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Department of Cell Biology and Human Anatomy, University of California, School of Medicine, Davis, CA 95616-8643
3To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONThe mucosal immune systemMethods used for study...Probiotic modulation of the...Possible future directionsREFERENCES |
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KEY WORDS: • probiotics • lactic acid bacteria • immune response • functional foods • mucosal immunity
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONThe mucosal immune systemMethods used for study...Probiotic modulation of the...Possible future directionsREFERENCES |
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The mucosal immune system |
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TOPABSTRACTINTRODUCTIONThe mucosal immune systemMethods used for study...Probiotic modulation of the...Possible future directionsREFERENCES |
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The lymphoid system contains those cells; it may be arranged into capsulated organs or may be represented as accumulations of diffuse lymphoid tissue. The thymus and bone marrow are primary lymphoid organs and are the major site of lymphopoiesis. T cells mature in the thymus, whereas B cells mature in the fetal liver and bone marrow. Secondary lymphoid organs and tissues, which include the spleen, lymph nodes and MALT, are sites in which cellular and humoral immune responses occur. In this scheme, the spleen responds mainly to blood-borne antigens, whereas the lymph nodes respond to antigens circulating in the lymph. Those antigens may be absorbed through the skin or from the intestine. A group of lymphoid tissues, tonsils, Peyer’s patches, bronchus-associated lymphoid tissue and urogenital lymphoid tissue respond to antigens, which have passed through the surface mucosal barriers. These aggregates of nonencapsulated lymphoid tissue, which may be found in the lamina propria and submucosal areas, make up the MALT.
The MALT.
Diffuse accumulations of lymphoid tissue may be present in the lamina
propria of the intestine wall. The epithelium over the Peyer’s patches
may be specialized to facilitate transport of antigen (see Heel et al. 1997
for review) due to the M cell, which is able to
absorb and transport antigen (Keren 1992
, Toy and Mayer 1996
). That cell may also be able to process and present
the antigen to lymphoid cells. Antigens, including pathogenic
microorganisms, use M cells to cross the digestive epithelial barrier.
The development of M cells appears to depend on the presence of
lymphoid cells. Thus, the passage of antigens through M cells is an
essential step in the development of the mucosal immune response as
well as in the pathology of many infectious diseases.
In addition to the nonencapsulated lymphoid tissue of the MALT,
lymphocytes are also found in the connective tissue of the lamina
propria and within the epithelial layer. In fact, a majority of the T
cells found in the intestine are present in the diffuse lymphoid tissue
of the lamina propria. Lymphocytes within the lamina propria are mainly
activated T cells; plasma cells may also be found in that location.
Another group of T cells, intraepithelial lymphocytes, have phenotypic
characteristics that differ from the lamina propria lymphocytes. Those
lymphocytes are similar to the cells circulating in peripheral blood,
many of which are T-cell receptor 
+ and
express CD8. Both populations of T cells have a subset of memory cells,
CD45RO, a restricted lymphocyte common antigen. With activation of
these lymphocytes, there is expression of a novel heterodimer.
Intraepithelial lymphocytes can release cytokines such as interferon
(IFN)- and interleukin (IL)-5. Activation of a primary T response
requires not only the antigen and MHC complex but also costimulating
molecules on the surface of antigen-presenting cells. Those cells
include bone marrow–derived B cells, macrophages and dendritic cells.
The last-mentioned are potent initiators of a T-cell–dependent
immune response.
Humoral immune response.
Humoral immune responses at the mucosal level are mainly of the immunoglobulin (Ig)A isotype. Although IgG-, IgM- and IgE-secreting cells are also present, their levels of activity and number are much lower. In contrast to IgA in the serum, secretory IgA (sIgA) is present as a dimeric form in the gut. After synthesis, IgA binds to the membrane receptor on the abluminal surface of the epithelial cells. The polymeric IgA is transported to the mucosal surface while still bound to the membrane of the transport vesicle. After fusion with the cell membrane at the mucosal surface, IgA with the secretory component is released. Secretory IgA is resistant to proteolysis; it does not participate in an inflammatory response. Thus, a major function of sIgA is to mediate immune exclusion of foreign antigens by preventing binding to the epithelial cells and penetration of microorganisms.
