Mechanisms of Ageing and Development
122 (2001) 1397– 1411
www.elsevier.com/locate/mechagedev

Aging impairs intestinal immunity
Douglas L. Schmucker a,b,e,*, Karine Thoreux a,b,
Robert L. Owen a,c,d
a

Cell Biology and Aging Section, 151E, Veterans Affairs Medical Center, 4150 Clement Street,
San Francisco, CA 94121, USA
b
Department of Anatomy, Uni6ersity of California, San Francisco, CA, USA
c
Department of Medicine, Uni6ersity of California, San Francisco, CA, USA
d
Department of Epidemiology and Biostatistics, Uni6ersity of California, San Francisco, CA, USA
e
Li6er Center, Uni6ersity of California, San Francisco, CA, USA
Received 27 October 2000; accepted 12 December 2000

Abstract
The elderly are characterized by immunosenescence accompanied by high rates of morbidity and mortality associated with infectious diseases. Despite suggestions that the mucosal
immune compartment is relatively unaffected by aging, there are marked deﬁcits in the
intestinal mucosal immune responses of old animals and elderly humans. Little is known
about the mechanism(s) whereby aging disrupts intestinal immunity. However, several events
in the genesis of the intestinal immune response may be perturbed during aging. The ﬁrst
step is the uptake of antigens by specialized epithelial cells (M cells) that overlie the domes
of Peyer’s patches. We are unaware of any studies on the efﬁcacy of antigen uptake in the
intestine as a function of age. The effects of aging on the next step, antigen presentation by
dendritic cells and lymphocyte isotype switching, have not been resolved. The third event is
the maturation of immunoglobulin A (IgA) immunoblasts and their migration from the
Peyer’s patches to the intestinal mucosa. Quantitative immunohistochemical analyses suggest
that the migration of these putative plasma cells to the intestinal effector site is compromised
in old animals. Local antibody production by mature IgA plasma cells in the intestinal
mucosa constitutes the fourth step. We recently reported that in vitro IgA antibody secretion
by intestinal lamina propria lymphocytes from young and senescent rats is equivalent. The
last event is the transport of IgA antibodies across the epithelial cells via receptor-mediated
vesicular translocation onto the mucosal surface of the intestine. Receptor-binding assays did
not detect age-associated declines in receptor number or binding afﬁnity in either rodent or
* Corresponding author. Tel.: +1-415-2214810 ext. 3450; fax: +1-415-7506927.
E-mail address: coach@itsa.ucsf.edu (D.L. Schmucker).
0047-6374/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 0 4 7 - 6 3 7 4 ( 0 1 ) 0 0 2 7 6 - 7

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primate enterocytes as a function of donor age. Efforts to identify the mechanism(s)
responsible for the age-related decline in intestinal mucosal immune responsiveness may
beneﬁt by focusing on the homing of IgA immunoblasts to the effector site. © 2001 Elsevier
Science Ireland Ltd. All rights reserved.
Keywords: Aging; IgA; Mucosal immunity; Intestinal immunity; Cholera toxin

