The mucosal immune system can be divided into organized secondary lymphoid tissue (which allows antigen sampling, uptake, and presentation for initiation of the mucosal immune response) and more diffuse collections of lymphoid cells constituting mucosal effector sites (2). It now well established that Peyer's patches, appendix, and solitary lymphoid nodules in the gastrointestinal (GI) tract constitute the inductive sites of the gut-associated lymphoreticular tissues (GALT). Similarly, the tonsils and adenoids may represent the nasal-associated lymphoreticular tissues (NALT) in the upper airway and aerodigestive tracts. Organized bronchus-associated lymphoreticular tissues
From: Immunotherapy for Infectious Diseases Edited by: J. M. Jacobson © Humana Press Inc., Totowa, NJ
(BALT) (3) were also described at airway branches of experimental animals such as rabbits, rats, and guinea pigs, but these structures rarely occur in humans (4). Collectively, GALT and NALT in humans and GALT, BALT, and NALT in experimental species are termed MALT. The mucosal effector tissues include the interstitial tissues of all exocrine glands, e.g., mammary, lacrymal, salivary, and sweat glands, as well as the lamina propria and the epithelium of the GI tract. In addition, lamina propria areas of the upper respiratory and genitourinary tracts are effector sites of this enormously large immune network. MALT is connected with effector sites through migratory patterns of lymphoid cells. Thus, immune effector cells initiated by encounter with antigen at one mucosal inductive site can migrate to distant mucosal effector sites, where they will exert their effector functions. The existence of this interconnected system of inductive and effector sites has been termed the common mucosal immune system (CMIS).
Mucosal Inductive Sites
Peyer's Patches of the GALT
The columnar epithelium that covers the MALT is infiltrated with B- and T-lymphocytes and antigen-presenting cells (APCs), which has led to the term follicle-associated epithelium (FAE). Soluble and particulate lumenal antigens are taken up by a microfold or M cell and delivered to adjacent APCs. M-cells have been described in human Peyer's patches, appendix, and tonsils (5). These cells appear to be ideal for antigen uptake (6). However, M-cells that only contain sparse numbers of lysosomes (7) probably do not degrade ingested antigens and thus are not classical APCs (8). M-cells serve as the entry points for uptake; as such they actively ingest soluble proteins as well as particulate antigens, which can include viruses, bacteria, small parasites, and microspheres (6,9-11). In addition to serving as a means of transport for lumenal antigens, the M-cells also provide an entry pathway for pathogens. A recent study suggested that lymphocytes and especially B-cells possess signaling molecules that induce M-cell differentiation of epithelial cells. In this study, mouse Peyer's patch T- and B-cells as well as a human B-cell line (Raji) induced Caco-2 cells to differentiate into M-like cells (12).
Peyer's patches contain a dome region underneath the FAE, as well as underlying follicles that contain five or more germinal centers (13). The dome region is characterized by the presence of T- and B-cells as well as both macrophages and dendritic cells (DCs). The presence of all three major APC types in the dome, e.g., memory B-cells, M0 and DCs make it likely that antigen uptake occurs immediately after release from M cells. Furthermore, Peyer's patch germinal centers differ from those in peripheral lymph nodes and spleen in that relatively high frequencies of SIgA+ B-cells predominate (14-17).
The regulation of Peyer's patch formation in mammals is only partially understood; nevertheless, recent studies suggest that interactions of membrane lymphotoxin (LT)/tumor necrosis factor (TNF) cytokines with LT-p receptor are of central importance in Peyer's patch development (18,19). For example, injection of pregnant mice with lymphotoxin p-receptor Ig (LT-p-R-Ig) fusion protein resulted in loss of Peyer's patches (19) and most lymph nodes except the mesenteric lymph nodes. Recent studies with this model showed that Peyer's patches are not strictly required for the induc tion of mucosal S-IgA Ab responses and suggest a role for mesenteric lymph nodes as alternative inductive sites in the GI tract. Indeed, S-IgA Abs were induced when mice from LT-p-R-Ig-treated mothers were orally immunized with cholera toxin (CT) and a soluble protein antigen (20). In contrast, neither systemic nor mucosal S-IgA Ab responses were seen after administration of the same oral vaccine regimen to TNF-a and LT-a double knockout mice that lack both Peyer's patches and mesenteric lymph nodes (20). However, Peyer's patches appear to be crucial for the development of oral tolerance to protein antigens since mice from LT-p-R-Ig-treated mothers showed impaired induction of this type of tolerance (21).
The NALT includes the palatine, lingual, and nasopharyngeal tonsils, which collectively create a ring of tissue (Waldeyer's ring) that is strategically positioned at the entry of the digestive and respiratory tracts. These tissues possess structural features resembling both lymph nodes and Peyer's patches, including an FAE with M-cells in tonsillar crypts that are essential for selective antigen uptake. In addition, germinal centers containing B-cells, and professional APCs are also present. Direct unilateral injection of antigens (cholera toxin B subunit [CT-B] and tetanus toxoid [TT]) into the tonsil of human volunteers resulted in the induction of mucosal immune responses manifested by the appearance of antigen-specific IgG- and (to a lesser degree) IgA-producing cells in the noninjected tonsil (22). These studies suggest that the tonsils may serve as an inductive site, analogous to Peyer's patches. Several recent nasal immunization studies have emphasized the importance of the NALT for induction of both mucosal and systemic immune responses that may exceed in magnitude those induced by oral immunization (22-30).
