MucosalImmunology | VOLUME 4 NUMBER 6 | NOVEMBER 2011
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As the most abundant class of antibodies found in the intesti-
nal lumen of humans and in most other mammals, secretory
IgA (SIgA) has long been recognized as a first line of defense
in protecting the intestinal epithelium from enteric pathogens
and toxins. SIgA production against specific mucosal antigens is
dependent on the sampling by Peyer ’ s patch M cells, processing
by antigen-presenting cells such as dendritic cells (DCs), T-cell
activation, and ultimately B-cell class switch recombination in
gut-associated lymphoid tissues (GALTs), mesenteric lymph
nodes, and possibly neighboring lamina propria. 1,2 Isolated
lymphoid follicles in the small and large intestines also func-
tion in the induction of mucosal immune responses. 3 Multiple
cytokines, including interleukin (IL)-4, transforming growth
factor- ? , IL-5, IL-6, and IL-10 are instrumental in intestinal
stimulation of SIgA production. A subset of these cytokines,
notably transforming growth factor- ? and IL-10, is also required
for maintaining mucosally induced tolerance, thus establishing
one of the many links between SIgA production, immunity, and
This review highlights our current understanding of SIgA ’ s
many (recently revealed) functions in mucosal immunity and
intestinal homeostasis. As SIgA essentially resides within an
external environment (i.e., the intestinal lumen), it must com-
bat microbial infections through mechanisms that are funda-
mentally different from those used by antibodies in systemic
compartments. Whereas IgG promotes killing and clearance of
pathogenic bacteria through coordinated activity of complement
and Fc-mediated uptake by macrophages and neutrophils, it is
generally assumed that SIgA acts primarily through receptor
blockade, steric hindrance, and / or immune exclusion. We sum-
marize evidence for each of these activities as revealed through
the use of animal models, but argue that the mechanisms under-
lying SIgA-mediated immunity are in fact much more complex
than previously appreciated.
With respect to intestinal homeostasis, we make the case that
SIgA ’ s multifaceted roles in controlling inflammation and in
regulating immune responses to certain dietary antigens, com-
mensal microflora, and enteric pathogens are only beginning to
be understood. The past several years have seen an emergence of
evidence that indicates that SIgA influences the composition
of the intestinal microbiota, promotes the uptake and delivery
of antigens from the intestinal lumen to DC subsets located
in GALTs, and influences inflammatory responses normally
associated with the uptake of highly pathogenic bacteria and
potentially allergenic antigens. Owing to space limitations, this
Secretory IgA ’ s complex roles in immunity and
mucosal homeostasis in the gut
NJ Mantis 1 , 2 , N Rol 3 and B Corth é sy 3
Secretory IgA (SIgA) serves as the first line of defense in protecting the intestinal epithelium from enteric toxins and
pathogenic microorganisms. Through a process known as immune exclusion, SIgA promotes the clearance of antigens
and pathogenic microorganisms from the intestinal lumen by blocking their access to epithelial receptors, entrapping
them in mucus, and facilitating their removal by peristaltic and mucociliary activities. In addition, SIgA functions in
mucosal immunity and intestinal homeostasis through mechanisms that have only recently been revealed. In just
the past several years, SIgA has been identified as having the capacity to directly quench bacterial virulence factors,
influence composition of the intestinal microbiota by Fab-dependent and Fab-independent mechanisms, promote retro-
transport of antigens across the intestinal epithelium to dendritic cell subsets in gut-associated lymphoid tissue, and,
finally, to downregulate proinflammatory responses normally associated with the uptake of highly pathogenic bacteria
and potentially allergenic antigens. This review summarizes the intrinsic biological activities now associated with SIgA
and their relationships with immunity and intestinal homeostasis.
