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Infection and Immunity, October 2000, p. 5539-5545, Vol. 68, No. 10
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Generation of Female Genital Tract Antibody
Responses by Local or Central (Common) Mucosal Immunization
Hong-Yin
Wu,
Samira
Abdu,
Dana
Stinson, and
Michael W.
Russell*
Department of Microbiology, University of
Alabama at Birmingham, Birmingham, Alabama
Received 17 April 2000/Returned for modification 19 June
2000/Accepted 3 July 2000
 |
ABSTRACT |
Genital antibody responses were compared in female mice immunized
intravaginally (i.vag.) or intranasally (i.n.) with a bacterial protein
antigen (AgI/II of Streptococcus mutans) coupled to the B
subunit of cholera toxin. Serum and salivary antibodies were also
evaluated as measures of disseminated mucosal and systemic responses.
Although i.vag. immunization induced local vaginal immunoglobulin A
(IgA) and IgG antibody responses, these were not disseminated to a
remote secretion, the saliva, and only modest levels of serum
antibodies were generated. In contrast, i.n. immunization was
substantially more effective at inducing IgA and IgG antibody responses
in the genital tract and in the circulation, as well as at inducing IgA
antibodies in the saliva. Moreover, mucosal and systemic antibodies
induced by i.n. immunization persisted for at least 12 months. Analysis
of the molecular form of genital IgA indicated that the majority of
both total IgA and specific IgA antibody was polymeric, and likely
derived from the common mucosal immune system.
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INTRODUCTION |
The continuing problem of sexually
transmitted diseases and the spread of human immunodeficiency
virus infection, especially by heterosexual transmission, have impelled
efforts aimed at generating appropriate immune responses in the
genital tract that would confer protection against these infections.
Successful vaccination against genital infections will require not only
the identification of suitable antigenic targets for each particular
pathogen but also the development of strategies for inducing
appropriate immune responses that are expressed at the sites of primary
infection and invasion. Depending on the nature of the pathogen, such
strategies might involve eliciting mucosal or circulating antibodies of
the appropriate isotype to engage protective immune defense mechanisms, or inducing cell-mediated immunity, including cytotoxic T cells.
Conventionally, the genital tract has been considered a component of
the common mucosal immune system (CMIS), and there is much evidence to
sustain that concept, especially with respect to the female tract. The
epithelium of the endocervix, fallopian tubes, and uterus, and the
ectocervical glands, express polymeric immunoglobulin receptor (pIgR),
and the underlying populations of plasma cells secrete predominantly
polymeric immunoglobulin A (pIgA), which is transported into the
luminal secretion by pIgR to form secretory immunoglobulin A (SIgA)
(reviewed in reference 25). Less information is
available for the male system, but IgA-secreting plasma cells and
pIgR-expressing epithelial cells occur in the urethral glands of
Littré, epididymis, prostate, and seminal vesicles of humans
(1, 37, 39) and mice (36). The secretions of both
male and female systems contain significant levels of SIgA, but these
may be exceeded by IgG levels, at least in humans and other primates
(3, 4, 6, 9, 18, 26, 27). Whereas SIgA is accepted as the
distinct product of the CMIS, the source and means of delivery of IgG
are less clear: both local production and transudation from the
circulation have been implicated (reviewed in references
2 and 23).
These uncertainties as to the origins of genital antibodies have
hampered efforts to define the most effective ways of actively immunizing the genital tracts. It seems clear that both male and female
tracts lack true mucosal inductive sites, which are collectively known
as mucosa-associated lymphoid tissues (MALT) and are typified by
intestinal Peyer's patches and similar organized lymphoepithelial structures in the lower bowel and upper respiratory tract.
Nevertheless, foci of lymphocytes and accessory cells, consisting of a
core of B cells surrounded by T cells and an outer area of
macrophage-like cells, have been described in the human vagina, cervix,
and endometrium (54). However, the T cells are predominantly
CD8+ CD4
, suggesting an immunoregulatory
role. The same group has identified CD8+ cytotoxic T cells
in the female genital tract (45, 46). CD4+ HLA
class II+ Langerhans cells occur in the cervicovaginal
epithelium (19) and might serve as antigen-presenting cells.
