Immunology00247 0003

Immunology 1980 41 249
Review
Mucosal immunology
J. BIENENSTOCK & A. D. BEFUS* Department of Pathology, McMaster University Health Sciences Centre, Hamilton, Ontario, Canada
Accepted for publication 23 May 1980
CONTENTS
Introduction IgA IgA function Lymphocyte migration to mucosae IgE Mucosal T cells Cells in the lumen and epithelium of the intestine Mucosal mast cells Goblet cells and mucosal resistance Antigen uptake and processing Regulation of the immune response by mucosal presentation of antigen Vaccination of mucosal surfaces Speculations and conclusions Acknowledgments References
Introduction In this review, we shall highlight some recent advances in mucosal immunology and also those concepts which seem to us to merit more attention than they normally receive. Since we cannot hope to be all inclu* Recipient of Rockefeller Foundation Fellowship in Tropical and Geographic Medicine. Correspondence: Dr J. Bienenstock, Department of Pathology, McMaster University Health Sciences Centre, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5. 00 1 9-2805/80/1000-0249502.00 A) 1980 Blackwell Scientific Publications
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sive, we recommend the following articles and books to the reader (Tomasi & Bienenstock, 1968; Tomasi & Grey, 1972; Bienenstock, 1974; Heremans, 1974; Mestecky & Lawton, 1974; Lamm, 1976; Tomasi, 1976; Waksman & Ozer, 1976; Porter & Knight, 1977; McGhee, Mestecky & Babb, 1978; Ogra & Dayton, 1979; Befus & Bienenstock, 1980).
IgA After Heremans, Heremans & Schultze (1959) isolated and characterized serum fl2A-globulin, Hanson (1961) showed that it predominated in milk and that it had
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unique characteristics. Tomasi, Tan, Solomon & Prendergast (1965) demonstrated that these were due to a polypeptide which was called transport piece, but now secretory component (SC). It is known that secretory IgA (sIgA) which is abundant in secretions can be synthesized in local plasma cells (Tomasi & Bienenstock, 1968) as a dimer containing an additional polypeptide, J chain (Koshland, 1975). This dimeric IgA binds to SC in the membrane of epithelial cells which synthesize this polypeptide (Brandtzaeg, 1974, 1978; Crago, Kulhavy, Prince & Mestecky, 1978) and this complex of sIgA is transported across the epithelial cell in vesicles to be released at the apical surface into the intestinal lumen (Allen, Smith & Porter, 1973; Nagura, Nakane & Brown, 1979). These observations of a specialized sIgA molecule in secretions provided an explanation for the longstanding observation that specific immunological resistance to mucosal infection could exist in the absence of demonstrable serum antibody. For example, IgA antibody to a variety of viruses, bacteria, other agents and even to components of food, were found in local secretions and resistance correlated best with this local antibody rather than with circulating antibody (Tomasi & Bienenstock, 1968). It was proposed that IgA in serum was specifically transported into secretions (South, Cooper, Wollheim, Hong & Good, 1966) but subsequent studies on the turnover of serum and sIgA in healthy and diseased patients provided little support for this suggestion. However, recent studies by the groups of Vaerman (Lemaitre-Coelho, Jackson & Vaerman, 1977; Jackson, Lemaitre-Coelho, Vaerman, Bazin & Beckers, 1978; Lemaitre-Coelho, Jackson & Vaerman, 1978a, b), Hall (Orlans, Peppard, Reynolds & Hall, 1978; Hall, Orlans, Reynolds, Dean, Peppard, Gyure & Hobbs, 1979; Birbeck, Cartwright, Hall, Orlans & Peppard, 1979) and Underdown (Fisher, Nagy, Bazin & Underdown, 1979; Socken, JeeJeeBhoy, Bazin & Underdown, 1979) have shown that dimeric IgA antibody synthesized at one mucosal site is selectively and rapidly transported across the hepatic parenchymal cell into the bile. If the common bile duct is ligated, a pronounced increase in IgA in the blood is seen (Lemaitre-Coelho et al., 1978a). This transport of dimeric IgA is dependent upon the expression of SC on the surface of the hepatic cell (Fisher et al., 1979; Socken et al., 1979) and only oligomeric IgA is transported. These results explain the original observations in which 7S serum IgA or myeloma IgA were used (Strober, Blaese & Waldmann, 1970; Coelho, Pereira
& Virella, 1974) and also why so little sIgA was found in nasal secretions following intravenous administration of secretory IgA (Butler, Rossen & Waldmann, 1967). Whether IgM can also be efficiently transported across the hepatic cell through the binding to SC remains to be clarified. In the rat where IgM has a weak affinity for SC, little IgM is transported by the perfused liver (Fisher et al., 1979). However, it is possible that IgM may be transported across the hepatocyte in species such as man where SC binds IgM with a high affinity (Socken & Underdown, 1978). IgM appears to be transported across the intestinal epithelial cell in the same manner as dimeric IgA and this is presumably significant in human conditions such as IgA deficiency where IgM is bound to SC non-covalently and is increased in quantity in secretions and IgM synthesizing cells are elevated in the intestinal lamina propria (Brandtzaeg, Fjellanger & Gjeruldsen, 1968). A similar replacement of IgA by IgM has also been shown in an avian model of selective IgA deficiency (Perey & Bienenstock, 1973; Lawrence, Arnaud-Battandier, Koski, Dooley, Muchmore & Blaese, 1979). Thus, antibody may be locally synthesized in a mucosal tissue, enter the circulation by local diffusion or by lymphatic drainage and then be selectively secreted into the bowel by way of the bile. Some direct and indirect evidence suggests that a similar selective transport system exists for the lacrimal and salivary glands (Montgomery, Khaleel, Goudswaard & Virella, 1977; Mestecky, McGhee, Arnold, Michalek, Prince & Babb, 1978). Whether such a system exists also for all mucosal tissues has not been confirmed, although recent evidence that it also exists in the breast has been reported (Chalsey, Johnson & Cebra, 1980). Although it is clear that this selective transport of IgA by SC must be important, only one SC-deficient patient has been well documented and that patient suffered from recurrent diarrheal disease (Strober, Krakauer, Klaeveman, Reynolds & Nelson, 1976). Recently, SC deficiency in saliva was identified in a family of patients with inflammatory bowel disease but this association has not been clarified (Engstrom, Arvanitakis, Sagawa & Abdou, 1978). A retrospective study suggested that SC deficiency might be a common factor in sudden infant death syndrome (Ogra, Ogra & Coppola, 1975) especially since such patients often appear to have evidence of defective mucosal barrier function and thus, a prospective examination of the role of SC deficiency is underway.