1. Introduction
The elderly constitute the most rapidly growing subpopulations in many countries. In US, the number of individuals over 65 years of age is estimated at 33
million and, at the current rate of expansion, this number will double by 2030.
Furthermore, this age group presents a considerable socioeconomic problem, as
well as the single most signiﬁcant ﬁscal burden, on the healthcare systems. The
‘greying’ of the world’s population is so critical that 97 major medical journals in
thirty-one countries recently selected aging as the most important topic to be
addressed in the Second Global Theme issue (Winker, 1997).
This marked shift in age demographics is accompanied by increases in patient
morbidity and in the incidence of infectious diseases and other age-related pathologies (Wick et al., 2000). The intestine is particularly sensitive to infectious diseases,
suggesting that mucosal immune defenses are compromised in the elderly (Batory et
al., 1984; Fagiolo et al., 1993; Powers, 1992 for a review; Gransden et al., 1994;
Jeandel et al., 1996; Owen and Lew, 1995). Infectious diseases are the fourth
leading cause of death and a signiﬁcant contributor to morbidity in the aged.
Statistics from the World Health Organization demonstrated a 400-fold increase in
mortality attributed to gastrointestinal infections in the elderly in comparison to
young adult populations (Schmucker et al., 1996; Schmucker and Owen, 1997 for
reviews). Furthermore, patients over 60 years of age comprise 25% of all hospitalizations for gastroenteritis and account for 85% of the deaths attributed to diarrhea
(Owen and Lew, 1995).
While the elderly seem predisposed to infections, the consensus is that the efﬁcacy
of many vaccines is diminished in this age group (Ganguly et al., 1986; Waldman
et al., 1987; Beyer et al., 1989). Strassburg et al. showed that elderly subjects exhibit
a 70% efﬁcacy in mortality reduction for inﬂuenza vaccine, but only a 30% efﬁcacy
in preventing the clinically deﬁned disease (Strassburg et al., 1986). However, recent
efforts to develop oral and mucosal vaccines, adjuvants for these vaccines and
mucosal immunostimulatory agents suggest that mucosal immunity may be enhanced in immunocompromised individuals and the elderly. Before such therapies
can be realized, however, it will be necessary to identify those events contributing
to the mucosal immune response that are most affected by aging and to determine
the mechanisms responsible for these perturbations. This information is critical
since therapeutic interventions (a) are targeted to speciﬁc events, e.g., the use of
attenuated organisms that bind to intestinal M cells, (b) may regulate the maturation and migration of gut-associated lymphoid tissue (GALT) immunoblasts, e.g.

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substance P, vasoactive intestinal peptide, (c) may enhance the expression of the
polymeric immunoglobulin receptor (pIgR), e.g. b-adrenergic agonists and (d) may
increase local antibody production, e.g. IL-2, dehydroepiandrosterone (Stanisz et
al. 1986; Stead et al., 1987; Thoman and Weigle, 1989; Herbert, 1995; Kelleher et
al., 1991; Langermann, 1996).

1.1. Intestinal mucosal immune system
Mucosal surfaces constitute a discrete compartment of the immune system that is
autonomous from the systemic arm by virtue of a different major immunoglobulin
isotype, immunoglobulin A (IgA), has a unique process for generating an immune
response and is populated by an independent lymphocyte subpopulation. Furthermore, the intestinal tract is the largest single immunological organ; contains over
70% of the organism’s immunoglobulin-producing cells and produces more IgA
than the organism’s total production of immunoglobulin G (IgG). Although
mucosal surfaces are directly exposed to potential pathogens and they constitute the
ﬁrst line of immune defense, the effect of aging on mucosal immunity has not been
studied extensively (see Arranz and Ferguson, 1992 for a review).
The mucosal immune system depends on the cooperation of lymphoid and
epithelial cells to initiate and maintain an immune response. An effective response
in the intestinal tract involves: (a) binding, uptake and transport of antigens at the
mucosal surface via specialized epithelial cells (M cells) that overlie the Peyer’s
patches; (b) antigen presentation to immunologically competent cells within the
Peyer’s patches by dendritic cells; (c) isotype switching, differentiation and migration (homing) of antigen-stimulated Peyer’s patch IgA+ B immunoblasts to the
intestinal lamina propria; (d) local antibody production by mature IgA plasma cells
in the lamina propria; and (e) transport of antibodies across the intestinal epithelium to the mucosal surface by the polymeric immunoglobulin receptor (pIgR) (Fig.
1). These secreted antibodies neutralize toxins on the mucosal surface, block the
adherence of bacteria to the epithelium and reduce the invasive penetration of
antigens across the mucosa. Diminished intestinal IgA antibody titers in elderly
subjects may reﬂect age-associated declines in one or more of these individual
events. Our studies, as well as those of others, support the hypothesis that intestinal
mucosal immunity declines during aging and that defects in either or both the
lymphoid and epithelial components contribute to this immunodeﬁciency.