1 Division of Infectious Diseases, Wadsworth Center, New York State Department of Health , Albany , New York , USA . 2 Biomedical Sciences Program, University at
Albany School of Public Health , Albany , New York , USA . 3 R & D Laboratory of the Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois , Lausanne ,
Switzerland . Correspondence: NJ Mantis or B Corth é sy ( firstname.lastname@example.org or email@example.com )
Received 5 June 2011; accepted 15 August 2011; published online 5 October 2011. doi: 10.1038/mi.2011.41
VOLUME 4 NUMBER 6 | NOVEMBER 2011 | www.nature.com/mi
review will be mainly focused on SIgA ’ s activities within the
intestinal lumen; we will not discuss the capacity of polymeric
IgA to neutralize pathogens intracellularly during transepithe-
lial transport or to promote excretion of antigens present in the
MULTIPLE NEUTRALIZING PROPERTIES OF SIgA AT GUT
Blocking attachment to epithelial cells by steric hindrance
and binding to receptor-recognition domains
SIgA is capable of interfering with the earliest steps in the infec-
tion process by virtue of its ability to block toxins and pathogens
from adhering to the intestinal epithelium. 4 – 9 One of the best
examples of this mode of protection involves cholera toxin (CT),
the toxin responsible for severe secretory diarrhea associated
with Vibrio cholerae infection. In mouse models, it has been
demonstrated that SIgA is essential in protecting the intestinal
epithelium from the effects of luminal CT exposure. 9,10 Not sur-
prisingly, mouse IgA monoclonal antibodies (mAbs) against the
toxin ’ s B subunit (CTB), a homopentameric molecule that binds
to ganglioside GM 1 on the apical surfaces of enterocytes, were
sufficient to prevent CT attachment to polarized intestinal epi-
thelial cell monolayers in vitro . These same IgA mAbs protected
neonatal mice from CT-induced secretory diarrhea, weight loss,
and death. 11 However, the mAbs did not directly interact with
the GM 1 -binding site on CTB. Therefore, it was suggested that
they likely interfere with CT binding to epithelial cells through
a mechanism involving steric hindrance.
SIgA has also been shown to be capable of blocking patho-
gens from attaching to intestinal epithelial cells by direct rec-
ognition of receptor-binding domains, as demonstrated in the
case of reovirus type 1 Lang. SIgA is required for full protection
against intestinal reovirus type 1 Lang infection, as revealed
through the use of IgA knockout mice. 12 To investigate the
molecular mechanism underlying SIgA-mediated immunity to
reovirus, a panel of reovirus-specific IgA mAbs was screened
for those that protected mice against an oral type 1 Lang chal-
lenge. Protection was conferred by IgA mAbs directed against
the ? 1 protein, an adhesin fiber known to promote viral
attachment to a number of epithelial cell types. 13 The exact
epitope recognized by one particular IgA mAb was localized
to a ~ 30 amino-acid region of the ? 1 receptor-binding head
domain, providing strong evidence that the mAb directly inter-
feres with epithelial recognition. 5 IgA mAbs against the other
viral surface antigens, including the capsid protein, were not
protective in the type 1 Lang peroral challenge model, under-
scoring the importance of epitope specificity in SIgA-mediated
Immune exclusion: agglutination, entrapment, and clearance
“ Immune exclusion ” generally refers to the ability of SIgA to
prevent microbial pathogens and antigens such as toxins from
gaining access to the intestinal epithelium through a stepwise
series of events involving agglutination, entrapment in mucus,
and / or clearance through peristalsis. 14 – 16 Although immune
exclusion has been recognized as a function of SIgA for nearly
four decades, 17 and often attributed as being an important com-
ponent of protective immunity, 18 very little is known about the
specific details of the process.
Agglutination is the formation of macroscopic clumps of
bacteria (or viruses) as the result of antibody-mediated cross-
linking through polyvalent surface antigens. There are no
reports in the literature to suggest that agglutination per se has
any detrimental effect on microbial physiology or virulence.
On the contrary, we (along with others) have reported that
bacterial growth rates in culture are unaffected by agglutina-
tion. 19,20 However, scanning and transmission electron micro-
scopy analysis of Salmonella enterica serovar Typhimurium
cross-linked by a protective IgA mAb ( “ Sal4 ” ) against the O
antigen has revealed evidence of antibody-mediated distor-
tion of the bacterial outer membranes ( Figure 1 ), secretion
of a capsular exopolysaccharide, and alterations in bacterial
gene expression (S. Forbes, J. Amarasinghe, J. Dornenburg, and
N. Mantis, manuscript in preparation). Cross-linking of
Salmonella typhimurium with antibodies against the flagella
did not elicit any ultrastructural changes in membrane integ-
rity, demonstrating that agglutination is qualitatively different
depending on the epitope recognized by the agglutinating anti-
body, and that some antibodies may have immediate effects on
bacterial physiology and gene expression.