Thus, at least in the female tract, there is an obvious potential to
induce immune responses by the local application of immunogens, and the
direct instillation of antigens into the vagina or uterus has been
examined experimentally. Results, however, have been quite variable. As originally observed by Ogra and Ogra (33) with inactivated
poliovirus vaccine, intravaginal or intrauterine immunization can
induce a modest local antibody response (reviewed in reference
24), and more-recent findings with the well-known
potent mucosal immunogen, cholera toxin B subunit (CTB), have confirmed
this (22, 29, 44). However, there has been controversy over
the effectiveness of local genital immunization in comparison to other
routes of mucosal immunization, and the dissemination of responses to
other mucosal sites or to the circulation. Because of anatomical
proximity to the genital tract, shared lymphoid drainage, and the
presence of lymphoid follicles resembling Peyer's patches, the rectum
and colon have been considered likely sites for inducing genital
antibody responses (12, 13, 21, 22, 32). However, variable
results have been obtained, depending upon the species and upon the
antigen, delivery system, and adjuvant used. In general, the most
effective way of inducing mucosal immune responses is by exploiting the CMIS and administering antigens in an appropriate form to sites where
organized MALT is present. We have extensively investigated mucosal
immunization with antigens coupled to CTB (10, 16, 42) and
have found that the intranasal (i.n.) route is especially effective at
generating genital antibody responses (41, 49, 52). The
present study is a direct comparison of the local genital, disseminated
mucosal, and circulating antibody responses induced in mice by
intravaginal (i.vag.) or i.n. administration of the same CTB-coupled immunogen.
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MATERIALS AND METHODS |
Animals, immunization, and sample collection.
Female BALB/c
mice were purchased from Taconic (Germantown, N.Y.) through the
University of Alabama at Birmingham (UAB) Animal Resources Program or
were bred locally under pathogen-free barrier conditions from stock
originally obtained from the National Cancer Institute (Frederick,
Md.). Animals were maintained in microisolator cages on standard
laboratory chow and water ad lib and were approximately 3 months old at
the start of experiments. Animal use protocols were approved by the
Institutional Animal Care and Use Committee of the University of
Alabama at Birmingham. Because of minor differences in Ig levels in
sera and secretions in the animals from the two sources, as well as
possible genetic drift, all animals used in any one experiment were
from the same source. However, essentially similar results were
obtained with both sets of mice.
After preimmune samples of sera and secretions had been collected,
groups of five mice were immunized either i.n. or i.vag. with
Streptococcus mutans antigen I/II (AgI/II) conjugated to CTB
(42). For i.n. immunization, a dose of 15 µg of
AgI/II-CTB conjugate was administered in 15 µl of sterile Dulbecco
phosphate-buffered saline (PBS) introduced into both nares with a
pipettor fitted with a plastic tip. For i.vag. immunization, a dose of
15 µg of AgI/II-CTB conjugate plus 5 µg of CT adjuvant was given
in 16 µl of Dulbecco PBS instilled into the vagina. Immunizations
were repeated at intervals of 10 days, for a total of three doses by each route.
Samples of sera and secretions were collected from the mice prior to
immunization and 7 days after the third immunization
(
53).
Serum was separated from 50 to 100 µl of tail vein blood
and stored
at
20°C. Up to 100 µl of saliva was collected after
intraperitoneal (i.p.) injection of carbachol (5 µg in 0.1 ml
of
sterile Dulbecco PBS) to stimulate flow and was stored at
20°C.
Vaginal secretions were collected (after the collection of saliva)
by
washing three times with 50 µl of sterile Dulbecco PBS instilled
into
the vagina and withdrawn using a pipettor fitted with a plastic
tip;
the washes were combined and stored at
20°C.
Assay of Ig's and antibodies.
Antibodies to S. mutans AgI/II and to CT were assayed by enzyme-linked
immunosorbent assay (ELISA) on microtiter plates coated with AgI/II (5 µg/ml) (40) or with GM1 ganglioside (2.5 µg/ml; Calbiochem, San Diego, Calif.) followed by CT (1.5 µg/ml; List Biological Laboratories, Campbell, Calif.), as described previously (42). Total IgM, IgG, and IgA concentrations were determined by ELISA on plates coated with unconjugated antibodies to mouse IgM,
IgG, or IgA (Southern Biotechnology Associates, Birmingham, Ala.).
Bound antibodies or Ig's were detected using peroxidase-conjugated antibodies to mouse IgM, IgG, or IgA, and the color developed with a
substrate of
o-phenylenediamine-H2O2 was
measured in a Dynatech MRX microplate reader interfaced to a Macintosh
computer for data retrieval and analysis. Antibody and Ig
concentrations were calculated by interpolation on calibration curves
constructed by a computer program using the four-parameter logistic
model. Antibody levels in secretions were also expressed relative to the total corresponding Ig isotype concentrations.