Recirculation of the mucosal immune system.
Lymphoid cells that are stimulated with antigen in the diffuse
aggregates of lymphoid tissue migrate to the regional lymph nodes.
Normally, lymphocytes leave the blood through regions of the
postcapillary venule. Lymphocytes from the lymph node return to
circulation via the efferent lymphatic pathways with ~2% of the
lymphocyte pool recirculating each hour. The MALT may be considered a
system distinct from the systemic lymphoid system because cells of the
MALT recirculate mainly within the mucosal system. Lymphocytes
activated in Peyer’s patches pass through regional lymph nodes, such
as the mesenteric group, through the thoracic duct and blood vascular
system back to the intestinal lamina propria as well as other secretory
tissues, including the respiratory tract, and the lachrymal, salivary
and mammary glands. This specific recirculation is possible because the
lymphoid cells recognize adhesion molecules that are specific for
endothelial cells of the mucosal postcapillary venule. However, little
is known about the immune regulation other than the strikingly
regionalized disparity in class distribution of mucosal immunocytes
(Brandtzaeg et al. 1999
).
Oral unresponsiveness or tolerance.
The MALT usually responds in two opposite fashions, i.e., in a positive
manner for immunity to pathogenic organisms and in a negative manner to
a large number of antigens of food as well as bacteria in the mucosal
environment. This tolerance prevents the immune system from
overresponding extensively to potential antigens. This unresponsiveness
may be both T- and B-cell mediated. One potential mechanism is the
induction of antigen-specific suppressor T cells found in Peyer’s
patches. Although the mechanism is unknown, antigen-nonspecific
regulatory cells can also play an important role in down-regulating
responses to specific antigens. Another possible mechanism would be a
direct effect of antigen on mucosal lymphocytes resulting in the
induction of clonal inhibition (Toy and Mayer 1996
).
Abnormalities or a reduction in oral unresponsiveness could result in
hypersensitivity to oral antigens such as milk proteins in young
children.
Activational pathways of nonspecific immunity by bacterial cell wall products.
Both gram-positive and gram-negative bacteria are found in the
human gut flora. Components of their cell wall may play an important
role in a number of homeostatic mechanisms as well as nonspecific
immunity. The bacterial cell wall consists of two major components. One
of those, peptidoglycan (PG), is present in both gram-positive and
gram-negative bacteria, whereas lipopolysaccharide (LPS) is
expressed only by the gram-negative group. Small amounts of both PG
and LPS are released continuously; during severe bacterial infection,
large amounts of those compounds may be released. Small amounts of LPS
or PG derived from the intestinal flora may be important for the
development, maintenance and function of the immune system
(Hamann et al. 1998
). The action of LPS and PG on cell
stimulation is a receptor-dependent process involving the cell
surface CD14. The Toll-receptors, a conserved family associated
with microbial pathogens, are coupled to signal transduction pathways
that control expression of several inducible immune response genes
(Kopp and Medzhitov 1999
). Macrophages, endothelial
cells, smooth muscle cells and neutrophils are activated by these cell
wall components and in turn may release several mediators. A large
group of proteins can be produced by LPS-activated macrophages,
including cytokines, such as tumor necrosis factor-
(TNF), IL-1,
IL-6, IL-8, IL-12; metalloproteases, such as elastase and cathepsin;
lipid mediators such as prostaglandins; as well as reactive oxygen and
nitrogen species. However, up to a 1000-fold higher concentration of PG
may be required to induce secretion of many of those compounds compared
with LPS. It is not known, however, whether sufficient levels of PG are
reached in vivo after severe bacterial infection to induce those
macrophage functions in vitro. Thus, differential production of
autocoids by probiotic bacteria vs. pathogenic bacteria in the
intestinal microflora may have a pronounced influence on the induction
of nonspecific immunity.