Mucosal immunology IgA function Much has been written about the function of IgA antibody in mucosal resistance (Tomasi, 1976; Lamm, 1976) and thus we shall not review this area extensively. Recently, the importance of IgA in mucosal resistance has been extended to intestinal parasites such as the coccidia of chickens, a protozoan infection of major economic importance (Davis, Parry & Porter, 1978). IgA has also been shown to be effective in passive transfer of immunity against the tapeworm, Taenia taeniaformis, a widely used model of parenteral tapeworm infection (Musoke, Williams, Leid & Williams, 1975; Lloyd & Soulsby, 1978). However, the exact mechanisms of immunity against most parasites are not well understood (Wakelin, 1978) and thus the relative contributions of various components of the immune response are unclear. As will be discussed more fully below, the demonstration of T lymphocytes which bear Fc receptors for IgA would appear to be a significant development (Strober, Hague, Lum & Henkart, 1978; Lum, Muchmore, Keren, Decker, Koski, Strober & Blaese, 1979), but as yet, the specific function of this T-cell subpopulation, if any, is unknown (Lum, Benveniste & Blaese, 1980). Similarly, the existence of IgA receptors on neutrophils is undoubtedly significant in the function of this cell type (Van Epps & Williams, 1976; Van Epps, Reed and Williams, 1978) and observations of defects in chemotactic activity in inflammatory bowel disease have been attributed to IgA complexes which bind to the surface of these cells (Patrone, Dallegri & Sacchetti, 1978). Further, the observations of IgA associated with Paneth cells (Rodning, Wilson & Erlandsen, 1976) suggests that the anti-microbial or other functions of this cell type (Sandow & Whitehead, 1979) may be influenced by IgA antibody in secretions. A more complete knowledge of the function of IgA receptors on these various cell types will undoubtedly improve our understanding of the functions of this immunoglobulin. Experiments on the role of oligomeric or monomeric IgA in regulation of antibody synthesis of any class have not been reported. Initial work in organ culture on the control of synthesis of secretory IgA by IgA fragments which seemed so promising has not been pursued (Lawton, Asofsky & Mage, 1970). It is interesting that secretion of a protease specifically able to cleave IgA I selectively, may be correlated with pathogenicity of Neisseria gonorrhoeae and meningitidis (Mulks & Plaut, 1979). The significance of
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this IgA protease is unclear since IgA2, which is resistant to its action, is present in secretions in as large amounts as IgA 1. The role of IgA in the regulation of dietary antigen ingress across mucosal epithelia has been much discussed (Walker & Isselbacher, 1977). We do not intend to review this important area. The role of intestinal antibodies in control of immunity by regulation of antigen uptake in the intestine in highly significant and may be crucial to out understanding of the development of allergy to environmental allergens (Mathew, Taylor, Norman, Turner & Soothill, 1977; see also section on speculations and conclusions).
Lymphocyte migration to mucosae It is well known that blast cells derived from the mesenteric lymph node (MLN) or thoracic duct (TD) have a predilection for the small intestine (Gowans & Knight, 1964; Griscelli, Vassalli & McCluskey, 1969; Hall & Smith, 1970). Twenty-four hours after adoptive transfer these cells are found predominantly in the small intestine, with about two- to ten-fold fewer in the large intestine (Guy-Grand, Griscelli & Vassalli, 1974; McWilliams, Phillips-Quagliata & Lamm, 1975), although in both sites the cells are predominantly of the IgA isotype. Moore & Hall (1972) showed that TD blasts can selectively lodge in the bowel of syngeneic, allogeneic and even xenogeneic recipients. Repopulation experiments in lethally irradiated rabbits using different donor lymphoid cell sources showed that Peyer's patches (PP) contain a precursor population largely destined to make IgA in the intestine several days after transfer (Craig & Cebra, 1971). The exact route of migration of these cells during the intervening time is not clear, but evidence suggests that the MLN is important in the IgA cell cycle (Husband & Gowans, 1978; Roux, McWilliams, Lamm & Phillips-Quagliata, 1979). From repopulation experiments in irradiated rabbits (Jones & Cebra, 1974) and from adoptive transfer experiments over a 24 h period in mice (McWilliams et al., 1975; McWilliams, Phillips-Quagliata & Lamm, 1977), the IgA precursor cell is known to possess IgA on its surface but lacks C3 receptors and surface IgM. It has been suggested that these precursor cells are already primed and Gearhart & Cebra (1979) have evidence that this is the case, since there is a predominance of IgA-producing cells reactive against determinants found on bacteria, such as inulin and phosphorylcholine, in the PP as compared with the spleen, whereas the reverse is true for dinitro-
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IgA precursor cells in the cervical mucosa was hormonally dependent, since three times as many cells were found in this site during proestrus than in metestrus, whereas no significant differences were found in the numbers of cells localizing in the small intestine at these various stages of the estrus cycle (McDermott, Clark & Bienenstock, 1980). When bronchial lymph node (BLN) cells were used as the donor population, IgA containing cells were found to predominate in the small intestine, lungs and MLN. However, when the actual numbers of cells were examined (see Table 1, McDermott & Bienenstock, 1979), relatively few cells from BLN localized in the small intestine; the majority returned to the lung. The corollary was that MLN cells localized to a greater extent in the intestine than in the lung. Thus, in addition to specificity of a mucosal seeking population, an additional specificity, that of the organ of origin is seen. Similar observations of organ specificity have been made by Smith, Martin & Ford (1980). Weisz-Carrington, Roux, McWilliams, Phillips-Quagliata & Lamm (1979) extended these observations to specific antibody containing cells and showed that following feeding of ferritin, specific IgA antibody producing cells of immune MLN origin predominated in the gut, lung and mammary and parotid glands. It should be noted that there are a small number of both IgA and IgG precursor cells from peripheral lymph nodes (PLN) which localize in the small intestine (McDermott & Bienenstock, 1979). The term PLN may be a misnomer, since many of these lymph nodes drain mucosal tissues such as the breast and salivary glands (Tilney, 1971), and this may account for the mucosal localization of some PLN cells. Alternately, it may be that there is integration of lymphoblasts from various lymph nodes draining mucosal and non-mucosal sites as they migrate in the body. Most studies which deal with the lodging of lymphoblasts in mucosae have emphasized the importance of IgA, so that the possibility of precursors of other isotypes selectively lodging in mucosal tissues has largely been ignored. This is despite the work of Jacobson, Marks, Simmons & Gaston (1961) which showed that a single shielded PP would repopulate the lymphoid tissues of an irradiated animal. Further, Perey, Cooper & Good (1968) showed that surgical removal of GALT in the rabbit led to a diminution in circulating immunoglobulins as well as immune responses to a variety of antigens. Our own experiments showed that more of the MLN-derived lymphoblasts which selectively lodged in the bronchus made IgG
phenol, a determinant not normally associated with bacteria. By extrapolation from data acquired using the Klinman clonotype assay, priming is thought to have occurred either in the PP themselves, or elsewhere with the subsequent commitment to IgA production. In 1973 we described the similarities between the bronchus associated lymphoid tissue (BALT) and gut associated lymphoid tissue (GALT) (Bienenstock, Johnston & Perey, 1973a, b). Recently Tenner-Raicz, Rdcz, Myrvik, Ockers & Geister (1979), have shown that the lympho-epithelium of BALT has selective antigen uptake characteristics similar to the lymphoepithelium of GALT and the follicle-associated epithelium of the bursa of Fabricius. Cells derived from the lung, but not isolated solely from the BALT follicles due to technical difficulties, behaved similar to GALT cells and repopulated the spleen, bowel and lung of lethally irradiated rabbits with predominantly IgAcontaining cells (Rudzik, Clancy, Perey, Day & Bienenstock, 1975). Conversely, GALT cells repopulated the bronchial mucosa with IgA containing cells. We therefore thought that this might represent a universal mucosal immune system (Bienenstock et al., 1973) and subsequently coined the term common mucosal immune system' (Bienenstock, 1974; Bienenstock, McDermott, Befus & O'Neill, 1978; Bienenstock, McDermott & Befus, 1979).
