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Mucosal Immunology

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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 249
IgA 249
IgA function 251
Lymphocyte migration to mucosae 251
IgE 254
Mucosal T cells 255
Cells in the lumen and epithelium of the intestine 255
Mucosal mast cells 256
Goblet cells and mucosal resistance 257
Antigen uptake and processing 257
Regulation of the immune response by mucosal presentation of antigen 259
Vaccination of mucosal surfaces 260
Speculations and conclusions 262
Acknowledgments 263
References 263

Introduction sive, we recommend the following articles and books

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 Path-
ology, 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
249
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
250 J. Bienenstock & A. D. Befus
unique characteristics. Tomasi, Tan, Solomon & Pren-
dergast (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 & Bienen-
stock, 1968) as a dimer containing an additional poly-
peptide, 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 anti-
body. For example, IgA antibody to a variety of vir-
uses, 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, Woll-
heim, Hong & Good, 1966) but subsequent studies on
the turnover of serum and sIgA in healthy and dis-
eased patients provided little support for this sugges-
tion. However, recent studies by the groups of Vaer-
man (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 anti-
body 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 trans-
ported. 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 administ-
ration 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 hepa-
tocyte in species such as man where SC binds IgM with
a high affinity (Socken & Underdown, 1978). IgM
appears to be transported across the intestinal epithe-
lial 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-cova-
lently 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 defi-
ciency (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 se-
creted 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 & Vir-
ella, 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 exten-
sively. 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 & Wil-
liams, 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 demonst-
ration of T lymphocytes which bear Fc receptors for
IgA would appear to be a significant development
(Strober, Hague, Lum & Henkart, 1978; Lum, Much-
more, Keren, Decker, Koski, Strober & Blaese, 1979),
but as yet, the specific function of this T-cell subpopu-
lation, 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 mono-
meric 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 specifi-
cally able to cleave IgA I selectively, may be correlated
with pathogenicity of Neisseria gonorrhoeae and men-
ingitidis (Mulks & Plaut, 1979). The significance of
251
this IgA protease is unclear since IgA2, which is resis-
tant 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 dis-
cussed (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 develop-
ment 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 adop-
tive 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. Repopula-
tion 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-Quag-
liata, 1979). From repopulation experiments in irra-
diated rabbits (Jones & Cebra, 1974) and from adop-
tive transfer experiments over a 24 h period in mice
(McWilliams et al., 1975; McWilliams, Phillips-Quag-
liata & 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 reac-
tive 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-
252 J. Bienenstock & A. D. Befus
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 lympho-
epithelium of GALT and the follicle-associated epith-
elium 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 IgA-
containing cells (Rudzik, Clancy, Perey, Day &
Bienenstock, 1975). Conversely, GALT cells repopu-
lated the bronchial mucosa with IgA containing cells.
We therefore thought that this might represent a un-
iversal mucosal immune system (Bienenstock et al.,
1973) and subsequently coined the term common
mucosal immune system' (Bienenstock, 1974; Bienen-
stock, McDermott, Befus & O'Neill, 1978; Bienen-
stock, 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 locali-
zation of MLN lymphoblasts occurred in the bron-
chial and cervical mucosa where IgA was the major
product of the transferred cells. The accumulation of
IgA precursor cells in the cervical mucosa was hor-
monally dependent, since three times as many cells
were found in this site during proestrus than in metes-
trus, 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 pre-
dominated 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 intes-
tine (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. Alter-
nately, it may be that there is integration of lympho-
blasts from various lymph nodes draining mucosal
and non-mucosal sites as they migrate in the body.