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Methods used for study of the mucosal immune system |
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TOPABSTRACTINTRODUCTIONThe mucosal immune systemMethods used for study...Probiotic modulation of the...Possible future directionsREFERENCES |
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).
To study the effects of probiotics on the immune system, the oral
route, the natural host route of the bacteria, should be the focus as
should the MALT. One of the major responses in mucosal immunity is a
humoral-immune response and the production of sIgA. Several
different methods are available to assess the type and concentration of
immunoglobulins (Table 1). The specificity of the immunoglobulin and the type are important
considerations. For example, sIgA is produced mainly by MALT and may
better reflect intestinal response than monomeric IgA, which may not
specifically reflect intestinal response. The sIgA may be more
difficult to measure than monomeric IgA; samples for assessment of sIgA
are best obtained from gut lavage fluid or saliva. Obtaining samples
for measurement of sIgA from those human fluids has the drawback of
being quite invasive. Saliva may not be the optimal source; however,
samples are easy to obtain from humans and saliva can be reflective of
MALT activity. In the intestinal immune system, IgM levels are usually
quite low compared with IgA and little to no IgG can be detected in a
mucosal response.
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). One of the most common methods used for assessment of immune function
in humans is ex vivo assessment of lymphocyte proliferation. Lymphocyte
proliferation in vitro may be induced specifically by a known antigen
or nonspecifically by a mitogen. Although a commonly used method, the
biological significance of mitogen stimulation is often questioned
because of the broad nonspecific nature of the stimulation. Moreover,
stimulation of lymphocyte proliferation with mitogens by-passes
many of the early events that occur in lymphocyte activation. Mitogens
stimulate large numbers of lymphocytes, whereas antigens stimulate far
fewer cells that are specifically sensitized to antigen. In addition,
with antigen-specific stimulation, only T cells respond. Because
stimulation of both specific and nonspecific immunity may result in the
production of cytokines, their assessment may be an important indicator
of intestinal immune response. Although production of cytokines may be
important for assessment, their constitutive levels are often difficult
to detect. In contrast, assays of cytokine production after in vitro
stimulation with agents such as LPS or PG are relatively
straightforward. Measurement of cytokine production by lymphocytes and
macrophages obtained from the MALT would be most reflective of
probiotic local effects vs. a systemic response. Because cytokines
often function at a focal or cell-to-cell level, the biological
significance of assessing the influence of probiotics on systemic
cytokine response remains to be established.
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Probiotic modulation of the immune system |
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TOPABSTRACTINTRODUCTIONThe mucosal immune systemMethods used for study...Probiotic modulation of the...Possible future directionsREFERENCES |
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Humoral responses.
There have been several reports recently describing the effects of
probiotics on sIgA in both rodents and humans (Table 3). Although the specific results varied, generally an enhanced sIgA
production was observed during probiotic treatment. For example,
L. casei, L. acidophilus and yogurt enhanced the
number of IgA-producing plasma cells in a dose-dependent manner
(Perdigon et al. 1995
). In another study, L.
casei was shown to significantly increase the amount of sIgA in
response to Salmonella typhimurium inoculation
(Perdigon et al. 1991
). This increased secretion of IgA
was sufficient to prevent enteric infection. Similarly, the effect of
feeding heat-killed L. casei, Shirota on IgE production
in mice was evaluated after intraperitoneal preinjection with ovalbumin
(Matsuzaki et al. 1998
). L. casei, Shirota
reduced serum IgE levels and IgE production in response to ovalbumin.
In addition, in vitro production of IgE by spleen cells from mice fed
L. casei, Shirota in response to restimulation with
ovalbumin was inhibited in contrast to spleen cells from the control
group (Matsuzaki et al. 1998
). From these limited
studies, it appears that Lactobacillus was able to enhance
IgA production in experimental animal models.