Work by Phalipon, Corth é sy, and colleagues 21,22 has exam-
ined in mouse and rabbit model systems the capacity of SIgA to
entrap bacterial pathogens in the mucus layer overlying respira-
tory and intestinal epithelia in vivo . Through the use of light
microscopy, immunohistochemistry, and autoradiography, it
was shown that a murine IgA mAb (IgAC5) specific for the
O antigen of Shigella flexneri readily entrapped the bacterium
within a thin layer of mucus overlying the epithelium. This
activity was considerably greater when IgAC5 was complexed
with bound secretory component (SC), apparently because the
oligosaccharide side chains of SC associate with mucus. The
mucus layer in the mouse and human small and large intes-
tines is complex, 23 and defining the specific molecular interac-
tions between SIgA and individual components of the mucus
layer will be necessary to fully understand the mechanisms
that govern immune exclusion. Moreover, it is unclear to what
degree (if any) SIgA promotes immune exclusion of commensal
Although the capacity of specific SIgAs to entrap bacteria in
the intestinal mucus in experimental settings is undeniable, it
remains to be determined to what degree immune exclusion
contributes to protective immunity to other enteropathogens,
especially viruses. Indeed, it has been argued that any SIgA
capable of binding to the surface of a pathogen is theoretically
sufficient to intercept that pathogen in the intestinal lumen and
to reduce or even block its attachment to the intestinal epithe-
lium. 24 However, coating of rotavirus or reovirus with “ non-
neutralizing ” IgA mAbs in the intestinal lumen of mice is not
sufficient to block infection. 6,25 Rather, the primary determinant
of protective immunity correlated with epitope specificity, thus
challenging the importance of immune exclusion in mucosal
immunity to viruses.
MucosalImmunology | VOLUME 4 NUMBER 6 | NOVEMBER 2011
Direct effects of SIgA on bacterial virulence
It has been recognized for years that neither immune exclusion
nor direct interference with attachment to epithelial receptors
can fully account for the protective effects observed by a number
of IgA mAbs, such as those against the O antigens of V. cholerae ,
S . typhimurium , and S. flexneri. 11,19,22,26,27 This prompted us
to examine the possibility that IgA may have a direct effect on
bacterial virulence. We found that the binding of a murine IgA
mAb (IgAC5) to the O antigen of S. flexneri suppressed activity
of the bacterial type 3 secretion system that is necessary for
S. flexneri to gain entry into intestinal epithelial cells. 28 The sup-
pressive effect of IgAC5 on type 3 secretion activity was rapid
(5 – 15 min) and coincided with a partial reduction in the bacte-
rial membrane potential and intracellular ATP levels. Although
IgAC5 is neither bacteriostatic nor bactericidal, it clearly has
the capacity to selectively “ quench ” certain virulence factors. It
remains to be determined whether other IgA antibodies share
Fab-independent interaction between natural SIgA and
intestinal pathogenic and commensal bacteria
SIgA is also capable of preventing pathogen and toxin attach-
ment to epithelial surfaces, independent of the antibody variable
region. In this respect, SIgA can be considered a component of
the innate immune system. Both the IgA heavy chain (Fc ? ) and
SC are heavily glycosylated. As the oligosaccharide side chains
present on SIgA share a high degree of similarity with those on
the luminal face of the intestinal epithelium, it has been pro-
posed that IgA and SC (free or bound to IgA) can effectively
serve as competitive inhibitors ( “ decoys ” ) of pathogen binding to
host cells. 29 – 35 For example, SIgA in concentrations at or below
those found in human milk inhibited the binding of Clostridium
difficile toxin A to purified enterocyte brush border membrane
receptors. 29 Toxin A bound to free SC as strongly as it did to
the heavy and light chains of IgA. Perrier et al. 32 identified the
galactose and sialic acid residues on free SC as being primarily
responsible for blocking toxin A attachment to epithelial cell
monolayers. SC ’ s activities are in fact quite broad, as free SC
has been shown to serve as a decoy receptor for other patho-
gens, including enteropathogenic Escherichia coli by binding to
intimin 32 and Streptococcus pneumoniae through interaction
with the choline-binding protein A. 36 Along the same lines, a
recent study has shown that mannose residues present on SIgA
(but not serum IgG or IgM) are implicated in the inhibition of
V. cholerae biofilm formation. 37
The interaction between SIgA and commensal bacteria
involves Fab- and Fc-independent structural motifs, featuring
bound SC as a crucial partner. Removal of glycans present on
free SC or bound in SIgA resulted in a drastic decrease in the
interaction with Gram-positive bacteria, indicating the essential
role of carbohydrates in the process. 38 Coating of commensal
microorganisms by SIgA may favor gut colonization and educa-
tion of the newborn ’ s mucosal immune system toward antigens
associated with symbiotic partners. For example, using human
intestinal epithelial Caco-2 cell grown as polarized monolayers,
we found that association of a Lactobacillus or a Bifidobacterium
with non-specific SIgA enhanced probiotic adhesion by a factor
of ? 3.4-fold. Moreover, SIgA affected epithelial permeability,
signaling events involved in nuclear factor- ? B nuclear transloca-
tion, production of pIgR, and induction of immune mediators. 39
Taken together, these observations suggest that although sugar-
mediated non-specific recognition occurs, its highly plastic,
combinatorial nature still permits a selective interaction with
commensal, non-pathogenic, and pathogenic bacteria.