Most studies which deal with the lodging of lym-
phoblasts in mucosae have emphasized the impor-
tance 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 re-
sponses to a variety of antigens. Our own experiments
showed that more of the MLN-derived lymphoblasts
which selectively lodged in the bronchus made IgG
 Mucosal immunology
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 exa-
mination 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 locali-
zation 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. Further-
more, 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 con-
tinuous 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 intes-
tine. This observation suggests that local cell division
may occur in the intestine, although an equal possibi-
lity is that there is an increased production of mucosal
(intestinal)-seeking IgA lymphoblasts in other muco-
sal 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-con-
taining cells using lamina propria cells from the rabbit
253
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 un-
doubtedly complex (Table 1). Although SC was consi-
dered a candidate for such cell localization (McWil-
liams et al., 1975), it does not appear to be important.
Hormones clearly influence cell localization in muco-
sae (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 localiza-
tion (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 experi-
ments 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 localiza-
tion 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 (?)
254 J. Bienenstock & A. D. Befus
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 Platts-
Mills, 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; Sue-
mura, Urban & Ishizaka, 1978; Rector, Carter, Kelly,
Lang & Sehon, 1979; Befus, Johnston, Berman &
Bienenstock, 1980) and BLN (Gerbrandy & Bienen-
stock, 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 regula-
tion 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 spe-
cies (Yodoi & Ishizaka, 1979, 1980; Fritsche & Spiegel-
berg, 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
amounts of antigen to rats given Bordetella pertussis
leads to significant levels of IgE in the circulation
(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 immuni-
zation leads to the production of IgE antibody in the
lymph nodes draining the lungs, and footpad immuni-
zation 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, intra-
tracheal 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 en-
vironment 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 use-
ful models for the study of IgE precursor cells and the
factors which govern their activities.
It has been reported, using parenteral but not muco-
sal immunization protocols, that neonatal exposure to
antigen may lead to an exclusive, or at least predomi-
nant, 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 im-
munization 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 eluci-
dation of mechanisms of allergic reactions in man and
animals and the possible role of IgA antibody in bloc-
king 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 (Jar-
rett & Hall, 1979).
 Mucosal immunology
Mucosal T cells
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 lymphob-
lasts in the mammary gland have not been conducted,
although T cells are found in breast secretions (Par-
mely & 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, Issel-
bacher & Warren, 1974) or the generation of cytotoxic
T lymphocytes in PP and extra-intestinal sites (Kag-
noff, 1978a). Administration of antigen to the gas-
trointestinal 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 (Freder-
ick & 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 experi-
enced-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-
255
ible effects of T-cell derived lymphokines or other
cytokines on the integrity of the epithelium and pro-
liferation 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 in-
volved in the regulation of goblet cell numbers and
their secretory activity must be seriously considered.
This concept may be profitably applied to immunolo-
gical 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 suck-
ling 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; Schles-
inger & Covelli, 1977).
In some murine strains, T cells in the thymus synthe-
size 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 impor-
tant. 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
256 J. Bienenstock & A. D. Befus
diagnostic tool for some time (Harris, Dupont & Hor-
nick, 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 com-
munication). 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 popula-
tion 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 communica-
tion). We have observed cells in the lumen ofthe rabbit
appendix and on the surface of PP (Heatley & Bienen-
stock, 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 simi-
larly arise from GALT, but whether these cells have
properties similar to, or different from, cells isolated
from the follicles remains to be determined. Our obser-
vations 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 popu-
lation 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 & Vas-
salli, 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 com-
munication) and there is evidence that they are derived
from T cells originating in the PP and MLN (Guy-
Grand et al., 1978). The relationship of these cells to
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 de-
rived 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-depen-
dent cytotoxicity systems (Arnaud-Battandier,
Bundy, O'Neill, Bienenstock & Nelson, 1978).