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Few studies have been published assessing the effects of probiotics on
the cellular aspect of the immune system. In one study, mice fed lactic
acid bacteria had increased splenocyte proliferation in response to
mitogens for T cells and T and B cells (De Simone et al. 1993
). Other effects of probiotics on cellular responses have
been observed in conjunction with specific diseases such as autoimmune
diseases.
Cytokine production.
Perhaps the most intriguing aspect of probiotic modulation of immune
response is through its effects on cytokine production. Cytokines and
their regulation of the immune system have been studied intensively in
the last several years in cell lines and primary cells of both rodents
and humans (Ha et al. 1999
, Marin et al. 1998
, Miettinen et al. 1998
, Nicaise et al. 1993
, Tejada-Simon et al. 1999a
and 1999b
).
Several studies have shown that cytokine production by cells of the
immune system can be altered by probiotic use (Table 4). For example, the effects of four commercial strains of
Streptococcus thermophilus found in yogurt on cytokine
production were evaluated with a macrophage cell line and a
T-helper cell line and compared with active strains of L.
bulgaricus, Bifidobacterium adolescentis, and B.
bifidum (Marin et al. 1998
). All cytokines studied,
TNF, IL-6, IL-2 and IL-5, were affected by heat-killed S.
thermophilus in a strain- and dose-dependent fashion. All
bacteria induced significant increases of IL-6 production in the
macrophage cell line with S. thermophilus, 133 showing the
greatest activity. The four S. thermophilus strains also
strongly induced TNF production. IL-6 and, to a lesser extent,
TNF production were also increased when the macrophages were
costimulated with LPS and cells of the three groups of lactic acid
bacteria. After concurrent stimulation of a T cell line with phorbol
12-myristate-13-acetate, seven of the eight strains enhanced IL-2 and
IL-5 production significantly (Marin et al. 1998
). In
another study, the effect of bacterial flora on cytokine production
from mouse resident peritoneal macrophages was investigated
(Nicaise et al. 1993
). The production of IL-1, IL-6 and
TNF was determined in germ-free mice and mice implanted with
either Escherichia coli or B. bifidum.
Macrophages from the implanted mice produced significantly more IL-1
and IL-6 in vitro than macrophages from germ-free mice
(Nicaise et al. 1993
).
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). In another study, human peripheral blood
mononuclear cells were stimulated with three nonpathogenic
Lactobacillus strains and with one pathogenic
Streptococcus pyogenes strain. All bacteria
strongly induced IL-1ß, IL-6 and TNF mRNA expression and secretion
of the cytokine protein. S. pyogenes was the most potent
inducer of secretion of IL-12 and IFN-, and two of the
Lactobacillus strains induced IL-12 and IFN-
production. All strains induced IL-18 protein secretion
(Miettinen et al. 1998
). Additional effects of
probiotics have been to reverse the age-related decline in the
production of cytokines (Famularo et al. 1997
). For
example, supplementing the diet of aging mice with several probiotic
species restored IFN and IFN levels compared with control mice
(Muscettola et al. 1994
). The mechanism of this reversal
is unknown but may involve the ability of lactic acid bacteria to
adhere selectively to M cells of Peyer’s patches. Nonspecific immunity.
Several studies have demonstrated the beneficial effects of
lactic acid bacteria in boosting a nonspecific immune response.
Probiotic bacteria have been shown to influence immune responses
nonspecifically by enhancing phagocytosis of pathogens as well as
modifying cytokine production (Table 5). Most studies that have reported the effects of probiotic treatment on
phagocytosis have used macrophages isolated from treated animals.