2. Evidence for intestinal mucosal immunosenescence

2.1. Serum and intestinal IgA and antibody titers
There is considerable evidence that the mucosal immune response is compromised in old animals and elderly humans (see Schmucker et al., 1996; Schmucker
and Owen, 1997 for reviews). However, several studies have reported increases or
no change in the serum IgA levels in old animals and humans in comparison to

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young subjects (Buckley et al., 1974; Amman et al., 1980; Finkelstein et al. 1984;
Ebersole et al., 1985; Arranz and Ferguson, 1992). Since the primary site for the
immunological action of IgA is the mucosal surface, increased serum immunoglobulin levels in the elderly may reﬂect diminished epithelial cell transport of antibodies
from the serum to the mucosal surface. Furthermore, serum IgA titers reﬂect the
level of the monomeric, non-J chain-containing form of this immunoglobulin that
does not bind to the pIgR and is not transported to the mucosal surface as

Fig. 1. Diagram of the major events in the genesis of an intestinal mucosal immune response. Secretion
across the acinar cells of the salivary glands represents an important route for entry of IgA into the oral
cavity and proximal gastrointestinal tract. In certain rodents, the hepatobiliary pathway accounts for
much of the IgA that enters the intestinal lumen, whereas in most other species, including humans, the
major transport of this immunoglobulin occurs across the intestinal epithelium. (1) Surveillance of the
intestinal lumen for antigens and initiation of the secretory immune response involves the Peyer’s
patches. Specialized epithelial cells (M cells) on the dome of the patches transport antigens to underlying
antigen-presenting cells, e.g. dendritic cells. (2) The precursors of IgA-secreting plasma cells, presumably
IgM-IgD double positive lymphocytes in the Peyer’s patches, undergo isotype switching to IgA
expression. (3) These IgA immunoblasts migrate to the mesenteric lymph nodes for further T
lymphocyte-dependent maturation and subsequent homing to the lamina propria of the intestinal
mucosa via the systemic circulation. (4) In the intestinal wall, these immunoblasts mature into IgA
plasma cells and serve as the primary source of IgA antibodies, i.e. local antibody production. (5) The
locally produced polymeric IgA antibodies bind to the polymeric immunoglobulin receptor (pIgR) on
the basolateral membranes of the epithelial cells. This pIgA – pIgR complex is endocytosed into vesicles
and translocated to the mucosal surface by a cytoskeletal-dependent mechanism. During this transit, the
pIgR is cleaved and a portion of the receptor (secretory component) complexed to pIgA is secreted onto
the mucosal surface as secretory IgA. Some free secretory component is also secreted and the pIgR is not
recycled. (Diagram modiﬁed from Schmucker et al., 1996).

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secretory IgA. A few studies reported the absence of age-related differences in the
amounts of nonspeciﬁc immunoglobulins secreted into the intestinal lumen in vivo
or into the medium by cultured duodenal biopsies (Penn et al., 1991; Arranz and
Ferguson, 1992). Most investigators agree, however, that nonspeciﬁc immunoglobulin levels in intestinal secretions are poor indices of mucosal immunity and that
speciﬁc antibody titers are a more critical measure of mucosal immune responsiveness (Fujimoto et al., 1981; Smith et al., 1983; Ebersole et al., 1985; Schmucker et
al., 1988; Taylor et al., 1992; Vajdy and Lycke, 1992).
Hepatobiliary and intestinal antibody titers following intraduodenal immunization with cholera toxin diminish with increasing age in rodents and monkeys,
respectively (Schmucker et al., 1988; Taylor et al., 1992, Fig. 2). Furthermore,
anti-cholera toxin IgM antibody titers in the intestine are higher in old in comparison with young rats and macaques, suggesting either a compensatory response to
diminished IgA antibody production or abnormal immunoregulation (Taylor et al.,
1992; Kang et al., 1993). Clinical studies have documented age-related declines in
mucosal IgA antibody responses, although there have been conﬂicting reports
(Amman et al., 1980; Ganguly et al., 1986; Waldman et al., 1987; Beyer et al.,
1989). Nevertheless, measurement of critical parameters, e.g. speciﬁc antibody
titers, under stringent conditions using appropriate reagents and methods, provides
convincing evidence of intestinal mucosal immunosenescence.