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 morpho-
logy at the light and electron microscopic levels (Ener-
back, 1966a; Enerback & Lundin, 1974), histochemi-
cal characteristic (Enerback, 1966b; Miller & Wal-
shaw, 1972), mucopolysaccharide content (Tas &
Berndsen, 1977), apparent T-cell regulation (Ruiten-
berg & Elgersma, 1976), content of IgE (Mayrhofer et
al., 1976) and responsiveness to mast cell degranulat-
ing 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 & Bienen-
stock, 1980). Recently, Nawa & Miller (1979) have
shown that TD lymphocytes which are surface im-
munoglobulin 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, Shi-
mada, Hatanaka & Miyano, 1977), these studies may
 Mucosal immunology
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 communica-
tion), we feel that the mucosal mast cell may be derived
from a lymphocyte-like cell that is at some stage indis-
tinguishable from the precursor of the connective tis-
sue mast cell. We have shown that basophils may be
selectively induced to proliferate in liquid culture sys-
tems 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 epithe-
lium we have not seen granular lymphocytes similar to
those described above for the intestinal epithelium,
but rather basophil-like cells (Bienenstock & John-
ston, 1976). Further, we have observed that the baso-
phil 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 muco-
sal 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 pheno-
menon which can be transferred by TD presumed T
lymphocytes. Moreover, mucous release from goblet
cells can be stimulated by immune complexes (Walker,
257
Wu & Bloch, 1977) and by antigen in orally im-
munized animals (Lake, Bloch, Neutra & Walker,
1979). The potential role of mucosal mast cells in the
function of goblet cells in mucosal epithelia is sug-
gested by evidence that IgE-mediated intestinal ana-
phylactic reactions can lead to mucous secretion
(Lake, Bloch, Sinclair & Walker, 1980) and also that
histamine may stimulate mucous secretion (Kowa-
lewski, Pachkowski & Secord, 1976). Most recently,
studies using animals sensitized to the nematode T.
spiralis have shown that upon challenge, marked sec-
retion 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 con-
trol 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 estab-
lished (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 poten-
tially 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 Sal-
monella 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 (Ten-
ner-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,
258 J. Bienenstock & A. D. Befus
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, macro-
phages are found in the thoracic duct (MacPherson &
Steer, 1979) and are also present in the afferent lymph
of the sheep mesenteric node (Hall, personal com-
munication). Macrophages are found both in
organized mucosal lymphoid tissue such as MALT
and also in the lamina propria (Bienenstock & Dole-
zel, 1971). It is only very recently that the role of the
mucosal macrophage has begun to receive increasing
attention (Lefevre, Hammer & Joel, 1979). The con-
centration 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 amaz-
ingly 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 docu-
mented 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 investiga-
tion.
Although PP and other MALT, have highly special-
ized 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 informa-
tion 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 sys-
temic 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 conven-
tional animals, but not germ-free mice, could show
delayed hypersensitivity reactions to sheep red blood
cells (SRBC).
The balance between antigen access to the circula-
tion 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 admini-
stration 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 & Wil-
loughby, 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 sub-
sequent 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 con-
figuration 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 acti-
vate membrane adenyl cyclase. It may well be that
binding of antigen to the mucosal epithelium is a
crucial first step in promoting a predominantly secre-
tory immune response. In this respect the first well-
documented 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 immuniza-
tion.
Regulation of the immune respome by mucosal presen-
tation 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 sub-
sequent 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 pheno-
menon is of great importance to the understanding of
mucosal immune responses and may have wide clinical
applicability, thus considerable efforts have been in-
vested 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 un-
responsiveness could be adoptively transferred with
cells (Miller & Hanson, 1979). Mice fed contact sensi-
tizer had suppressor cells which appeared sequentially
in PP, MLN and spleen and which were Thy-l nega-
tive 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. Matt-
ingly & Waksman (1978) showed that suppressor cells
for IgG and IgM appeared sequentially in the PP,
259
MLN and spleen of rats following the feeding of
SRBC. These suppressor cells were identified as T2
lymphocytes as they were susceptible to anti-lympho-
cytic serum and evidence was obtained that macro-
phages 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 paren-
teral 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 toler-
ance to ingested antigens. Functional portacaval
shunts as exist in cirrhosis, may lead to hypergamma-
globulinaemia 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 investi-
gated. Whether the liver is crucial in the regulation of
the immune response and how it may affect immuno-
logical function is not clear, but recent techniques for
the isolation of Kupffer cells from the liver of experi-
mental animals (Diesselhoff-Den Dulk, Crofton &
Van Furth, 1979; Richman, Klingenstein, Richman,
Strober & Berzofsky, 1979) should make significant
contributions to our understanding of the immunolo-
gical functions of this organ.