Follicular structures analogous to Peyer's patches are also found in the large intestine, with especially pronounced accumulations in the rectum. In fact, monkeys immunized intrarectally with simian immunodeficiency virus (SIV) developed both T- and B-cell-mediated immune responses, including the induction of anti-SIV Abs in rectal washes and genital secretions (31,32). Similarly, mice immunized intrarectally with CT or recombinant vaccinia virus expressing gp120 of SIV exhibited Abs responses in genital tract secretions as well as in serum; this immunization route was frequently superior to either the intragastric or intravaginal route (33).
Homing of Effector Lymphocytes into Mucosal Compartments
Early studies in rabbits showed that GALT B-cells repopulated the gut with IgA plasma cells, suggesting a direct connection for B-cell migration between Peyer's patches and GI tract lamina propria (34,35). Furthermore, orally immunized experimental animals possessed antigen-specific precursors of IgA plasma cells in GALT-associated mesenteric lymph nodes, which repopulated the lamina propria of the gut and the mammary, lacrymal, and salivary glands (36-39). These studies, when combined with others showing that oral immunization led to S-IgA antibodies in multiple mucosal sites, served as the basis for suggesting a "common" mucosal immune system in humans (40-42). Studies in recent years have unveiled molecular mechanisms involved in the migration of immune cells into the GI tract and, to a lesser extent, homing into other mucosal effector sites.
Naive lymphocytes enter mucosal or systemic lymphoid tissues from the blood through the endothelium via specialized high endothelial venules (HEVs) (43). In GALT, HEV are present in the interfollicular zones rich in T-cells (44). The mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is the major addressin expressed by Peyer's patch HEV (45). The major homing receptors expressed by lymphocytes are the integrins, which represent a large class of molecules characterized by a het-erodimeric structure of a and (3 chains. In general, expression of the a4 chain paired with either (31 or (37 integrins differentiates between homing receptors for the skin or gut, respectively. Thus, the a4p1 pair allows binding to vascular cell adhesion mole-cule-1 (VCAM-1) and is associated with homing to inflamed sites and skin (46,47). Pairing of a4 with (37 represents the major integrin molecule responsible for lymphocyte binding to MAdCAM-1 expressed on HEVs in Peyer's patches (48). A number of studies have now established that MAdCAM-1 is the major mucosal homing receptor ligand (48-50). In addition to a4p7 integrin, L-selectin, which also binds to carbohydrate-decorated MAdCAM-1, is an important initial receptor for homing into GALT HEVs. Interestingly, L-selectin is expressed on all naive lymphocytes; however, memory T- and B-cells can be separated into a4p7hi, L-selectin+, and L-selectin~ subsets (51).
It is now clear that chemokines are directly involved in lymphocyte homing and that they trigger arrest and cell activation via specific Gsai receptors (52). For example, loss of secondary lymphoid tissue chemokine (SLC) results in lack of naive T-cell or dendritic cell migration into the spleen or Peyer's patches (53). Furthermore, thymus-expressed chemokine (TECK) mediated human memory T-cell migration into the lamina propria of the GI tract. In fact, the gut homing a4p7hi T-cells expressed a TECK receptor, designated G-protein-coupled receptor-9-6, or CCR-9 (54). Interestingly, human aEp7+ as well as a4p7hi CD8 T-cells expressed CCR-9, suggesting that TECK-CCR-9 is also involved in lymphocyte homing and arrest of intraepithelial lymphocytes (IELs) into the GI tract epithelium (54).
Lymphocyte Homing in NALT and Lung-Associated Tissues
Unlike Peyer's patch HEVs which are found in T-cell zones, murine NALT HEVs are found in B-cell zones and express, peripheral node addressin ( PNAd) either alone or associated with MAdCAM-1 (55). Furthermore, anti-L-selectin but not anti-MAdCAM-1 Abs blocked the binding of naive lymphocytes to NALT HEV, suggesting predominant roles for L-selectin and PNAd in the binding of naive lymphocytes to these HEVs (55). In a rat model of antigen-induced lung inflammation, the percentage of activated T-cells expressing a4 was increased in the bronchial lumen compared with blood and lymph node T-cells after antigen challenge (56). An interesting approach used to address the homing of human cells in the NALT was the analysis of tissue-specific adhesion molecules after systemic, enteric, or nasal immunization (57). This study showed expression of L-selectin by most effector B-cells induced by systemic immunization, with only a small proportion expressing a4p7; the opposite was seen after enteric (oral or rectal) immunization. Interestingly, effector B-cells induced by intranasal immunization displayed a more promiscuous pattern of adhesion molecules, with a large majority of these cells expressing both L-selectin and a4p7 (57).
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