Figure 1 IgA-mediated agglutination of S. typhimurium is accompanied
by gross changes in cell shape. Mid-log phase cultures of S . typhimurium
strain 14028S were exposed to Sal4 mAb (5 ? g ml − 1 ) for 45 min and then
subjected to scanning electron microscopy. ( a ) S . typhimurium control
cells not treated with Sal4; ( b and c ) cells treated with Sal4, at (panel b )
low and (panel c ) high magnification. The gross changes in cell shape
and the bridging that occurs between cells in the presence of Sal4
(panels b and c ) but not in the absence of Sal4 (panel a ) must be noted.
Figure kindly provided by Dr Steve Forbes. mAb, monoclonal antibody.
VOLUME 4 NUMBER 6 | NOVEMBER 2011 | www.nature.com/mi
ROLE OF SIgA IN HOMEOSTASIS OF THE INTESTINAL
Induction of SIgA by neonatal exposure to commensal
Immediately after birth, mammals are exposed to microbes
associated with the external and maternal environments. The
transition from a sterile environment to a highly colonized envi-
ronment is accompanied by concomitant exposure of the new-
born ’ s gastrointestinal tract to maternal IgA antibodies acquired
through breast feeding. Natural and specific SIgA antibodies in
breast milk are capable of binding commensal bacteria and may
be involved in the progressive, controlled establishment of the
newborn ’ s microbiota. 40,41 The microbiota, in turn, stimulates
maturation of GALTs, resulting in the production of IgA with
both a limited affinity and repertoire to redundant epitopes on
gut microorganisms. 42 – 44 By direct visualization of a fluores-
cently labeled commensal bacterium administered in the form of
an SIgA-based complex into the intestines of mice, we observed
both preserved association with the antibody and specific target-
ing to, and passage across, Peyer ’ s patch M cells ( Figure 2 ). This
observation suggests that SIgA, by virtue of its ability to associ-
ate with commensal bacteria and promote their uptake through
M cells (see below), may have an important role in control-
ling the sampling of commensal bacteria in the form of SIgA-
immune complexes by GALTs (N. Rol, L. Favre, J. Benyacoub,
and B. Corth é sy, submitted for publication).
The past several years have yielded important information
about the mechanisms involved in intestinal IgA response
against commensal microorganisms. It has been proposed that
in mice, a proportion of the specific SIgA against commensal
bacteria are induced in a T cell-independent pathway, independ-
ent of the development of follicular lymphoid structures. 45,46
Subsequent studies in mice revealed that commensal bacteria
persist in Peyer ’ s patch DCs, contributing to induction of local
specific immune responses that limit dissemination no farther
than the mesenteric lymph nodes, ultimately preventing sys-
temic spread. 47 Recently, Hapfelmeier et al. 48 reported using a
“ reversible ” germ-free mouse model that the intestinal-specific
IgA response against commensal bacteria (i) requires a high
threshold for induction ( ~ 10 9 bacteria), (ii) has a slow onset
( ? 14 days) with a long half-life ( > 16 weeks), and (iii) constantly
adapts to the predominant commensal species in the intestinal
lumen. However, it remains an open question as to whether this
type of selective SIgA response actually reflects the situation in
conventionally raised mice, which encounter a complex and
diverse microbiota in the context of a fully matured GALTs.