Goldblum, Ahlstedt, Carlsson, Hanson, Jodal, Lidin-Janson & Sohl Akerlund (1975) showed after feeding of non-pathogenic E. coli that specific IgA antibody appeared in breast secretions of lactating females. Similarly, IgA cells containing the specific antibody against the appropriate serotype of E. coli and capable of its secretion in a plaque assay were also found in the milk. The extent to which this observation is valid has been questioned recently by Mestecky & McGhee (1980) who have pointed out that many of these cells contain lactoferrin and have characteristics of macrophages. However, MLN B lymphoblasts selectively do localize in breast tissue where they make IgA and this localization appear to be hormonally controlled (Roux, McWilliams, Phillips-Quagliata, Weisz-Carrington & Lamm, 1977; Weisz-Carrington, Roux, McWilliams, Phillips-Quagliata & Lamm, 1978). Further evidence for the common mucosal immune system based upon IgA, was provided by McDermott & Bienenstock (1979) who showed that selective localization of MLN lymphoblasts occurred in the bronchial and cervical mucosa where IgA was the major product of the transferred cells. The accumulation of
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when compared to peripheral nodes and also that the MLN is a source of IgG and IgM precursor cells which localize in the intestinal lamina propria (McDermott & Bienenstock, 1979). Similarly, BLN provided twelve times as many IgG precursor cells to the lungs as did PLN cells. Thus there is a mucosal selectivity to IgG precursor cells derived from mucosal lymph nodes. Small lymphocytes emigrate from the circulation through specialized endothelial post-capillary venules (Gowans & Knight, 1964). In the intestine and lungs, such specialized structures are found only in the organized lymphoid aggregates (GALT and BALT). Total surgical extirpation of PP in the rat produced no alteration in the numbers of IgA-containing cells or in the localization of MLN lymphoblasts 24 h after their adoptive transfer (McDermott, Heatley, Befus & Bienenstock, 1980). Further, autoradiographic examination of tissues after MLN transfers revealed that labelled cells were first found in the crypt and basal lamina propria of the intestine but that no specialized vascular structures could be identified in these areas. These results strongly suggest that the mucosal localization of lymphoblasts is not dependent on high endothelial post-capillary venules. It has been widely assumed that lymphoblasts do not recirculate from lymph to blood to lymph, but Howard (1972) and Smith et al. (1980) have shown that this is not the case, as some TD lymphoblasts may be found in TD after intravenous transfer. Furthermore, it is possible that lymphoblasts may divide in tissues and subsequently appear in lymph as small lymphocytes. Recently, evidence has accumulated that such local cell division may occur in the intestine (Husband & Gowans, 1978; Mayrhofer & Fisher, 1979). For example, when rats were subjected to continuous TD drainage (Mayrhofer & Fisher, 1979) the numbers of IgA-containing cells in the intestine dropped. However, they did not fall exponentially, as might be expected if most such cells were derived from the organized lymphoid tissue and migrated through the lymph nodes to the TD and returned to the intestine. This observation suggests that local cell division may occur in the intestine, although an equal possibility is that there is an increased production of mucosal (intestinal)-seeking IgA lymphoblasts in other mucosal associated lymphoid tissue such as BALT (see Sanders & Florey, 1941). Other evidence that cells in the lamina propria of the intestine are capable of proliferation comes from our observations on the repopulation of irradiated recipients with IgA-containing cells using lamina propria cells from the rabbit
intestine (Befus, O'Neill & Bienenstock, 1978). The role of IgA-specific T helper cells, which are abundant in the PP relative to the spleen (Elson, Heck & Strober, 1979), in the localization of IgA precursor cells in mucosal tissues remains to be determined. Such IgA-specific T helper cells may be necessary for the IgA immune response not only at the level of cell traffic, but also for the priming of the precursor, its secretion or for secondary responses. The significance of the T alpha cell in this regard awaits clarification (Strober et al., 1978; Lum, Benveniste & Blaese, 1980). The factors controlling the mucosal localization of various precursor cells are largely unknown and undoubtedly complex (Table 1). Although SC was considered a candidate for such cell localization (McWilliams et al., 1975), it does not appear to be important. Hormones clearly influence cell localization in mucosae (Weisz-Carrington et al., 1978; McDermott et al., 1980) but whether these are of primary or secondary importance is not presently clear. Similarly, blood flow is important (Ottaway & Parrott, 1979), but appears to us not to be the entire answer. Antigen to which cells are primed amplifies their localization (Pierce & Gowans, 1975) but considerable evidence exists to indicate that it is not essential for this localization (Halsted & Hall, 1972; Pierce & Gowans, 1975). The nature of the organ specificity described above is not clear but presumably chemotactic factors may be of some importance (Parrott, 1979). Recent experiments in our laboratory support a role for hormonal regulation of lymphoblast localization in mucosae as the transfer of male MLN lymphoblasts into male recipients yielded approximately 2-5 times as many
Table 1. Factors which affect the localization of lymphoblasts in mucosal tissues
Lymphocyte characteristics Mucosal vs non-mucosal source Surface IgA Secretory component (?) Antigen receptors Hormone receptors (?) Chemotactic factor receptors (?) Receptors for T helper cell products (?) Vasculature Regulation of blood flow High endothelial cells Other specializations of endothelium (acceptors, receptors ?) Hormonal influences (?)
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amounts of antigen to rats given Bordetella pertussis leads to significant levels of IgE in the circulation
cells in the recipient intestine as similar transfers between female donors and recipients (Mirski et al., unpublished results).
IgE IgE, the major class of reaginic antibody, is present in secretions of target organs of allergy such as the nose, eyes, bronchial and intestinal mucosa (see PlattsMills, 1979). Early studies using immunofluorescent techniques suggested that in the monkey and human, IgE was abundant in mucosal tissues and draining lymph nodes (Tada & Ishizaka, 1970). However, many of the original observations have been revised since the application of more sensitive double antibody radioimmunoassays, which have shown that contrary to earlier results, there is almost no IgE in human milk (Underdown, Knight & Papsin, 1976), and similar revisions have occurred for earlier estimates of IgE in urine (Stokes, Hosking, Turner & Johansson, 1973; Turner, McClelland, Medlen & Stokes, 1977). It has also become evident that there may be problems with the identity of the cells which contain IgE in mucosal sites, as Mayrhofer, Bazin & Gowans (1976) showed that mast cells, but not plasma cells, in the intestine of parasitized rats contained IgE. However, studies ofthe synthesis of IgE using PP (Ngan and Kind, 1976, 1978), MLN (Gerbrandy & Bienenstock, 1976; Suemura, Urban & Ishizaka, 1978; Rector, Carter, Kelly, Lang & Sehon, 1979; Befus, Johnston, Berman & Bienenstock, 1980) and BLN (Gerbrandy & Bienenstock, 1976; Befus et al., 1980) have confirmed the mucosal association of this immunoglobulin. IgE does not share the same transport system as IgA and IgM, and although a good deal is known about the regulation of IgE synthesis (M6ller, 1978), almost nothing is known about the migratory properties ofcells destined to make this immunoglobulin. Durkin & Waksman (1979) identified large numbers of IgE-bearing, presumably B lymphocytes, in the PP of germ-free rats. In conventional rats, IgE-bearing cells were abundant in the bone marrow but not so frequent in the PP. Recently, lymphocytes bearing Fc receptors for IgE have been identified in various species (Yodoi & Ishizaka, 1979, 1980; Fritsche & Spiegelberg, 1978) and it would appear that some of these cells may represent IgE-bearing B lymphocytes whereas others represent T lymphocytes bearing IgE Fc receptors that might be involved in the regulation of IgE synthesis. Intraperitoneal or oral administration of small
(Jarrett & Stewart, 1974; Jarrett, Haig, McDougall & McNulty, 1976; Bazin & Platteau, 1976). Ngan & Kind (1978) showed suppressor cells specific for IgE in the PP following oral feeding. Intratracheal immunization leads to the production of IgE antibody in the lymph nodes draining the lungs, and footpad immunization leads to IgE synthesis in the draining popliteal nodes, albeit in much lower amounts (Gerbrandy & Bienenstock, 1976). No single group of experiments has yet been done in which the synthesis and secretion of IgE antibody by various tissues was followed after immunization by different routes including oral, intratracheal and other parenteral means. From the data which is available it is tempting to speculate that the synthesis of IgE antibody is dependent upon mucosal lymphoid follicles such as BALT and GALT and that the migration, localization and differentiation of IgE precursor cells is in large part controlled by the environment of the nasopharynx, intestine and lungs. The observations of Durkin and Waksman (1979) on IgE-bearing cells in PP of germ-free animals, as well as those of Urban, Ishizaka & Ishizaka (1977) on the generation of IgE-bearing lymphocytes, provide useful models for the study of IgE precursor cells and the factors which govern their activities. It has been reported, using parenteral but not mucosal immunization protocols, that neonatal exposure to antigen may lead to an exclusive, or at least predominant, IgE antibody response in serum (Pinckard, Halonen & Meng, 1972). In guinea-pigs (Coombs, Devey & Anderson, 1978) as well as in piglets and calves (Barratt, Strachan & Porter, 1978), oral immunization with dietary proteins such as cow's milk and soya protein have led to digestive disturbances or specific anaphylaxis following challenge which were attributed to IgGl-mediated hypersensitivity. These studies, together with evidence of local synthesis of reaginic antibody in its absence in the circulation (Huggins & Brostoff, 1975; Platts-Mills, 1979), open a large field for study which may be crucial to the elucidation of mechanisms of allergic reactions in man and animals and the possible role of IgA antibody in blocking antigen uptake (Stokes, Soothill & Turner, 1975) or other activities. Recent observations by Jarrett on the transfer of specific regulatory influences on IgE synthesis from mother to young by colostrum suggest that immunotherapeutic measures may ultimately be used in the control of mucosal allergic reactions (Jarrett & Hall, 1979).