Molecular form of IgA.
The molecular forms of IgA in serum,
saliva, and vaginal-wash samples were analyzed by size exclusion
chromatography on a 30- by 0.78-cm silica column (Biosep SEC-S3000;
Phenomenex, Torrance, Calif.) connected to a Perkin-Elmer series 10 high-performance liquid chromatograph (HPLC) (41). The
column was calibrated by chromatographing Mr
standard proteins, as well as monomeric IgA, dimeric IgA, and SIgA. To
ensure that apparently polymeric IgA was not simply aggregated or
antigen-complexed IgA, samples were run under dissociating conditions
(0.1 M acetate [pH 3.6] plus 0.05 M Na2SO4).
Three-drop fractions (~100 µl) were collected in tubes containing 1 M Tris (pH 9.5) to neutralize the acid and were assayed by ELISA to
estimate IgA concentrations.
Statistics.
Antibody and Ig assay data were transformed to
logarithms before statistical analysis in order to improve
("normalize") the distribution and variance characteristics. For
presentation of results, means ± standard deviations (SD) (of log
data) were back-transformed into arithmetic values to generate
geometric means ×/
SD, or were plotted on log10 scales.
Student's t test was performed on log-transformed data to
assess the significance of difference of means, and a P
value of <0.05 was considered significant.
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RESULTS |
Comparison of antibody responses to immunization by the i.vag.
versus the i.n. route.
Consistent with our previous observations,
i.n. immunization of mice with three doses of AgI/II-CTB conjugate at
10-day intervals resulted in strong serum IgG antibody responses
against both AgI/II and CT by day 7 after the last dose (Fig.
1). Serum IgM antibodies were not induced
above preimmune levels (shown in Table
1), but serum IgA antibodies to both
components of the immunogen were strongly elevated. i.vag. immunization
with the same immunogen also elicited serum IgG and IgA antibodies
(Fig. 1), though at substantially (10- to 100-fold) lower mean levels
than those generated by i.n. immunization (P = 0.012
and P < 0.001 for IgG and IgA anti-AgI/II,
respectively, and P < 0.001 for both IgG and IgA anti-CT). Particularly in the case of the serum IgG responses, i.vag.
immunization resulted in much greater variability, as revealed by the
SD. All mice displayed substantially higher total serum IgG
concentrations after immunization by either route (7,052 ×/ 1.31 µg/ml for the i.n. group and 12,702 ×/ 1.49 µg/ml for the i.vag.
group, compared with 308 ×/ 2.23 µg/ml for preimmune animals [Table 1]). This finding probably reflects low initial levels of IgG
in immunologically naive young mice, which were elevated upon exposure
to a potent immune stimulus.
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FIG. 1.
Serum IgM, IgG, and IgA antibody responses to AgI/II and
CT 7 days after the third i.n. or i.vag. immunization with AgI/II-CTB
conjugate. Results are shown as geometric means and SD (n = 5 animals per group).
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Likewise, i.n. immunization was very effective at generating salivary
IgA antibodies to AgI/II and CT (Fig.
2),
whereas no
IgA antibodies to AgI/II were detectable above the assay
background
in the saliva of i.vag. immunized animals, and only two of
five
animals in this group developed low levels of salivary IgA
antibodies
to CT (Fig.
2). As noted previously, i.n. immunization
resulted
in an overall increase in total salivary IgA concentrations,
whereas
i.vag. immunization had a lesser effect (Table
1 and Fig.
2).
Allowing for this difference by expressing salivary IgA antibody
levels
relative to total salivary IgA concentrations showed that
i.n.
immunization resulted in substantial salivary IgA antibody
responses,
whereas i.vag. immunization did not (Table
2).
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FIG. 2.
Mucosal antibody responses to AgI/II and CT 7 days after
the third i.n. or i.vag. immunization with AgI/II-CTB conjugate.
Results are shown as geometric means and SD (n = 5
animals per group).
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i.vag. immunized mice developed vaginal IgA antibodies to AgI/II (Fig.
2), but these were consistently and significantly lower
(
P = 0.025) than those induced by i.n. immunization. i.vag.
immunization
was as effective at inducing vaginal IgA antibodies to CT
as i.n.
immunization, but these were at a much lower level than the
response
to AgI/II induced by i.n. immunization (Fig.
