles.

Mucosal inductive site

Mucosal effector site

Antigen

Mucosal inductive site

Antigen

Lymphatic vessels

Organized mucosa-associated lymphoid tissue (MALT)

Antigen

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Lymphatic vessels

Organized mucosa-associated lymphoid tissue (MALT)

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Intestinal solitary lymphoid follicles

Appendix

Waldeyer's ring (tonsils)

Peyer's patches

Intestinal solitary lymphoid follicles

Appendix

Waldeyer's ring (tonsils)

Mucosal effector site

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Balt Immune Function
Endothelial gatekeeper function

Fig. 14.3. Schematic depiction of the human mucosal immune system. Inductive sites are constituted by regional mucosa-associated lymphoid tissue (MALT) with their B-cell follicles and M cell (M)-containing follicle-associated epithelium, through which exogenous antigens are actively transported to reach professional antigen-presenting cells (APCs), including B-cells (B) and follicular dendritic cells (FDCs). In addition, mucosal dendritic cells (DCs) may capture antigens and migrate via draining lymph to regional lymph nodes, where they become active APCs, which stimulate T-cells (T) for positive or negative (down-regulatory) immune responses. Naive B- and T-cells enter MALT (and lymph nodes) via high endothelial venules (HEVs). After being primed to become memory/effector B- and T-cells, they migrate from MALT and regional lymph nodes via lymph and peripheral blood for subsequent extravasation at mucosal effector sites. This process is directed by the profile of adhesion molecules and chemokines expressed on the microvasculature, the endothelial cells thus exerting a 'gatekeeper' function for mucosal immunity. The intestinal lamina propria is illustrated with its various immune cells, including B lymphocytes, J-chain-expressing immunoglobulin (Ig)Aand IgM plasma cells, IgG plasma cells with a variable J-chain level (J), and CD4+ T-cells. Additional features are the generation of secretory IgA (SIgA) and secretory IgM (SIgM) via pIgR (SC)-mediated epithelial transport, as well as paracellular leakage of smaller amounts (broken arrow) of serum-derived and locally produced IgG antibodies into the lumen. Note that IgG cannot interact with J chain to form a binding site for pIgR. The distribution of intraepithelial lymphocytes (mainly T-cell receptor a/p+CD8+ and some 7/8+ T-cells) is schematically depicted. Insert (lower left corner) shows details of an M cell and its 'pocket' containing various cell types.

Pioneer studies performed in animals almost 30 years ago demonstrated that immune cells primed in GALT are functionally linked to mucosal effector sites by an integrated migration or 'homing' pathway (Brandtzaeg, 1996a). T-cells activated by microbial and other antigens in GALT preferentially differentiate to CD4+ helper cells, which, aided by DCs and the secretion of cytokines, such as transforming growth factor (TGF)-p and interleukin (IL)-10, induce the differentiation of antigen-specific B-cells to predominantly IgA-committed plasma blasts. These blasts proliferate and differentiate further on their route through mesenteric lymph nodes and the thoracic duct into the bloodstream (Fig. 14.3). Thereafter, they home preferentially to the gut mucosa, where they complete their terminal differentiation to IgA-producing plasma cells (see below). As reviewed elsewhere (Brandtzaeg et al., 1999a, c), this migration of lymphoid cells is facilitated by 'homing receptors' interacting with ligands on the microvascular endothelium at the effector site ('addressins'), with an additional fine-tuned navigation mechanism conducted by chemoattractant cytokines (chemokines). Under normal conditions, therefore, the local microvasculature exerts a 'gatekeeper' function to allow selective extravasation of primed lymphoid cells belonging to the mucosal immune system (Fig. 14.3).

Although GALT constitutes the major part of MALT, induction of mucosal immune responses can also take place in the palatine tonsils and other lym-phoepithelial structures of Waldeyer's pharyngeal ring, including nasal-associated lymphoid tissue (NALT), such as the adenoids in humans (Brandtzaeg, 1999; Brandtzaeg et al., 1999b, c), and probably also bronchus-associated lymphoid tissue (BALT). Because BALT is lacking in normal lungs of newborns and adults (Pabst and Gehrke, 1990; Tschernig et al., 1995), Waldeyer's ring may represent a significant component of human MALT. Accumulating evidence suggests that a certain regionalization exists in the mucosal immune system, especially a dichotomy between the gut and the upper aerodigestive tract with regard to homing properties and terminal differentiation of B-cells (Brandtzaeg et al., 1999a, b, c). This disparity may be explained by microenvi-ronmental differences in the antigenic repertoire as well as the adhesion molecules and chemokines involved in preferential local leucocyte extravasation. It appears that primed immune cells selectively home to effector sites corresponding to the inductive sites where they were initially triggered by antigens. Such regionalization within the 'common' or integrated mucosal immune system has to be taken into account in the development of local vaccines.

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