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Mucosal T cells
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T lymphoblasts from normal adult MLN and TD selectively lodge in the lamina propria and epithelium of the normally situated intestine as well as in foetal gut isografts (Guy-Grand et al., 1974). T lymphoblasts from TD of irradiated Fl mice injected with parental thymocytes also home into the intestinal epithelium (Sprent, 1976). However, T lymphoblasts derived from PLN do not normally localize in the intestine unless the latter is inflamed as occurs in Trichinella spiralis infection in mice (Rose, Parrott & Bruce, 1976). Experiments on the localization of T lymphoblasts in the mammary gland have not been conducted, although T cells are found in breast secretions (Parmely & Williams, 1979; Head & Beer, 1979). It is controversial whether small recirculating lymphocytes selectively localize at mucosal sites. In sheep, Cahill, Poskitt, Frost & Trnka (1977) have shown that such mucosally derived cells may localize in mucosal sites, whereas studies in the mouse (Freitas, Rose & Parrott, 1977) are contradictory. These differences may reflect the particular experimental designs utilized or species differences. Oral immunization can lead to systemic delayed hypersensitivity reactions (Perrotto, Hang, Isselbacher & Warren, 1974) or the generation of cytotoxic T lymphocytes in PP and extra-intestinal sites (Kagnoff, 1978a). Administration of antigen to the gastrointestinal or respiratory tract can lead to the appearance of cells capable of releasing macrophage migration inhibition factor (MIF), but whether these cells are T lymphocytes remains to be clarified (Frederick & Bohl, 1976; Huntley, Newby & Bourne, 1979; Henney & Waldmann, 1970; Nash & Holle, 1973). Cellular immune activities of human T lymphocytes in milk suggest that they are reactive to antigens experienced-at other mucosal sites (Parmely, Reath, Beer & Billingham, 1977). These observations suggest that the extent of T-cell integration of various mucosal sites requires further study. The functional significance of mucosal-associated T cells has received some investigation. T-cell mediated hypersensitivity in the small intestine contributes to partial villus atrophy in Nippostrongylus brasiliensis infection of rats (Ferguson & Jarrett, 1975) or T. spiralis (Manson-Smith, Bruce & Parrott, 1979) or Giardia muris infection of mice (Roberts-Thomson & Mitchell, 1978). In man, partial villus atrophy such as in coeliac disease and tropical sprue may have a similar aetiology (Ferguson & MacDonald, 1977). The poss-
ible effects of T-cell derived lymphokines or other cytokines on the integrity of the epithelium and proliferation of crypt cells must be studied. Recently, Miller has shown that it is possible to transfer primed surface immunoglobulin negative, presumed T lymphocytes from the thoracic duct of rats infected with N. brasiliensis and induce goblet cell hyperplasia in infected recipients (Miller & Nawa, 1979a). Thus the possibility that T cells may be involved in the regulation of goblet cell numbers and their secretory activity must be seriously considered. This concept may be profitably applied to immunological reactions in the lung such as asthma and chronic bronchitis where goblet cell hyperplasia occurs and where T-cell hypersensitivity has not been seriously considered previously. In milk it has been shown that there may be vertical transmission of resistance to tumours during the suckling period (Head, Beer & Billingham, 1977). Whether this is due to the transfer of T or other cells, or even non-cellular factors across the neonatal gut has not been determined, but it is known that in the human, delayed hypersensitivity reactivity may be passed to the offspring during lactation (Mohr, 1973; Schlesinger & Covelli, 1977). In some murine strains, T cells in the thymus synthesize and incorporate IgA into their surface (Lahat, Moroz & Askenazi, 1978). Cottier and co-workers (Joel, Hess & Cottier, 1972; Chanana, Schaedeli, Hess & Cottier, 1973) have shown that shortly after birth the majority of lymphocytes found in the PP come from the thymus. Albini & Wick (1975) used several different antisera to IgA to show that in the chicken, the thymus possessed cells which expressed surface IgA. Lastly, there are in both man and mouse, T lymphocytes which have receptors for IgA (Strober et al., 1978; Lum et al., 1979). It is far from clear how these separate observations may be connected, but a number of speculations might be entertained. First, the early seeding of these cells may be important. In the mucosa associated lymphoid tissue (MALT) they may represent IgA class-specific helper cells. Alternatively, in the MALT these cells may, contrary to dogma, either represent B cells having received some significant education in the neonatal thymus, or even more heretical a notion, could even be MALT-seeking T cells which subsequently acquire B-cell characteristics.
Cells in the lumen and epithelium of the intestine Although the presence of cells in the faeces has been a
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mast cells, globule leucocytes and thymocytes, and whether they are related to the epithelial lymphocytes found in other mucosal tissues, such as the respiratory and urogenital tracts and mammary glands (Seelig et al., 1979) is unknown. We have shown that cells derived primarily from the epithelium of the intestine of the guinea-pig have more cytotoxic potential than cells derived from the lamina propria when studied using spontaneous, mitogen-induced and antibody-dependent cytotoxicity systems (Arnaud-Battandier, Bundy, O'Neill, Bienenstock & Nelson, 1978).