2). In other
words,
the vaginal IgA response to CT was low, whether induced by i.n.
or i.vag. immunization. Total vaginal IgA concentrations in vaginal
washes were highly variable both prior to and after immunization
by
either route, possibly reflecting varying efficiency in sampling
as
well as inherent variations in the animals. When vaginal IgA
antibodies
were expressed relative to the total IgA concentration
in each animal,
the difference with respect to antibodies to AgI/II
induced by i.vag.
and i.n. immunization was sustained, and antibodies
to CT remained
comparable and at lower levels (Table
2). There
was no consistent
effect of immunization by either route on the
total concentration of
IgA recovered in vaginal washes (Table
1 and Fig.
2).
Vaginal IgG antibodies were also detectable in both immunized groups of
mice, but at much lower levels than IgA antibodies
to both components
of the immunogen (Fig.
2). i.vag. immunized
mice showed a greater
elevation of total IgG concentrations in
vaginal washes than i.n.
immunized mice (Table
1 and Fig.
2),
so that when specific IgG antibody
responses were expressed relative
to total IgG concentration, it again
became evident that i.n.
immunization resulted in a stronger vaginal
IgG antibody response
to both AgI/II and CT than i.vag. immunization
(Table
2).
Duration of responses.
In another experiment, mice that had
been immunized i.n. with AgI/II-CTB (as previously) were sampled at 4, 8, and 12 months after the last immunization. Antibodies to AgI/II
persisted in serum, saliva, and vaginal wash samples throughout this
period (Table 3), although levels
declined from the initial high values. Salivary IgA and vaginal IgG
antibody levels expressed as a proportion of total corresponding IgA or
IgG appeared to increase at 12 months, but this reflects a decrease in
the total IgA or IgG concentration recorded in those secretions at this
time point. Overall, these results show that mucosal antibodies induced
by i.n. immunization can persist for prolonged periods.
Origins of vaginal antibodies.
To examine the molecular forms
of IgA as evidence of the origins of vaginal antibodies, two sets of
experiments were performed. In the first, the molecular form of IgA and
of IgA antibody to AgI/II present in vaginal wash was examined by HPLC
on a calibrated size-exclusion column and was compared with the
molecular profiles of IgA in serum and saliva (Fig.
3). Serum IgA occurred in both monomeric
and polymeric forms as expected in mice (data not shown). Salivary IgA
and IgA antibody developed after i.n. immunization were predominantly
polymeric, with a minor monomeric peak (Fig. 3A). Vaginal-wash IgA, and
IgA antibody induced by either i.n. or i.vag. immunization, also
resembled salivary IgA in having a main peak corresponding to polymeric
(dimeric) IgA and a minor peak of monomeric IgA (Fig. 3B and C). These
findings indicate that the majority of IgA in vaginal washes was likely
to be polymeric SIgA derived from the mucosal immune system. Moreover,
vaginal IgA antibodies induced by either common mucosal or local
immunization were also predominantly polymeric, and therefore probably
mostly SIgA.
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FIG. 3.
HPLC size exclusion analysis of total IgA and IgA
antibody to AgI/II in saliva (A) and vaginal wash (B and C) from mice
immunized i.n. (A and B) or i.vag. (C) with AgI/II-CTB conjugate.
Fractions were assayed by ELISA, and results are shown as optical
densities (OD) which are not comparable among panels A, B, and C or
between total IgA and specific antibody curves, since different sample
dilutions and substrate development times were used to reveal the
distribution of molecular forms in each sample. Monomeric IgA peaked at
approximately fraction 18, and dimeric IgA peaked at approximately
fraction 10; higher polymers eluted in earlier fractions.
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We also took advantage of the effect of carbachol, primarily used to
stimulate salivary flow, as it enhances the flow of other
secretions,
including those of the genital tract. We first washed
the vaginas of
mice without administering carbachol (wash 1).
Forty minutes later, the
vaginas were washed again, also without
carbachol stimulation (wash 2).
Then carbachol was injected i.p.,
and after a further 40 min the
vaginas were washed again (wash
3). As a control, a similar group of
mice was sampled, but without
the administration of carbachol between
the second and third vaginal
washes. IgA and IgG concentrations were
assayed in these washes,
and some wash samples were subjected to HPLC
size exclusion analysis.
We expected that wash 1 would contain most of
the IgA that had
accumulated over the previous indeterminate period,
whereas wash
2 would contain much lower levels of residual IgA; wash 3 from
carbachol-treated mice would contain higher levels of IgA in
vaginal
fluid that had been newly secreted under the influence of
carbachol.