Andre, Heremans, Vaerman & Cambiaso (1975)
showed that following the intragastric administration
260 J. Bienenstock & A. D. Befus
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 re-
sponses 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, in-
fluence 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, Yosh-
ida & 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 trans-
mitted from mother to offspring via the milk (Auer-
bach & 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 IgE-
specific factors which were transferred in the colos-
trum from mother to young and which regulated the
subsequent development of IgE antibody in the off-
spring. 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 peri-
pheral 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 cir-
culation 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 pre-
requisite to vaccination is that the mucosal immuno-
logical system is capable of expressing a memory
response. However, over the last decade this has been a
controversial issue. In extensive discussions at a Con-
ference 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 evi-
dence for memory in upper respiratory tract secretions
following intranasal immunization. More recently
Montgomery, Cohen, Skandera & Connelly (1979)
provided some evidence that oral and bronchial im-
munization may lead to selective secretion of antibody
in mammary glands without evidence for IgA anti-
body 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.
 Mucosal immunology
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 com-
munication) 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 fol-
lowed by oral challenge induced an anamnestic
response (Pierce & Gowans, 1975; Pierce, Sack & Sir-
car, 1977; Husband & Gowans, 1978). It is unreason-
able 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 secre-
tory system is difficult to sort out as the results of
various studies utilize different immunization proto-
cols, different species and different assays.
If recent data that memory exists within the secre-
tory immunological system is accepted, the next fun-
damental question is, what is the best route of vaccina-
tion to induce a protective secretory immune re-
sponse? 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 pro-
duced 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 immuniza-
tion 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 vaccina-
tion 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 pre-
sented antigen in Freund's complete adjuvant and so
was not comparable. Following intraduodenal boost-
ing 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
261
remarkably effective in preventing enteritis in the neo-
natal pig and in optimizing weight gain (Porter, Ken-
worthy & 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, Lind-
blad, 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 bac-
terium. A similar explanation could be put forward for
the observations of Lawrence, Shann, Freestone &
Walker (1979) who showed that parenteral vaccina-
tion 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 pre-
cise 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 protec-
tion against Adenovirus type 4 was produced in a
group of military recruits who received oral enteric
coated vaccine capsules (Edmondson, Purcell & Gun-
delfinger, 1966; Smith, Buescher, Top, Altemeier &
McCown, 1970). Oral vaccination with Herpes sim-
plex 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
262 J. Bienenstock & A. D. Befus
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 com-
bination 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, deter-
gent and mucolytic properties allowed better access of
the antigenic material to the appropriate sites in the
intestine. A recent suggestion that the oral admini-
stration 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 adju-
vant DEAE-dextran markedly enhanced the antibody
response in sheep. Respiratory tract and serum anti-
body responses in guinea-pigs can be enhanced by
exposure to aerosols of antigen dissolved in solutions
of sodium dodecylbenzene sulphate (Markham & Wil-
kie, 1979). The association of antigens with lipid has
been shown to stimulate antibody formation in rats
following either intramuscular or intestinal admini-
stration 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 bind-
ing affinity for epithelial membranes, might be used for
oral vaccination provides a new and potentially sig-
nificant development for the future.
Speculations and conclusions
The gut and lung are known to contain mucosal aggre-
gates 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 com-
pletely 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 re-
sponse 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 IgA-
immune complexes, not as expected via the reticulo-
endothelial 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 polymorpho-
nuclear 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 secre-
tions. Here, since the majority of these are secreted
onto surfaces which themselves have mucosal lym-
phoid tissue, there would be a chance to provide pro-
longed antigenic material for mucosal immune re-
sponse 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 (Hal-
sey & 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
 Mucosal inmunology
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 lym-
phoblasts 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 possi-
bilities 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 secretar-
ial 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 col-
leagues 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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