2.2. Binding and uptake of antigens
At present, there is no evidence of age-related differences in the binding and/or
uptake of antigens by M cells or other epithelial cells that cover the domes of
Peyer’s patches and other lymphoid follicles in the intestine. Both follicle weight
and the yield of Peyer’s patch lymphocytes decline substantially with increasing age
in mice, but we found that neither the number of Peyer’s patches, i.e. 15.5, 15.7 and
14.4 patches per intestine, in young, mature and old rats, respectively, nor the yield
of lymphocytes from these aggregates, varied with age in male rats (Schmucker et
al., 1988). In view of the limited data, it is impossible to conﬁrm or deny that this
initial event in the intestinal immune response is affected by aging.

2.3. Antigen processing, isotype switching and shifts in lymphocyte populations
After uptake, antigens are subsequently processed by dendritic cells and, in the
absence of tolerance, a mucosal immune response is initiated. A few studies have
reported conﬂicting evidence concerning the effect of aging on the number, distribution and function of the epidermal analog of dendritic cells, i.e. Langerhans cells
(Sprecher et al., 1990; Fagiolo et al., 1993; Haruna et al., 1995; Steger et al., 1996).
However, the results of a recent study by Grubeck-Loebenstein et al. suggest that
antigen-presenting capacity, as well as other functions, of human monocyte-derived
dendritic cells remain unchanged as a function of donor age (Lung et al., 2000).
Surface immunoglobulin isotypes and IgA-positive cells comprise 60– 70% and
6–17%, respectively, of Peyer’s patch cells in all age groups of naıve and immunized
¨

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Fig. 2. (A) Reciprocal titers of anti-cholera toxin IgA antibodies in the bile of young (3 – 6 months),
mature (12 – 14 months) and old ( \ 24 months) male Fischer 344 rats on day 19 after primary
intraduodenal immunization (day 0) and boosting (day 14) with holotoxin. The concentration of
antibodies in young bile (**) is signiﬁcantly greater than that in old bile (*; P B0.01;). Each value
represents the mean 9S.E.M. for four to ﬁve rats. (Data from Schmucker et al., 1988) (B) Anti-cholera
toxin IgA antibody concentrations in the intestinal lavage of young (2 – 6 years) and old (20 – 25 years)
rhesus macaques at intervals before (day 0) and during (days 14, 21 and 28) intraduodenal immunization
with holotoxin via endoscopy. Antibody concentrations were markedly reduced in the lavage of old
macaques on days 12 and 28 in comparison to young animals. The arrows indicate intraduodenal
immunizations. Each value represents the mean 9 S.E.M. for ﬁve animals per age group. (Data from
Taylor et al., 1992).

rats (Daniels et al., 1993). However, documented losses in B and/or T lymphocyte
subpopulations or changes in the distributions of lymphocyte subsets, may contribute to or result from mucosal immunosenescence (Haaijman et al., 1977; Rivier
et al., 1983; Bienenstock et al., 1984; Wade et al., 1988; Fleming et al., 1993). Data
from several studies suggest that aging impairs the differentiation of IgA surfacebearing immunoblasts into mature antibody-secreting plasma cells (Haaijman et al.,
1977; Ebersole et al., 1988). Our studies have shown that, although the populations
of most surface immunoglobulin-bearing lymphocytes in the GALT remain unchanged during aging in rats, there is a two-fold increase in the number of

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IgA-positive cells in the Peyer’s patches (Schmucker et al., 1988, Fig. 3). This
age-related increase in Peyer’s patch IgA-positive cells, coupled with quantitative
immunohistochemical evidence of an age-related decline in the number of this
surface isotype in the intestinal lamina propria, suggest that aging compromises a
subsequent step in the intestinal mucosal immune response, namely the migration
of IgA-positive immunoblasts from the Peyer’s patches (inductive site) to the
mucosa (effector site). Concomitant with the increase in the number of IgA isotype
cells, the number of antibody-positive cells in the Peyer’s patches is markedly
diminished in old versus young rats (not shown). This observation lends credence to
the possibility of an age-related deﬁcit in antigen presentation.
Kawanishi and Kiely reported a loss of CD8 cells in the Peyer’s patches of old
mice, but our ﬂow cytometric studies did not demonstrate an age-related shift in the
relative proportion of Peyer’s patch CD8 cells in rats ((Kawanishi and Kiely, 1987;
Daniels et al., 1993). However, quantitative immunohistochemical analysis revealed
marked age-related differences in the distribution of CD8 lymphocytes in these
tissues. The percentages of Peyer’s patch and mesenteric lymph node CD4 cells
remain stable during aging, but the number of CD8 lymphocytes in the intestinal
lamina propria increases
2.5-fold in rats between 3 and 29 months of age. This
observation suggests that age-related shifts occur in the distribution of CD8 cells in
the inductive and effector sites and clariﬁes the contradiction between immunohistochemical and ﬂow cytometric data concerning the effect of aging on the relative
abundance of CD8 lymphocytes in rodent Peyer’s patches (Crowley et al., 1983;
Ebersole et al., 1988; Daniels et al., 1993).