diagnostic tool for some time (Harris, Dupont & Hornick, 1972), the presence of cells in the lumen of the intestine has only recently become an area of active investigation (Bellamy & Nielsen, 1974; Owen, Nemanic & Stevens, 1979; Parrott, personal communication). Lymphocytes are normally found in large numbers in other secretions such as those of the breast (Seelig, Holt & Beer, 1979; Head & Beer, 1979) and respiratory tract (Kaltreider & Salmon, 1973; Daniele, Altose & Rowlands, 1975; Kazmierowski, Fauci & Reynolds, 1976). Cells in the lumen of the lung may be antigen sensitive (Clancy & Bienenstock, 1974; Hill & Burrell, 1979) and derived from a population of recently dividing cells (Daniele, Beacham & Gorenberg, 1977). In the gut, lumenal cells have been found in G. muris infected mice (Owen et al., 1979) and more recently in man (Owen, personal communication). We have observed cells in the lumen ofthe rabbit appendix and on the surface of PP (Heatley & Bienenstock, unpublished results). From cytokinetic studies using in vivo labelling with tritiated thymidine, we have suggested that cells in the lumen of the lung may be derived from the BALT follicles (Bienenstock et al., 1973b). Cells in the lumen of the intestine may similarly arise from GALT, but whether these cells have properties similar to, or different from, cells isolated from the follicles remains to be determined. Our observations on lumenal cells in the rabbit appendix show that they include both IgA-containing cells as well as T lymphocytes. Recently, cells have been observed in the lumen of the avian bursa (Odend'hal & Breazile, 1979) and their role, as well as the role of lumenal cells from various mucosal surfaces is obscure. These cells may be derived from the lymphoid population found in the intestinal epithelium, but this suggestion may not be correct since intra-epithelial lymphocytes, although often recently divided (Marsh, 1975), are thought to be almost exclusively T cells (Guy-Grand et al., 1974; Guy-Grand, Griscelli & Vassalli, 1978; Sprent, 1976), and have a different half life than the columnar epithelial cells which migrate over them (Darlington & Rogers, 1966). Intra-epithelial lymphocytes often possess a large number of granules (Collan, 1972; Rudzik & Bienenstock, 1974) which can be shown to be metachromatic and may contain low concentrations of histamine (Guy-Grand et al., 1978). These cells may be degranulated in the process of systemic anaphylaxis (Guy-Grand, personal communication) and there is evidence that they are derived from T cells originating in the PP and MLN (GuyGrand et al., 1978). The relationship of these cells to
Mucosal mast cells Mast cells in the mucosa of the gut and lung have characteristics which distinguish them from mast cells in other sites. For example, mucosal mast cells differ from those in connective tissue according to morphology at the light and electron microscopic levels (Enerback, 1966a; Enerback & Lundin, 1974), histochemical characteristic (Enerback, 1966b; Miller & Walshaw, 1972), mucopolysaccharide content (Tas & Berndsen, 1977), apparent T-cell regulation (Ruitenberg & Elgersma, 1976), content of IgE (Mayrhofer et al., 1976) and responsiveness to mast cell degranulating agents (Befus, Pearce, Gauldie, Horsewood, Goodacre, Cole, Heatley & Bienenstock, 1979). The massive intestinal mast cell hyperplasia which occurs in nematode infections, such as with N. brasiliensis in the rat, may be adoptively transferred by immune MLN cells or by immune serum into infected animals (Befus & Bienenstock, 1979). The mast cell response in the bowel is also accelerated when immune BLN cells are transferred (Befus, McDermott, Mirski & Bienenstock, 1980). Recently, Nawa & Miller (1979) have shown that TD lymphocytes which are surface immunoglobulin negative and thus presumably T cells, will transfer this intestinal mast cell hyperplasia. It is unknown at present whether these mucosal mast cells are derived from T cells as has been suggested by Guy-Grand et al. (1978) or whether what is being transferred in these experiments is a factor derived from T cells which acts upon mast cell precursors. Burnet (1977) has previously postulated that mast cells may be derived from T lymphocytes, since both Ginsburg & Sachs (1963) and Ishizaka, Okudaira, Mauser & Ishizaka (1976) have shown that mast cells grow from cultures of cells derived from the thymus. Although recently it has been suggested that mast cells may be derived from bone marrow (Kitamura, Shimada, Hatanaka & Miyano, 1977), these studies may
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apply only to mast cells in connective tissues. Since there is evidence that mast cells may be derived from lymphocytes and even the basophil, which is thought to descend from the granulocyte series, may also come from a stem cell morphologically indistinguishable from a lymphocyte (Dvorak, personal communication), we feel that the mucosal mast cell may be derived from a lymphocyte-like cell that is at some stage indistinguishable from the precursor of the connective tissue mast cell. We have shown that basophils may be selectively induced to proliferate in liquid culture systems using T-cell factors (Denburg, Davison & Bienenstock, 1980) and are pursuing the possibility that this model may also apply to the mucosal mast cell (Denburg, Befus & Bienenstock, 1980). It is interesting that in the rabbit bronchial epithelium we have not seen granular lymphocytes similar to those described above for the intestinal epithelium, but rather basophil-like cells (Bienenstock & Johnston, 1976). Further, we have observed that the basophil in the rabbit carries a T-cell marker as shown by a hetero-antiserum (Day, Singal & Bienenstock, 1975). Thus, the relationship between the intra-epithelial lymphocyte, the globule leucocyte, the mast cell and the T cell, as well as the basophil, is far from distinct and the factors which control the proliferation and possible migration of these cells are unknown. Since in Crohn's disease and ulcerative colitis the content of histamine and mast cells may be elevated (Befus et al., 1979), and in some patients disodium cromoglycate, an agent which depresses mast cell degranulation, is thought to be of some benefit (Heatley, Calcraft, Rhodes, Owen & Evans, 1975), improved knowledge of the nature of mucosal mast cells and the factors which control their differentiation and proliferation may be important in our understanding of mucosal immunology in health and disease. Goblet cells and mucosal resistance Goblet cells have been considered important in mucosal infection for a number of years (Ackert, Edgar & Frick, 1939; Wells, 1963). However, only recently has this cell begun to receive much attention with regard to mucosal resistance. As mentioned briefly above, Miller & Nawa (1979a, b) have documented goblet cell hyperplasia following intestinal nematode infection in rats and shown that this is a thymus-dependent phenomenon which can be transferred by TD presumed T lymphocytes. Moreover, mucous release from goblet cells can be stimulated by immune complexes (Walker,
Wu & Bloch, 1977) and by antigen in orally immunized animals (Lake, Bloch, Neutra & Walker, 1979). The potential role of mucosal mast cells in the function of goblet cells in mucosal epithelia is suggested by evidence that IgE-mediated intestinal anaphylactic reactions can lead to mucous secretion (Lake, Bloch, Sinclair & Walker, 1980) and also that histamine may stimulate mucous secretion (Kowalewski, Pachkowski & Secord, 1976). Most recently, studies using animals sensitized to the nematode T. spiralis have shown that upon challenge, marked secretion of goblet cell products would appear to be relevant in protection against reinfection (Ogilvie & Lee, 1980). Therefore, in the last few years much new information has been generated on this cell type and its relationship to the immune system. Undoubtedly, the future will uncover important mechanisms in the control of the numbers and functions of goblet cells that will be relevant to our concepts of non-specific resistance mechanisms, mucosal immunity, and approaches to vaccination.