This was indeed the case (Table
4), and IgG in vaginal washes
followed a
similar pattern, although at a much lower level. Moreover,
HPLC
analysis showed that the newly secreted IgA in the third
wash was
predominantly polymeric (Fig.
4A), and if
the washes
were taken from an immunized animal, newly secreted IgA
antibodies
were also polymeric (Fig.
4B).
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TABLE 4.
Effect of carbachol treatment on concentrations of IgA
and IgG in sequential vaginal washes collected at 40-min intervals
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FIG. 4.
HPLC size exclusion analysis of total IgA (A) and IgA
antibody to AgI/II (B) in three sequential vaginal washes taken at
40-min intervals; carbachol was administered i.p. after the second
wash. IgA concentrations in fractions were assayed by ELISA and are
shown as optical densities (OD) which are not comparable between panels
A and B, as different sample dilutions and substrate development times
were used for total IgA and specific antibody assays. Monomeric IgA
peaked at approximately fraction 18, and dimeric IgA peaked at
approximately fraction 10; higher polymers eluted in earlier
fractions.
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DISCUSSION |
We find that mucosal immunization using the i.n. route is very
effective for generating antibody responses in the female genital tract. Most likely, this depends on the operation of the CMIS, since we
have previously shown that i.n. immunization stimulates cells in the
nasal lymphoid tissue (NALT) and its draining cervical lymph nodes
(50, 51). We have also shown previously that NALT serves as
an inductive site for the CMIS, especially with respect to the salivary
glands as a representative effector site of the head and neck region
(49), as well as the respiratory and genital tracts
(52). Numerous other reports have described the
effectiveness of i.n. immunization for inducing genital-tract antibody
responses in humans as well as experimental animals (5, 11, 14,
15, 17, 28, 34, 41, 43, 47). The compartmentalization of the CMIS
(7, 31), such that the gut-associated lymphoid tissues
preferentially supply 
4
7-expressing pIgA-secreting cell precursors to the lamina propria of the gut (and also lactating mammary
glands), reflects the distribution of the mucosal addressin MAdCAM-1 on
venular endothelial cells mainly within these tissues (8).
In distinction, the NALT also supplies antibody-secreting precursor
cells to extraintestinal effector sites, including the genital tract,
where the venules apparently do not express MAdCAM-1, and where the
receptor-addressin systems responsible for lymphocyte homing are not as
well defined. Our finding, however, that i.vag. immunization does
induce antibodies in the genital tract, albeit at a lower level than
those generated by stimulation of the CMIS through one of its inductive
sites, demonstrates the ability of mucosal tissues to mount local
immune responses that are not generally distributed to remote mucosal
effector sites (30).
Our results, however, differ markedly from recently published findings
on immune responses to herpes simplex virus given i.n. or i.vag. in
mice (35), in which it was shown that i.vag. immunization was superior both for generating antibodies in the vagina and for
protecting against genital viral infection. It is therefore pertinent
to consider why this should be the case. We suggest that a major factor
in these divergent results is that Parr and Parr used a live infectious
agent, whereas we used a nonviable protein, as an immunogen. Infection
of the genital epithelial cells with herpesvirus was clearly capable of
inducing a strong local immune response manifested in terms of both
antibodies and gamma interferon secretion by T cells, as well as a
serum IgG antibody response that was approximately twofold higher than
that obtained after i.n. immunization. These authors, however, did not
report on total Ig concentrations in the genital secretions, which we
have found to be variable between individuals and strongly influenced
by local immunization, possibly as a result of inflammatory changes
induced by the immunogen. It would be interesting to know if the immune
response to herpesvirus given i.vag. extends to remote sites of the
CMIS. Our findings suggest that responses would not be disseminated,
since although we detected IgG and IgA antibodies in vaginal washes
after local immunization with AgI/II-CTB, these antibodies were not
expressed in the saliva. Furthermore, Parr and Parr's findings of
protection against herpesvirus could involve additional cellular
mechanisms of immunity.
Parr and Parr also treated their animals with hormones in order to
stabilize the estrous cycle, which is known to influence immune
responses, especially within the genital tract (35). However, they report essentially no difference in the response to
i.vag. administered herpesvirus, whether the animals were treated with
progestin or estradiol. We chose not to resort to hormone treatments
because they have complex effects on genital immune responses. For
example, estradiol enhances the expression of pIgR (and hence transport
of SIgA) in the uterus but decreases it in the vagina (48).