Involvement of SIgA in the control of commensal
Different model systems have been used to investigate the role of
SIgA on intestinal homeostasis. Among them are mouse strains
deficient in AID (activation-induced cytidine deaminase), which
are unable to class switch from IgM to IgA. AID knockout mice
were shown to have profound increases in the number of non-
pathogenic, anaerobic bacteria throughout their small intestines,
as well as hyperplasia of isolated lymphoid follicles. 49 As AID − / −
mice do not have functional SIgM, this study demonstrated that
SIgA is essential in preventing hyper-stimulation of the mucosal
and systemic immune systems. However, it has been noted that
SIgM has compensatory activities in selectively IgA-deficient
mice, possibly explaining why these mice are “ healthy ” under
normal laboratory conditions. These observations in mice can
be compared with human IgA deficiency in which a maturation
defect in B cells is commonly observed. 50 IgA-deficient patients
are generally asymptomatic, but do exhibit a tendency to develop
gastrointestinal disorders such as celiac disease (CD) 51 and
allergies. 52 IgA-deficient patients often have airway infections;
however, these problems are mainly seen because compensatory
SIgM is lacking in the airways (in contrast to the gut). 53 Taken
together, this supports the notion that adaptive SIgA responses
may allow the host to respond to fluctuations in commensal
bacteria without eliciting a deleterious response, and thus favor
mucosal homeostasis. 54
The dynamics between the commensal microbiota and SIgA
are likely highly complex, considering that a considerable pro-
portion (24 – 74 % ) of the microbiota is coated with SIgA. 55,56
Peterson et al. 57 used an ingenious germ-free mouse model to
directly examine the impact of SIgA on host – commensal inter-
actions. The authors first produced an IgA mAb against the cap-
sular polysaccharide of Bacteroides thetaiotaomicron . Germ-free,
immunodeficient mice secreting this particular IgA mAb into
the intestinal lumen by virtue of a hybridoma “ backpack ” were
then challenged with B. thetaiotaomicron and both the host ’ s
and the commensal ’ s responses were analyzed. The authors
found that B. thetaiotaomicron , in the absence of specific anti-
capsular SIgA, elicited a robust oxidative stress response in the
host. The presence of SIgA antibodies suppressed this response,
Figure 2 Entry of commensal bacteria coated with SIgA in a Peyer ’ s
patch through M cells. Image acquired by laser scanning confocal
microscopy. Lactobacillus rhamnosus labeled with FITC was injected
in the form of SIgA-based complexes into a mouse-ligated ileal loop
comprising a single Peyer ’ s patch. After a 2-h incubation, the tissue
was removed and cryosectioned. M cells (blue), SIgA (red), and cell
nuclei (gray) were stained with UEA-1, anti-SC antibodies, and DAPI,
respectively. Arrowheads indicate bacteria in the form of SIgA-based
complexes. The appearance of SIgA-based complexes in the lumen, at
the surface of M cells, and transiting through an M cell reflects the various
steps in the passage from the lumen to the SED region. Bars in insets
represent 5 ? m. DAPI, 4 ? -6-diamidino-2-phenylindole; FITC, fluorescein
isothiocyanate; SED, subepithelial dome; SIgA, secretory IgA;
UEA-1, Ulex europaeus agglutinin-1.
MucosalImmunology | VOLUME 4 NUMBER 6 | NOVEMBER 2011
thereby underscoring SIgA ’ s potential to dampen deleterious
host responses to commensal microbiota.
An interesting observation from the study by Peterson et al. 57
was that the capsular polysaccharide-specific IgA mAb reduced,
but did not prevent B. thetaiotaomicron from colonization of the
mouse gut. Thus, under steady-state conditions, the presence of
specific SIgA antibodies against surface antigens does not neces-
sarily lead to bacterial clearance. Zitomersky et al. 58 performed
a longitudinal study of Bacteroidales species in 15 healthy adults
over a period of a year and reached a similar conclusion. In fact,
it has been argued that bacteria that bind SIgA may actually have
a selective advantage in the gut. 59 Bollinger et al. 60,61 have shown
that SIgA and mucin facilitate the formation of biofilms by non-
pathogenic E. coli on epithelial cell monolayers grown in vitro .