Antigen uptake and processing Macromolecular and even particulate uptake across the intestine into the circulation is now well established (Volkheimer & Schulz, 1968; Schreiber, 1974; Warshaw, Walker & Isselbacher, 1974; Cook & Olsoa, 1979). The lymphoepithelium overlying MALT which contains specialized M cells (Owen & Jones, 1974) selectively samples the environment and passes potentially antigenic material to lymphocytes below the epithelium (Owen, 1977). In mice given drinking water containing latex particles with a mean diameter of 2 pm, latex could be found in the PP, villi and MLN subsequently (LeFevre, Olivo, Vanderhoff & Joel, 1978). Further, in mice given oral infections with Salmonella typhi, the PP were the first sites of appearance of the organism which subsequently disseminated throughout the body (Carter & Collins, 1974) and it is interesting that PP are thought to be the route of infection for a variety of organisms including the polio virus (Sabin, 1956). The lymphoepithelium of BALT serves a similar function by sampling particulate material such as BCG organisms (Raicz, Tenner-Racz, Myrvik & Fainter, 1977) and soluble antigens (Tenner-Racz et al., 1979). The quantitative significance of the uptake of antigenic material at sites other than the lympho-epithelium in the gut (Walker, Cornell, Davenport & Isselbacher, 1972) or lung (Richardson, Bouchard & Ferguson, 1976) is not clear. Regardless,
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from feeding experiments (Rothberg, Kraft, Farr, Kriebel & Goldberg, 1971; Warshaw et al., 1974), up to 2% of the dose of protein ingested may appear relatively intact in the circulation and this material retains its antigenic activity. When mesenteric adenectomy is performed, macrophages are found in the thoracic duct (MacPherson & Steer, 1979) and are also present in the afferent lymph of the sheep mesenteric node (Hall, personal communication). Macrophages are found both in organized mucosal lymphoid tissue such as MALT and also in the lamina propria (Bienenstock & Dolezel, 1971). It is only very recently that the role of the mucosal macrophage has begun to receive increasing attention (Lefevre, Hammer & Joel, 1979). The concentration in these cells of environmental noxious agents is obviously of great biological importance. Carageenan in the diet can cause mucosal ulceration and is found in mucosal macrophages (Abraham, Fabian, Goldberg & Coulston, 1974). Asbestos in the drinking water can similarly be localized and amazingly eliminated from the urine by the use of filtered drinking water (Cook & Olson, 1979). The possibility that mucosal macrophages have a selective migration pattern and themselves traffic between mucosal tissues would require careful examination and only then will it become clearer how we balance our contact with our environment. It is totally erroneous to assume that man can keep large molecules and even particulate matter away from his internal milieu. It is well documented but not well known that coal miners have anthracosis of their PP. The significance of mucosal macrophages, their function, derivation, traffic and eventual distribution awaits more extensive investigation. Although PP and other MALT, have highly specialized mechanisms for antigen uptake, these lymphoid aggregates lack antibody-containing cells as evidenced by autoradiography using radiolabelled antigen (Bienenstock & Dolezel, 1971). This apparent defect in antigen processing in PP has been attributed to the absence or relative defect in accessory adherent cells necessary for the primary immune response (Kagnoff & Campbell, 1974; Challacombe, Krco, David & Tomasi, 1980). At present there is insufficient information to determine the relative importance of local sensitization of cells in GALT and BALT and the sensitization of cells elsewhere with regard to immune responses both locally and systematically. Clearly, the mucosal presentation of antigen can influence systemic responses. Mattingly, Eardley, Kemp & Ger-
shon (1979) showed that in conventional animals there was an indomethacin-sensitive splenic suppressor cell, but that germ-free rats lacked this activity. In addition, MacDonald & Carter (1979) showed that conventional animals, but not germ-free mice, could show delayed hypersensitivity reactions to sheep red blood cells (SRBC). The balance between antigen access to the circulation and the local immune response which can provide antibodies capable of blocking such antigen uptake, has been effectively shown by Walker and co-workers for the gut (Walker, Abel, Wu & Bloch, 1976) and Stokes et al. (1975) for the lung. Aerosol administration of antigen to rabbits can lead to high levels of circulating IgG and Ig'M antibody and one might predict that subsequent administration of antigen by aerosol would lead to Arthus reactions locally, but this did not prove to be the case (Willoughby & Willoughby, 1977). Brandtzaeg and co-workers (Tolo, Brandtzaeg & Jonsen, 1977) have shown that whereas antibody within the mucosa can depress the uptake of intact homologous antigen, immune reactions within the mucosa may enhance the penetration of unrelated macromolecules. In conclusion, it would seem possible to utilize mucosal presentation of antigen for systemic immunization but at present this area is too poorly understood to be of immediate practical value. Another factor which may be important in the subsequent immune reactivity of the host, is the nature of the antigen and the site of its processing. For example, Hunter (1972) showed that Salmonella flagellin appeared on intravenous administration to selectively localize in bronchial and intestinal lamina propria, whereas hen egg albumin was found widely distributed in many types of phagocytic cells but not specifically in the lamina propria. Whether these patterns of antigen localization were due to the presence of antibodies directed against determinants, or to the chemical configuration of the antigen which may predispose its selective localization, is unclear. Similarly, Pierce (1978) showed that mucosal antitoxin response in rats after oral administration of different forms of cholera antigen could be placed in a hierarchy which depended upon their ability to bind to cell membranes and activate membrane adenyl cyclase. It may well be that binding of antigen to the mucosal epithelium is a crucial first step in promoting a predominantly secretory immune response. In this respect the first welldocumented studies of oral immunization (Besredka, 1927) presented bacteria in ox bile. The role of bile is not clear but it may have caused acid neutralization
Mucosal immunology and through its mucolytic activity, allowed increased antigen access to the intestinal epithelial membrane. It has been reported that the administration ofvitamin A may act as an adjuvant for mucosal immune responses (Falchuck, Walker, Perrotto & Isselbacher, 1977). It is predicted that exploration of these concepts should lead to improved approaches to mucosal immunization.
Regulation of the immune respome by mucosal presentation of antigen One hundred and fifty years ago Dakin (quoted by Richman, 1979) noted that American Indians ingested poison ivy leaves to prevent dermatitis upon subsequent contact with that plant. This was subsequently termed the Sulzberger-Chase phenomenon (Chase, 1946), has now been described for oxazolone (Glaister, 1973; Asherson, Zembala, Perera, Mayhew & Thomas, 1977), ovalbumin (Richman, 1979; Hanson, Vaz, Rawlings & Lynch, 1979; Miller & Hanson, 1979), bovine serum albumin (Thomas & Parrott, 1974) and even for SRBC (Mattingly & Waksman, 1978). The induction of tolerance by oral feeding is influenced by a variety of factors including the dose of antigen, frequency ofadministration and the timing of feeding relative to subsequent challenge. This phenomenon is of great importance to the understanding of mucosal immune responses and may have wide clinical applicability, thus considerable efforts have been invested in attempting to understand the mechanisms involved. It may not be peculiar to the bowel since Parker & Turk (1978) showed that the instillation of soluble metal salts into the lungs could render mice tolerant to subsequent challenge with the specific agent. An antigen-specific T suppressor cell which depresses the ability of lymphocytes to proliferate in response to antigen, appeared in the lymph nodes and spleen following oral antigen administration and unresponsiveness could be adoptively transferred with cells (Miller & Hanson, 1979). Mice fed contact sensitizer had suppressor cells which appeared sequentially in PP, MLN and spleen and which were Thy-l negative but complement receptor and surface Ig positive (Asherson et al., 1977). Richman, Chiller, Brown, Hanson & Vaz (1978) demonstrated the appearance of antigen-specific T suppressor cells for IgG and IgM responses in the spleens of mice fed ovalbumin. Mattingly & Waksman (1978) showed that suppressor cells for IgG and IgM appeared sequentially in the PP,