Fig. 3. Number of IgA+ cells per microscopic ﬁeld in the Peyer’s patches of young (3 – 6 months), mature
(12 –14 months) and old ( B 24 months) male Fischer 344 rats immunized and boosted intraduodenally
with cholera holotoxin (immunized) or vehicle alone (naıve). Patches in old rats contain nearly twice the
¨
number of cells as do those in young animals regardless of immune status. The number of IgA isotype
positive cells was determined by quantitative immunohistochemistry using an ocular grid of area 0.0144
mm2 and double-blind protocol. Each value represents the mean 9S.E.M. for ﬁve animals. (Data from
Schmucker et al., 1988)

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Fig. 4. Number of IgA positive (A) and cholera toxin positive (B) cells in the small intestinal lamina
propria of young (3 –6 months) mature (12 – 14 months) and old ( \ 24 months) male Fischer 344 rats
immunized and boosted intraduodenally with cholera holotoxin (immunized) or vehicle alone (naıve).
¨
The number of IgA+ cells drops markedly between young and mature animals, whereas the decline in
antibody-containing cells occurs between maturity and senescence. The data were obtained by quantitative immunohistochemistry as described in Fig. 3 above. Each value represents the mean 9S.E.M. for
ﬁve animals. (Data from Schmucker et al., 1988).

2.4. IgA immunoblast migration to the intestine
We suggest that aging diminishes the migration of Peyer’s patch IgA-positive
immunoblasts to the intestinal lamina propria. Quantitative immunohistochemical
analyses demonstrated signiﬁcant age-related declines in the numbers of IgA-positive (\60%) and cholera toxin-positive (\ 50%) cells in the intestinal lamina
propria of rats at similar post-immunization intervals (Fig. 4, Schmucker et al.,
1988). Flow cytometric analyses showed that these cell populations declined 3– 4
fold in the peripheral blood of old rhesus macaques in comparison to young
animals soon after intraduodenal immunization (Fig. 5, Taylor et al., 1992). Since
Kantele et al. reported that 99% of peripheral blood B lymphocytes secreting
antibodies against mucosal antigens migrate to the mucosal effector site, we suspect
that the number of antibody-bearing cells in the peripheral blood is an index of
immunoblast homing to the intestinal lamina propria (Kantele et al., 1997).
Lymphocyte adoptive transfer studies in our laboratory clearly demonstrate that
the homing of mesenteric lymph node cells is diminished in old rats in comparison
to young animals. This migration is dependent on the ages of both the cell donor

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Fig. 5. The percentages of IgA positive (A) and cholera toxoid positive (B) mononuclear cells in the
peripheral blood of young and old rhesus macaques before and during intraduodenal immunization with
cholera holotoxin. The number of cells expressing either the IgA isotype or antibodies against cholera
toxoid was signiﬁcantly greater in the young animals (*) in comparison to the old macaques by day 21
(P B 0.01). The arrows reﬂect intraduodenal immunization by endoscopy (Data obtained from Taylor et
al., 1992).

and the recipient animals. The homing of ﬂuorescent-labeled cells was lowest when
old recipients were injected with cells from old donors and greatest with young cells
in young hosts (Fig. 6, Thoreux et al., 2000). However, the homing of mesenteric
lymph node lymphocytes from young donors was slower in old recipients than in
young hosts. These data suggest that the age-related decline in immunoblast

Fig. 6. The number of ﬂuorescent-labeled (PKH26) mesenteric lymph node cells isolated from young or
old donor rats, transferred intravenously into young or old recipient animals and, subsequently,
localized to the small intestinal lamina propria by quantitative ﬂuorescence microscopy. The values
represent the mean 9 S.D. of ﬂuorescent-labeled mesenteric lymph node cells 20 h following adoptive
transfer. Values are signiﬁcantly lower than (a) young recipients receiving young cells (*) and (b) both
young and old recipients receiving young cells (**). (Data obtained from Thoreux et al., 2000).