Biofilms have been proposed as a means by which endogenous
microbiota colonize mucosal surface and ensure a steady-state
growth rate in the intestinal lumen. 62 The association of SIgA
with biofilm formation in the gut has been demonstrated using
sections from rat, baboon, and human tissues. 63 Fluorescence
in situ hybridization analysis has revealed that Lactobacilli spe-
cies establish biofilms in different parts of the gastrointestinal
tract, although it remains to be determined whether SIgA anti-
bodies are involved in the process. 64
RETRO-TRANSPORT OF SIgA ACROSS THE INTESTINAL
SIgA-based transport of immune complexes by M cells
It has been known for some time that Peyer ’ s patch M cells selec-
tively bind SIgA and SIgA-immune complexes. 65,66 Although
there is evidence for a SIgA-specific receptor on M cells, this
receptor has not been identified. Therefore, the exact mecha-
nism by which M cells selectively internalize SIgA – antigen com-
plexes in the face of a large excess of free SIgA present in the
intestinal lumen remains unknown. Nonetheless, we recently
provided evidence that SIgA undergoes conformational changes
following antigen binding. 67 Using specific SIgA antibodies
with antigens of various sizes and complexity, we found that
SIgA protease sensitivity profiles were altered upon antigen
engagement, presumably reflecting differences in heavy chain
backbone conformations. The conformational changes induced
upon antigen interaction resulted in enhanced binding of SIgA
to cellular receptors (Fc ? RI and pIgR), as compared with free
(unbound) SIgA. These data reveal that antigen recognition by
SIgA triggers structural changes in the immunoglobulin that
result in enhanced receptor-binding properties. It remains to
be determined whether this is relevant to M cell recognition of
SIgA-based immune complexes.
Consequences of SIgA-based immune complex uptake by
The recognition that SIgA-based immune complexes are trans-
ported by Peyer ’ s patch M cells into the subepithelial dome
(SED) regions has led us to investigate the role of “ retro-trans-
location ” in the regulation of intestinal immune responses. 68
Oral delivery to mice of recombinant SIgA consisting of mouse
polymeric IgA and human bound SC as a surrogate non-self
antigen, triggered human bound SC-specific mucosal and
systemic immune responses, as evidenced by antigen-specific
serum and salivary antibody titers, T-cell proliferation in drain-
ing mesenteric lymph nodes and spleen, and pronounced expres-
sion of IL-10 and transforming growth factor- ? by cells recovered
from mesenteric lymph nodes. 68 Furthermore, analysis of IgG
isotypes and cytokine profiles demonstrated the tendency of
recombinant SIgA immunization to induce a mixed Th1 / Th2,
tolerance-biased pattern of mucosal immune responses. It was
also observed that recombinant SIgA induced migration of DCs
from the SED region to the interfollicular region, a phenomenon
indicative of DC activation. Although these responses were sig-
nificantly less marked when compared with responses triggered
upon mixing of human bound SC with the prototype mucosal
adjuvant CT, they nonetheless reveal that IgA can function as an
immunopotentiator in the mucosal environment.
Reduction of pathogen-mediated proinflammatory
responses by mucosal SIgA
Besides being a weak immunopotentiator, there is evidence that
SIgA may actively quench the capacity of certain antigens to
elicit severe proinflammatory responses after uptake through
Peyer ’ s patch M cells. SIgA-coated S. flexneri , when injected
into ligated ileal loops are detected in the SED region in close
association with myeloid CD11c + CD11b + DCs, which are
known to be tolerogenic. In the rabbit model (unlike the mouse),
S. flexneri elicits a local severe acute inflammatory response
that is reminiscent of that observed in humans. 69 This model
was used to assess the non-inflammatory capacity of protective
SIgA at mucosal surfaces. 21 Analysis of cytokine expression in
Peyer ’ s patches demonstrated that SIgA-coated S. flexneri results
in downregulation of proinflammatory cytokines tumor necrosis
factor- ? , IL-6, interferon- ? , while maintaining a sustained level
of regulatory IL-10. This resulted in preservation of the integrity
of the intestinal barrier, and suggests that under homeostatic
conditions, SIgA exerts its anti-inflammatory effects by reducing
bacteria-induced proinflammatory circuits (rather than promot-
ing the onset of anti-inflammatory pathways). It is therefore
tempting to speculate that the retro-transport of antigen – SIgA
complexes is important for the maintenance of tolerance toward
innocuous proteins, including allergens.