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MLN and spleen of rats following the feeding of SRBC. These suppressor cells were identified as T2 lymphocytes as they were susceptible to anti-lymphocytic serum and evidence was obtained that macrophages might also be important in this response. It is interesting that to date, these suppressor phenomena have been identified in the spleen of orally immunized animals and appear to be specific for IgG and IgM responses, as well as cell-mediated responses. Whether such specific suppressor cells exist for IgA following oral feeding has not been documented, although Elson et al., (1979) have presented evidence that IgA-specific suppressor cells exist in the spleen and the PP, but that in the PP, IgA-specific helper cells seem to be dominant. Thus, initial exposure to small amounts of antigen via the mucosal route appears to lead to immune unresponsiveness, which may explain why parenteral priming followed by oral immunization is so effective in producing local mucosal immunity (Pierce & Gowans, 1975). Because of the known sequential appearance of suppressor cells in various lymphoid tissues following feeding, it is important that the factors influencing their migration among lymphoid tissues be characterized. The role of the liver as an immunological organ and particularly in the generation of the Sulzberger-Chase phenomenon is not clear (Triger, 1976). Controversy exists as to whether patients with cirrhosis produce excessive amounts of antibody in response to parenteral vaccination, but there is considerable evidence that patients with liver disease possess elevated titres of antibody to a variety of gastrointestinal antigens. Further controversy exists regarding the effects of portacaval anastomosis on the production of tolerance to ingested antigens. Functional portacaval shunts as exist in cirrhosis, may lead to hypergammaglobulinaemia and the significance of this observation to the recent demonstration of IgA transport from the serum into the bile by the liver remains to be investigated. Whether the liver is crucial in the regulation of the immune response and how it may affect immunological function is not clear, but recent techniques for the isolation of Kupffer cells from the liver of experimental animals (Diesselhoff-Den Dulk, Crofton & Van Furth, 1979; Richman, Klingenstein, Richman, Strober & Berzofsky, 1979) should make significant contributions to our understanding of the immunological functions of this organ. Andre, Heremans, Vaerman & Cambiaso (1975) showed that following the intragastric administration
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of SRBC, the serum of treated animals contained an antigen-specific factor which suppressed the humoral immune response and which was thought to be an IgA antigen-antibody complex. Kagnoff (1978b) made similar observations but did not identify the serum factors involved. Recently, Vaerman and co-workers have shown that IgG I antibody in the serum of orally immunized mice suppressed the in vitro primary responses of normal spleen cells to SRBC (Chalon, Milne & Vaerman, 1979). The effect of this factor on the production of IgA antibody by splenic cells or those from the PP or other mucosal tissues was not studied. Currently, there is much interest in the role of protein-energy malnutrition in immune responses in mucosal and systemic sites (Chandra, 1980). For example, there is evidence that specific amino acid deficiencies may influence the function of suppressor T cells (Bounous & Kongshavn, 1978) and that specific metal deficiencies such as the deprivation of zinc, influence the generation of helper T cells and general thymic function (Fraker, DePasquale-Jardieu, Zwickl & Luecke, 1978; Iwata, Incefy, Tanaka, Fernandes, Menendez-Botet, Phi & Good, 1979). Further, various monosaccharides such as L-fucose and L-rhamnose can inhibit the in vitro activities of lymphokines such as MIF and neutrophil chemotactic factors and also the in vivo generation of cutaneous and peritoneal manifestations of cell-mediated immunity (Amsden, Ewan, Yoshida & Cohen, 1978; Baba, Yoshida, Yoshida & Cohen, 1979). Therefore, the nature of the diet may be crucial in the resultant balance between the generation of mucosal immune responses or of specific unresponsiveness. Evidence that IgE-specific suppressor cells may be found in PP (Ngan & Kind, 1978) suggests that orally induced tolerance might be a possible therapeutic approach to allergic disease. Tolerance may be transmitted from mother to offspring via the milk (Auerbach & Clark, 1975) and Halsey & Benjamin (1976) showed that antigen injected into female mice within 24 h of delivery, could be found in the colostrum and subsequently be absorbed intact through the intestine of the offspring leading to their tolerization to the specific antigen. Jarrett & Hall (1979) showed IgEspecific factors which were transferred in the colostrum from mother to young and which regulated the subsequent development of IgE antibody in the offspring. More work must be done to explore the various factors in colostrum and milk which regulate potential allergic disease in offspring.
Thus, many factors might be responsible for the Sulzberger-Chase phenomenon, including the nature and type of antigen; whether it is processed by the epithelium, lymphoid aggregates, liver or some peripheral lymphoid tissue; age at exposure; antigen dose; humoral antibody responses and the nutritional status of the individual to name but a few. It is increasingly
clear that mucosal associated unresponsiveness may be fundamental in disease mechanisms since dietary antigens in the form of antigen-antibody complexes may be found in the circulation of patients with a wide variety of disorders such as glomerulonephritis, Henoch-Schdnlein purpura as well as various forms of dermatitis. However, such complexes occur in the circulation of apparently normal individuals as well. A better understanding of the regulation of antigen uptake across the mucosal barrier is essential for more logical approaches to immunotherapy and disease control.
Vaccination of mucosal surfaces A prime objective of studies of mucosal immune mechanisms is to manipulate the mucosal immune system so as to immunize against disease and obviate potentially pathogenic responses of the system. A prerequisite to vaccination is that the mucosal immunological system is capable of expressing a memory response. However, over the last decade this has been a controversial issue. In extensive discussions at a Conference on secretory immunity in 1969, evidence for a lack of memory in the mucosal immunological system was discussed (Dayton, Small, Chanock, Kaufman & Tomasi, 1971, p. 417) and Porter and co-workers have provided similar evidence in studies of large mammals (Porter, Linggood & Chidlow, 1978). On the other hand, Gerbrandy & Van Dura (1972) provided evidence for memory in upper respiratory tract secretions following intranasal immunization. More recently Montgomery, Cohen, Skandera & Connelly (1979) provided some evidence that oral and bronchial immunization may lead to selective secretion of antibody in mammary glands without evidence for IgA antibody in the circulation. Whether this anamnestic response was due to cell traffic from the gut and/or lung to the mammary gland, or due to the selective transport of dimeric IgA antibody, as has been recently shown for the liver (see above), is unknown. Lally, Zitron, Fiorini & Montgomery (1978) provided clear evidence of memory for splenic IgA-producing cells, but the relationship of this systemic anamnestic response to the local mucosal sites was not studied.