However, in one study, a strain of L. acidophilus isolated
from a human newborn was inoculated into germ-free and conventional
mice, and phagocytosis of E. coli was assessed in vivo
(Neumann et al. 1998
). The monoassociation of
germ-free mice with this lactic acid bacteria for 7 d improved
macrophage phagocytic capacity, as demonstrated by the clearance of
E. coli inoculated intravenously. In another study,
probiotic bacteria appeared to modulate the nonspecific immune response
in normal, healthy subjects compared with hypersensitive subjects
(Pelto et al. 1998
). Milk-hypersensitive and healthy
adults were challenged with milk with or without
Lactobacillus GG. In the hypersensitive subjects, milk
challenge significantly increased the expression of CR1, FcRI and
FcR in neutrophils and CR1, CR3 and FcR in monocytes. In
contrast, milk with Lactobacillus GG prevented the increase
of the receptors expressed. In healthy control subjects, milk challenge
did not influence receptor expression, whereas milk with
Lactobacillus GG significantly increased the expression of
CR1, CR3, FcRIII and FcR in neutrophils. From this work, the
authors concluded that the response was immunostimulatory in healthy
subjects, but down-regulatory in milk-hypersensitive subjects.
Collectively, it appears that probiotic bacteria may have a selective
influence on components of nonspecific immunity, but the mechanisms by
which that occurs remain to be determined.
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Possible future directions |
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TOPABSTRACTINTRODUCTIONThe mucosal immune systemMethods used for study...Probiotic modulation of the...Possible future directionsREFERENCES |
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). Although probiotic bacteria such as L. caseii have been
well documented to reduce some pathologic processes such as diarrhea,
their ability to influence human immune function is not as clearly
documented (Table 7). Although preliminary work is promising, an extensive number of
well-controlled studies must be done to clarify specifically the
influence that probiotic bacteria may have. Effects of these bacteria
may be through alterations of nonspecific immunity, potentially
mediated through LPS, PG or both. One important issue will be to
determine whether probiotics reduce inflammation either at the local or
at the systemic level. Because probiotic bacteria cell wall products
are likely to act at a local level, it will be important to know which
processes are modified and what are the mechanisms for those
modifications. Crohn’s disease and ulcerative colitis are examples of
potentially important models of intestinal nonspecific immune
dysfunction. Not only will it be important to determine whether
probiotics can alter pathogenesis, but it will also be important to
determine the optimal use of probiotics for either prophylaxis or
treatment.
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).
It is also possible that genetically engineered lactobacilli could be
used as carriers for antigens to help induce oral tolerance
(Maassen 1999
). Some preliminary studies have indicated
that probiotics could play a role in allergy, autoimmunity or
gastrointestinal disease. It will be important to determine whether
probiotic bacteria can influence those immunological processes in
humans and which specific step may be altered. Protein-energy malnutrition may be associated with immune suppression, particularly T-cell functions. Thus, it would be important to determine whether probiotics provided through food sources would enhance immune function. In all of these potential studies, it will be very important to identify the strains and determine the levels that are required to achieve the desired effects, whether it is prophylaxis or treatment for a general or specific health condition. It has already been demonstrated that not all strains of lactic acid bacteria exhibit probiotic effects. Extensive variation among species and strains belonging to the same species can be expected. It will also be important to assess whether the probiotics act to modulate the MALT or induce a generalized systemic response. To understand the mechanisms by which probiotics achieve their effects, the development of an in vitro model to mimic MALT would be very helpful.
Although the application of probiotics shows some promising results and trends with respect to select aspects of immune modulation, the underlying mechanisms are unclear. Nevertheless, it will be important to understand the role of gut bacteria as immune modulators in health and disease.
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FOOTNOTES |
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2 Supported by a grant from the California Breast Cancer Research Program, 4CB-0157.
4 Abbreviations used: GALT, gut-associated lymphoid tissue; IFN, interferon; Ig, immunoglobulin; IL, interleukin;
LPS, lipopolysaccharide; MALT, mucosa-associated lymphoid tissue;
MHC, major histocompatability complex; PG, peptidoglycan; sIgA,
secretory immunoglobulin A; Th, T-helper cell; TNF, tumor necrosis factor.
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