SIgA as a scavenger of allergenic antigens
Numerous animal and human studies have postulated that the
secretory immune system is important in controlling allergic
symptoms. Inhibition of allergens in the airways occurred with
the abundant SIgA found in mucosal secretions and contributed
toward limiting the access of allergen to the lamina propria and
thus the inflammatory responses. 70 Passive administration of
antigen-specific or non-specific IgA reduced airways responsive-
ness and lung eosinophilia 71 or allergic rhinitis. 72 The impact of
IgA and SIgA titers during the first 2 years on the development
of allergy was also reported. 73 Reduction of fecal SIgA when
compared with mice actively tolerized with the same protein
antigen 74 argue in favor of the importance of SIgA in controlling
allergic reactions, yet the role of IgG-based complexes with Ag
VOLUME 4 NUMBER 6 | NOVEMBER 2011 | www.nature.com/mi
cannot be excluded. 75 Furthermore, pIgR knockout mice, which
are unable to produce SIgA and have increased intestinal per-
meability, display a greater systemic immune response toward
commensal bacteria, but not toward food antigens, 76 a phenom-
enon possibly linked to increased uptake of food antigens. 77 In
the same knockout model, the capacity of mice to trigger oral
tolerance and protect against systemic hypersensitivity by the
same tolerizing antigen has also been demonstrated; 78 this sug-
gests a delicate balance between the development of secretory
immunity and mucosal leakiness.
Moreover, first-line mucosal defenses were documented in
grass pollen immunotherapy. 79 CD89 (Fc ? RI) cross-linking
by IgA inhibits Fc ? RI-dependent activation of mast cells, and
diminishes allergic asthma in transgenic mice expressing the
human receptor. 80 Aggregated milk allergens are taken up by
Peyer ’ s patches rather than by classical epithelial cell-mediated
phagocytosis: 81 this resulted in the increased production of
both Th2-associated IgE and SIgA. Although the authors con-
cluded on enhanced sensitization, they neglected to consider the
increase in luminal SIgA, and the contribution of the Ab in neu-
tralizing the allergens, ultimately limiting allergic responses.
However, the presence of allergen-specific SIgA is not always
augmented in successfully tolerized animals, and can even be
present in large amounts in sensitized animals without confer-
ring protection. 82 Moreover, the importance of SIgA against
allergic diseases remains unclear with respect to recent clinical
studies; patients with IgA deficiency display an increased risk
of food hypersensitivity at the age of 4 years solely, 52 whereas in
another cohort, IgA deficiency does not show any correlation
with food allergy. 83 It is an open question whether the produc-
tion of compensatory SIgM can explain this discrepancy. The
sum of these data suggests that SIgA production is more critical
for homeostasis toward commensal bacteria than food antigens.
Additional studies are required to clarify the importance of SIgA
in the maintenance of oral tolerance, and hence the integrity of
the intestinal barrier.
Figure 3 Multi-functional interactions between SIgA and pathogenic and non-pathogenic bacteria in the intestinal mucosa. In all pathways,
pathogenic and non-pathogenic bacteria are coated by SIgA (depicted as a dimer with bound SC) in a Fab-specific or in a Fab-independent, glycan-
mediated manner. ( a ) Enhanced interaction between SIgA-coated commensal bacteria and the epithelium reinforces its barrier function through
multiple mechanisms, including reinforcement of tight junctions, overproduction of pIgR, and reduction in nuclear translocation of NF- ? B. ( b ) SIgA-
based immune complexes with commensal and / or pathogenic bacteria are taken up by M cells wherein they are targeted to underlying myeloid DCs,
possibly upon binding to DC-SIGN, resulting in the downregulation of local proinflammatory responses. ( c ) SIgA, as well as free SC (not depicted in the
figure), may have a role of “ selection ” by excluding pathogenic bacteria off the epithelial surface through anchoring within mucus and favoring biofilm
formation of non-pathogenic bacteria in the space in close contact with epithelial cells. + : activatory effect; − : inhibitory effect. DC, dendritic cell; IFN- ? ,
interferon- ? ; IL, interleukin; NF- ? B, nuclear factor- ? B; SC, secretory component; SIgA, secretory IgA; TNF- ? , tumor necrosis factor- ? .