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Pierce & Reynolds (1975) concluded from studies of antitoxin activity in the jejunal washings of immunized dogs, that the secretory immunological system mounts a rapid but brief secondary immune response to locally administered antigen. Andrew & Hall (personal communication) have recently shown that direct injection of bacteria into rat PP produces clear evidence in rat bile of a secondary IgA response, but as yet do not have evidence of this with orally presented antigen. Studies on the appearance of antibody-containing cells in the TD and lamina propria of immunized rats and dogs showed that parenteral immunization followed by oral challenge induced an anamnestic response (Pierce & Gowans, 1975; Pierce, Sack & Sircar, 1977; Husband & Gowans, 1978). It is unreasonable to equate the appearance of antibody-containing cells with inferred secretion especially since it is well known that in disease these two functions may be separable as in the non-secretor myelomas. Thus, the controversy on immunological memory in the secretory system is difficult to sort out as the results of various studies utilize different immunization protocols, different species and different assays. If recent data that memory exists within the secretory immunological system is accepted, the next fundamental question is, what is the best route of vaccination to induce a protective secretory immune response? Following various attempts to answer this question, Pierce & Gowans (1975) showed that a single intraperitoneal dose of antigen in Freund's complete adjuvant followed by an intra-intestinal boost produced an effective mucosal immune response in rats. This was subsequently confirmed in dogs following subcutaneous primary vaccination and an oral boost (Pierce et al., 1977). However, parenteral immunization has also been shown to suppress the local immune response under certain conditions (Hamilton, Yardley & Brown, 1979; Pierce & Koster, 1980). Whereas in rats this protocol for vaccination leads largely to IgA antibody-containing cells, in sheep Beh, Husband & Lascelles (1979) showed that intraperitoneal vaccination in the absence of oral boost gave a predominantly IgM and IgG I antibody-containing cell response in the TD. It should be emphasized that this study presented antigen in Freund's complete adjuvant and so was not comparable. Following intraduodenal boosting of animals previously primed by an intraperitoneal route, virtually no antibody-containing cells appeared in the intestinal lymph. In pigs, it has been shown that oral immunization with an E. coli vaccine incorporated into feed has been
remarkably effective in preventing enteritis in the neonatal pig and in optimizing weight gain (Porter, Kenworthy & Allen, 1974). Recently, these workers have shown that oral vaccination followed by parenteral immunization produced primarily IgM antibody in the colostrum of the sow and that these antibodies were protective in piglets (Porter, 1979). Systemic priming with oral boosting stimulated the appearance of IgA antibody-containing cells in the intestine of lambs which were subsequently shown to be protected against challenge with enteropathogenic bacteria (Husband, 1978). In man, Svennerholm, Holmgren, Hanson, Lindblad, Quereshi & Rahimtoola (1977) have shown that a single subcutaneous vaccination with cholera can induce specific IgA antibodies in milk, saliva and secretions. This response was thought to be due to previous sensitization by natural exposure to the bacterium. A similar explanation could be put forward for the observations of Lawrence, Shann, Freestone & Walker (1979) who showed that parenteral vaccination with Clostridium welchii type C toxoid markedly reduced the incidence of necrotizing enteritis ('pigbel') in children of Papua, New Guinea over a 24 month study. Thus, although it is possible to vaccinate both animals and man against mucosal infection, the precise mechanisms involved and the most effective routes of vaccine administration remain to be clarified. As our understanding improves it may be possible to provide protection for sites other than the intestine through oral vaccination. The problems include the observation that concomitant suppressor activity is generated during the immunization process, with the balance a delicate one in favour of immunity (Pierce & Koster, 1980; Swarbrick, Stokes & Soothill, 1979). The concept of a common mucosal immune system in which various mucosal sites are integrated through the movement of cells or of antibody provides an important principle upon which to base studies for the provision of protection of one mucosal site through immunization of another. For example, total protection against Adenovirus type 4 was produced in a group of military recruits who received oral enteric coated vaccine capsules (Edmondson, Purcell & Gundelfinger, 1966; Smith, Buescher, Top, Altemeier & McCown, 1970). Oral vaccination with Herpes simplex type I virus has enhanced the protection against intravaginal challenge with Herpes simplex type II virus (Sturn & Schneweis, 1978) presumably due to cross-reactivity between these two serotypes. In guinea-pigs, a live oral chlamydial vaccine proved to
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be effective against both eye and vaginal challenge with the homologous organism (Nichols, Murray & Nisson, 1978). The advantages of oral vaccination for the protection of distant mucosal sites are obvious when one considers the administration of vaccine to large rural populations where health care delivery is less than optimal. The possible beneficial effects of adjuvant in combination with an oral vaccine must be considered. Pierce (1978) showed that the ability of cholera toxoid and toxin to bind to cell membranes and the ability of the latter to activate adenyl cyclase was important in immunogenicity. It is interesting that the original oral vaccination experiments against dysentery during the first world war utilized ox bile for the administration of the vaccine (Besredka, 1927). It is tempting to speculate that the bile with its acid neutralizing, detergent and mucolytic properties allowed better access of the antigenic material to the appropriate sites in the intestine. A recent suggestion that the oral administration of lysozyme increases secretory IgA levels is interesting in this respect and deserves follow-up (Lodinova & Jouja, 1977), as does the observation that Vitamin A has a mucosal adjuvant effect (Falchuk et al., 1977). Beh (1979) has shown that the intra-intestinal administration of antigen with the polycation adjuvant DEAE-dextran markedly enhanced the antibody response in sheep. Respiratory tract and serum antibody responses in guinea-pigs can be enhanced by exposure to aerosols of antigen dissolved in solutions of sodium dodecylbenzene sulphate (Markham & Wilkie, 1979). The association of antigens with lipid has been shown to stimulate antibody formation in rats following either intramuscular or intestinal administration of antigen (Heatley & Stark, 1975). More recently it has been shown that protein, loaded in liposomes which are administered orally, can enter plasma in significant concentrations (Hemker, Muller, Hermens & Zwaal, 1980). The possibility that antigen-laden liposomes, into whose membranes would be incorporated a substance with marked binding affinity for epithelial membranes, might be used for oral vaccination provides a new and potentially significant development for the future.
Speculations and conclusions The gut and lung are known to contain mucosal aggregates which can and do concentrate samples of the environmental milieu. The investigation of these tis-
sues and the effect ofthe external environment on local and systemic immune responses must be more completely explored. It is tempting to think of the mucosal immune response as part defence against potential pathogens, and part a method of regulation of entry and distribution of particulate and high molecular weight environmental products. An IgA immune response at a mucosal surface should provide a very effective means for such control since the dimeric molecule already has such a selective transport system provided by the hepatic parenchymal cells for removal from the circulation and into the bile. Extension of this concept would suggest that the mucosal IgA, wherever synthesized, would provide the body with a mechanism for rapid clearance of dimeric IgAimmune complexes, not as expected via the reticuloendothelial system, but by the parenchymal cells ofthe liver. It is possible also that the controversies over the opsonization potential of IgA might be resolved against the known binding of IgA to polymorphonuclear cells (Van Epps & Williams, 1976; Zipursky, Brown & Bienenstock, 1973). Thus oligomeric IgA would be expected to opsonize whereas secretory IgA would not. The increasing complexity of mammalian diet might have provided for the evolution of this system, especially geared to rapidly clear from the circulation dietary products (Swarbrick, Stokes & Soothill, 1976) which had evaded satisfactory removal and degradation and allow a second chance for the intestine to degrade these substances. Further, the specialized character of the hepatic parenchymal cell, evolved to breakdown and detoxify a wide variety of substances, might be additionally called into play by this mechanism. Another more distant advantage of this system is provided by the selective secretion of dimeric IgA into a variety of glandular exocrine secretions. Here, since the majority of these are secreted onto surfaces which themselves have mucosal lymphoid tissue, there would be a chance to provide prolonged antigenic material for mucosal immune response stimulation distal to the initial site of entry. The thought that selective antigen secretion may occur at all mucosal sites is entirely compatible with the observations of the secretion of tolerogenic antigen into the milk following parenteral introduction (Halsey & Benjamin, 1976). It might also explain why IgA-synthesizing cells remain at all at a mucosal site such as the breast, normally regarded as being sterile and antigen free (Bienenstock et al., 1979). This explanation might provide an answer to how cells
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seeded to a distal mucosal site could provide defence at that point, and may take into account the observations that blast cells in mucosal tissues may be capable of local proliferation (Husband & Gowans, 1978; Befus et al., 1978; Mayrhofer & Fisher, 1979). Additionally the suggestion that specific antigen may cause lymphoblasts to cease migration in mucosal tissues might be helpful in locally amplifying an immune response distal to the initial antigenic exposure. We hope from this review, that it is clear much remains to be learned about how mucosal immune responses are induced and regulated. The movement of cells among various mucosal tissues, the regulation of their proliferation at particular sites and the possibilities that various subclasses of T, B and other cells may have selective mucosal specificity deserve further investigation. The practical application of some recent advances also deserves exploration and we are optimistic that new approaches to vaccination will develop in the near future.
Acknowledgments We are pleased to acknowledge the excellent secretarial assistance of Ms P. Gendron. The Medical Research Council of Canada provides grants in aid to both authors. JB is very grateful to the many colleagues who in the last few months have discussed their ideas so freely with him, particularly Tony Davies and Joe Hall; and also for the generous support given by the Chester Beatty Research Institute (Institute of Cancer Research) to this sabbaticant.
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Immunology 1980 41 249

Accepted for publication 23 May 1980

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chial lymphoid tissue. I. Morphologic characteristics. Lab. Invest. 28,686.

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J. Bienenstock & A. D. Befus

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