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migration reﬂects deﬁcits in both the homing cells isolated from old rats and the old
recipient animals.
The a4b7 integrin and the addressin MAdCAM-1 expressed on the surfaces of
IgA immunoblasts and on the endothelial cells of lamina propria venules, respectively, are critical to the homing of the IgA immunoblasts. Although we have no
data to support our hypothesis, the decline in IgA immunoblast migration may
reﬂect altered expression or afﬁnity of homing receptors or their ligands. Interestingly, the expression of L-selectin, an integrin implicated in the homing of naıve
¨
and memory lymphocytes to peripheral lymph nodes, is diminished during aging
and interferes with the migration of lymphocytes to secondary lymphoid tissues
(Steeber et al., 1996). Therefore, there is reason to suspect that aging may
compromise the intestinal mucosal immune response by interrupting the migration
of putative IgA plasma cells to the effector site.

2.5. Local antibody production
Aging is accompanied by 40– 70% declines in antibody secretion by Peyer’s patch
and lamina propria lymphocytes isolated from mice and rats (Rivier et al., 1983;
Kawanishi and Kiely, 1989; Kawanishi et al., 1989; Daniels et al., 1993). Daniels et
al. measured antibody secretion by GALT lymphocytes isolated from young and
old rats following intraduodenal immunization with cholera holotoxin (Daniels et
al., 1993). Five days after immunization, in vitro IgA antitoxin secretion by ‘young’
mesenteric lymph node lymphocytes was greater than that of ‘old’ cells. However,
Peyer’s patch cells isolated from immunized old animals secreted signiﬁcantly more
antibodies than similar cells from young rats. These results support the hypothesis
that IgA immunoblast emigration from the Peyer’s patches of old animals is
delayed in comparison to young animals. However, these data are difﬁcult to
reconcile with our previous observation that the Peyer’s patches in old rats contain
fewer antibody-positive cells in comparison to those of young animals (see
Schmucker et al., 1996; Schmucker and Owen, 1997 for reviews).
We recently reported that the in vitro secretion of anti-cholera toxin IgA
antibodies by lymphocytes isolated from the intestinal lamina propria of old rats
was signiﬁcantly lower (\60%) than that measured in cultured cells obtained from
young immunized animals (Fig. 7, Thoreux et al., 2000). However, when antibody
secretion was expressed relative to the number of anti-cholera toxin IgA-secreting
cells in each culture, this age-related difference was no longer evident. Our results
suggest that the age-related decline in antibody secretion at the effector site reﬂects
fewer secreting cells, rather than diminished antibody secretion per cell.

2.6. Secretion of IgA antibodies onto the mucosal surface
The culmination of the intestinal immune response is the transport of antibodies
produced in the lamina propria to the apical surface of enterocytes and their
secretion into the intestinal lumen. This requires receptor-mediated endocytosis of
the antibodies at the basal plasma membrane and their movement to the mucosal

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Fig. 7. Anti-cholera toxin IgA levels in culture medium supernatants of cells isolated from Peyer’s
patches and intestinal lamina propria of young and old rats 21 days after primary immunization. The
data are expressed as ng of IgA antibody per 106 total cells (A) and ng of IgA antibody per 1000
antibody-secreting cells in culture (B). The antibody concentrations in cultures of old cells (*) are
signiﬁcantly lower than those measured in cultures of cells from young rats (PB0.05). The values reﬂect
the mean 9 S.E.M. for ﬁve animals per age group.