Moreover, antigen-presenting activity is highest at proestrus and
lowest at estrus (38), and progesterone treatment has been
found to enhance responses especially to local vaginal immunization
(20). Thus, overall antibody responses can fluctuate depending on the particular hormone treatment or stage of the cycle,
and on the particular site of study within the genital tract. However,
the mouse estrous cycle lasts approximately 4 days (compared to the
10-day cycle of immunizations given in these studies), and female mice
kept together in the absence of males tend to synchronize their cycles
or even become anestrous, thereby diminishing the variation due to
asynchronous cycles between animals. By reporting vaginal antibody
responses relative to total corresponding Ig isotype concentrations, we
could apply a correction for cycle-dependent (or other) variations in
Ig secretion rates as well as for differences in the efficiency of
vaginal washing. In spite of the potential for hormone-dependent
effects to enhance or suppress Ig secretion in the genital tract, we
could show that i.n. immunization with a CTB-coupled protein immunogen
was more effective for the generation of specific antibodies,
especially of the IgA isotype, in the genital tract than i.vag.
immunization. This effect was evident even though i.vag. immunization
was supplemented with the potent mucosal adjuvant CT, which we
previously found to be necessary for obtaining significant responses by
this route (29; H.-Y. Wu, unpublished data), whereas
addition of CT to AgI/II-CTB conjugates delivered i.n. is not
necessary and furthermore tends to promote responses to itself rather
than to the AgI/II component of the conjugate (53).
The origins of Ig's and antibodies in the genital tract are important
with respect to the routes of immunization, because IgG is a major
component of genital-tract immunity, at least in humans, where it may
predominate over IgA (26), and is probably derived from the
circulation as well as local synthesis, though the mechanisms of
transport are uncertain. Mice are clearly different in that the major
isotype of Ig in female secretions, as collected by vaginal washing, is
IgA. The findings that total IgA and specific IgA antibodies were
predominantly polymeric and that IgA antibodies were preferentially
induced by remote mucosal (i.n.) immunization suggested that these were
mainly SIgA derived from the CMIS, but no antibody against a murine
secretory component was available for direct confirmation of this.
Nevertheless, the high specific activity of the anti-AgI/II IgA
antibody relative to the total IgA concentration in vaginal washes
after i.n. immunization (mean, 38.2% [Table 2]), comparable with the
specific activity in the saliva of the same animals (mean, 48.2%),
further suggests that it is of mucosal rather than circulatory origin.
The higher ratio of IgA to IgG in vaginal washes compared with serum is
also consistent with the selective transport of IgA into the
secretions. Both IgA and IgG antibody-secreting cells have been found
in the genital mucosa after i.vag. or i.n. immunization
(20).
The immune responsiveness of the female genital tract must be seen in
relation to its physiological functions in reproduction. The lower
tract (vagina) is colonized with a specialized microbiota and has a
partially keratinized pseudostratified epithelium. The upper tract
(uterus and fallopian tubes) is normally sterile but must permit the
passage of allogeneic sperm and support the development of a
semiallogeneic fetus engrafted into the endometrium for a prolonged
period. Standing guard between these two regions is the cervix, which
possesses a population of subepithelial plasma cells secreting IgG and
pIgA, and a pIgR-expressing epithelium that can transport SIgA
(23, 25). Although it lacks organized MALT, it is clear that
the female genital tract can mount immune responses to
histoincompatible fetal antigens, sperm acrosomal antigens, and certain
infectious agents as well as experimental vaccines. However, infectious
agents clearly differ in their abilities to induce responses in the
genital tract: herpes simplex virus can induce responses that may
confer protection against further infection (35), whereas
Neisseria gonorrhoeae does not (18). Different
routes and strategies of immunization against sexually transmitted
diseases may therefore be required depending on the particular pathogen
and vaccine antigen concerned. However, we find that the most effective
strategy for inducing SIgA and IgG antibodies in the female genital
tract is by stimulating the CMIS through one of its inductive sites
with an antigen coupled to CTB.
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ACKNOWLEDGMENT |
This study was supported by US-PHS grant DE06746 from the
National Institute for Dental and Craniofacial Research.
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FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Microbiology, University of Alabama at Birmingham, 845, 19th St. South, Birmingham, AL 35294-2170. Phone: (205) 934-4480. Fax: (205) 934-3894. E-mail: MWR{at}uab.edu.
Present address: Wyeth-Lederle Vaccines and Pediatrics, Pearl
River, NY 10965.
Editor:
J. D. Clements
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Infection and Immunity, October 2000, p. 5539-5545, Vol. 68, No. 10
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