MucosalImmunology | VOLUME 4 NUMBER 6 | NOVEMBER 2011
CD: SIgA as a Trojan horse
An exception to the generally accepted function of immune
exclusion of SIgA is the observation that the antibody acts as a
Trojan horse in people suffering from CD. In genetically suscep-
tible individuals with CD, complexes of luminal specific SIgA
antibodies and gluten-derived deamidated gliadin peptides are
retro-transcytosed across epithelial cells, leading to the basal
delivery of intact, highly reactive peptides that stimulate inflam-
matory processes through activation of target CD4 + T cells. 84
This abnormal intestinal transport is mediated by the recogni-
tion of SIgA – gliadin complexes by the transferrin receptor (TfR,
CD71) expressed at high levels on the apical surface of intestinal
epithelial cells in CD patients. The disease thus seems a deficient
confining of SIgA-based immune complexes resulting from the
misaddressing of CD71, and its subsequent fortuitous capac-
ity to transcytose toxic gliadin peptides. However, it remains
unclear why in the physiological context the large excess of lumi-
nal SIgA displaying multiple specificities cannot prevent most of
receptor-mediated endocytosis, although effective competition
occurs in the presence of polymeric IgA, SIgA, or soluble CD71
in Ussing chambers in vitro .
Recognition of SIgA – antigen complexes by antigen-
The SED region is the primary depot for antigens and SIgA –
antigen complexes after M-cell transcytosis. 68,85 Although both
mouse- and human-derived DCs are capable of binding and
internalizing SIgA, the specific IgA receptor(s) on DCs involved
in SIgA recognition have not been fully identified. Heystek
et al. 86 speculated that the interaction of SIgA with human
monocyte-derived DCs occurs through a member(s) of the
C-type lectin family of receptors. We recently tested this hypo-
thesis and found that human colostral SIgA is recognized (and
internalized) by human DC-specific intracellular adhesion mole-
cule-3 grabbing non-integrin (DC-SIGN), as well as the man-
nose receptor (MR; CD206). 87 DC-SIGN (but not the MR) is
expressed on myeloid DCs in the SED region, arguing for a pos-
sible role for a subset of C-type lectins in immune sampling. 88
The mouse homolog of DC-SIGN, SIGNR1 (specific intracel-
lular adhesion molecule-3 grabbing non-integrin-related-1;
CD209b) has a binding specificity similar to human DC-SIGN, 89
and is similarly expressed on intestinal CD11c + CD11b + DCs. 90
On the other hand, the possibility that other receptor(s) besides
DC-SIGN are involved in sampling SIgA cannot be excluded.
In the mouse, e.g., it was noted that the association of SIgA with
Peyer ’ s patch DCs was largely unaffected by the glycosylation
state of IgA. 91
Besides its well-documented capacity to protect the intestinal
epithelium from toxins, viruses, and pathogenic bacteria, SIgA
demonstrates an array of other activities that are integral to the
maintenance of mucosal homeostasis ( Figure 3 ). SIgA influ-
ences the composition of the intestinal microbiota, downregu-
lates proinflammatory responses normally associated with the
uptake of highly pathogenic bacteria and potentially allergenic
antigens, and promotes the retro-transport of antigens across
the intestinal epithelium to DC subsets in GALTs. SIgA ’ s ability
to multitask is due in large part to it intrinsic complexity, par-
ticularly the diverse glycan arrays on both polymeric IgA and
bound SC. Our increasing ability to biochemically dissect SIgA
into its individual components and then test them in defined
animal models will ultimately permit us to ascribe specific tasks
to SIgA in molecular detail.
The research topics presented in this review are supported by research
grants from the Swiss Science Research Foundation (3200-122039)
to B.C. and the National Institutes of Health (HD061916) to N.J.M. We
are grateful to Dr Steve Forbes and the Wadsworth Center ’ s Electron
Microscopy Core facility for Figure 1 .
The authors declared no conflict of interest.
© 2011 Society for Mucosal Immunology
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