surface in endocytic vesicles (see Underdown and Schiff, 1986 for a review). All
mucosal epithelial cells express pIgR on their basolateral surfaces. Several mammalian species, e.g. rabbits, mice, rats, express pIgR on hepatocytes and transport
polymeric IgA from the blood to the bile. The hepatobiliary pathway is a signiﬁcant
route for the secretion of IgA antibodies into the intestinal lumen in these species,
at least during the initial stage of the intestinal immune response. However, since
our ligand binding studies demonstrated that human and monkey hepatocytes do
not express pIgR, the importance of this pathway in these species remains unresolved (Daniels and Schmucker, 1987; Perez et al., 1989).
The expression of pIgR in the rat liver is highly regulated and the transport of
pIgA is identical to that observed in enterocytes (Brown and Kloppel, 1989).
Fifteen years ago, we observed a four to six-fold decline in the transport of pIgA
from blood to bile in rats between 3 and 25 months of age (Schmucker et al., 1985).
We subsequently showed a concomitant three to four-fold decline in the number of
hepatic pIgA receptors between these same ages, whereas receptor binding afﬁnity
remained unchanged (Daniels et al., 1985). This age-related decline in hepatic pIgR
expression has been demonstrated both in vivo and in vitro (Gregoire et al., 1992).
Our observations that (a) the rat hepatic pIgR mRNA steady state level declines
20% during this age span and that (b) the incorporation of [35S]-cysteine into pIgR
lags in cultured hepatocytes isolated from old rats versus cells from young animals

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suggest that aging affects the expression of this receptor (Gregoire et al., 1992; Van
Bezooijen et al., 1994). Our laboratory also demonstrated that the hepatocellular
transport of pIgA is dependent on the integrity of the cytoskeletal system (Goldman et al., 1983). Subsequently, we showed an age-related loss of polymerized
tubulin in rat liver and suggested that this may contribute to the decline in the
hepatobiliary transport of IgA (Taylor et al., 1991).
However, these studies were performed with rat hepatocytes and we are unaware
of any data concerning the effect of age on pIgA transport in small intestinal
enterocytes. The expression of pIgR on the basolateral plasma membranes of rat
small intestinal enterocytes remains unchanged during aging and this receptor
exhibits binding characteristics similar to those measured in rat liver pIgR (Daniels
and Schmucker, 1987). Rat intestinal crypt enterocytes exhibit three-fold greater
speciﬁc pIgA binding than villus tip cells (Fig. 8). This crypt-to-villus tip gradient
in pIgA binding (and pIgR expression) is identical in young and old rats and a
similar pattern is seen in rhesus macaques (Daniels et al., 1988; Taylor et al., 1992).
Despite the lack of data concerning the effect of aging on the transport of pIgA by
intestinal enterocytes, the absence of an age-related change in the expression of
pIgR in these cells suggests that the mechanism of antibody secretion onto the
mucosal surface remains unscathed by aging.

Fig. 8. Polymeric immunoglobulin receptor (pIgR)-speciﬁc binding of (A) [125I] rat dimeric IgA to rat
intestinal enterocyte basolateral plasma membranes and (B) [125I] human polymeric IgA to rhesus
macaque intestinal enterocyte basolateral membranes as a function of animal age. The increasing
gradient of pIgR expression from the villus tip (fraction I) to the crypt (fraction IV or V) remains
unchanged during aging in both models and reﬂects the age of the intestinal epithelial cells rather than
that of the animals. The data reﬂect the mean 9S.E.M. for four to seven animals in each age group.
(Data obtained from Daniels et al., 1985; Daniels and Schmucker, 1987; Taylor et al., 1992).

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3. Conclusions
Information concerning the effect of aging on the sequence of events that
culminate in an intestinal mucosal immune response is conﬂicting and limited.
Current evidence from both animal and human studies strongly suggests that this
response is compromised in old animals and in the elderly. There are few, if any,
data on the effect of aging on the initial steps in this response, e.g. those occurring
at the inductive site (antigen uptake and processing). However, there is considerable
evidence for an age-related deﬁcit in the homing of IgA immunoblasts to the
effector site. Neither the local production nor the secretion of IgA antibodies seems
to be impaired in the intestinal mucosa. Subsequent efforts should be directed
towards conﬁrming the speciﬁc step(s) that are sensitive to age perturbations and
identifying the mechanisms responsible in order to develop effective therapeutic
interventions to enhance the intestinal immune response.
Acknowledgements
This research was supported by the Department of Veterans Affairs, the National
Institute on Aging, the American Federation for Aging Research and the Danone
Company.
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