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*
Yakult Central Institute for Microbiological Research, Tokyo, Japan, and
Institute of Medical Science, University of Tokyo, Tokyo, Japan
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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66 mg/kg of body weight/day) is much more than
the combined amount of IgG (34 mg/kg/day) and IgM (8 mg/kg/day)
(1). Moreover, the most striking feature of IgA is that it
appears in multiple molecular forms (monomer, dimer, and polymer), and
dimeric IgA (dIgA)2
and polymeric IgA (pIgA) as well as IgM contain J-chain, a 15-kDa
glycoprotein. DIgA is secreted across the epithelial layer, and
externally released dIgA (secretory IgA; sIgA) is readily detected in
the saliva, bile, intestinal secretion, tear, or breast milk. It has been proposed that a polymeric Ig receptor (pIgR) plays a critical role for transepithelial transport of dIgA (2). pIgR, after binding dIgA on the basolateral surface, carries it to the apical side and a specific protease cleaves the extracelluar region of pIgR, followed by release of sIgA into the lumen. The extracelluar region of pIgR is called secretory component (SC), and thus sIgA includes dIgA and SC. Since the pioneering work by Mostov et al. (3) in which cDNA of rabbit pIgR has been cloned, cDNAs and genes of pIgR were isolated from various species one after another and their nucleotide sequences determined (4, 5, 6, 7, 8, 9, 10, 11). These results demonstrate that pIgR is a member of Ig superfamily and highly conserved during the evolution.
Many researchers have tried to verify that pIgR is involved in the transepithelial transport of dIgA. Using Madin-Darby canine kidney cell line stably transfected by rabbit pIgR cDNA or human pIgR cDNA, dIgA was shown to be transported through pIgR (12, 13, 14). In addition, 125I-labeled human pIgA i.v. given to rats was secreted into the bile, and the incubation of pIgA with anti-J-chain Ab beforehand blocked the biliary transport of pIgA (15). These results suggest that pIgA should bind pIgR via J-chain on epithelial cells of the liver and then sIgA is released into the bile. On the other hand, rat hepatocytes are known to capture human pIgA via asialoglycoprotein receptor and introduce IgA into the degradation process (16). Therefore, it is of great interest to determine the relative significance of pIgR in the transepithelial transport of dIgA and pIgA.
Recently, mice that have a disrupted J-chain gene (J-/- mouse) were established. J-/- mice contained much higher IgA in the serum, leaving IgM and IgG levels unchanged. By contrast, fecal and biliary IgA levels were drastically reduced in J-/- mice, whereas the IgA levels in breast milk, intestinal secretions, and nasal washes were comparable between wild-type and J-/- mice (17, 18). These results indicate that hepatic transport of IgA is severely hindered in the absence of J-chain, although intestinal and nasal secretion of IgA can occur independently of J-chain.
Mouse pIgR gene has been mapped on chromosome 1 and found to be composed of 11 exons (9, 10). As the translation of pIgR protein starts at the initiation codon in exon 2, we tried to inactivate the synthesis of pIgR protein by deleting the exon 2 of pIgR gene. pIgR and SC proteins were not detected in the intestines and bile of pIgR-deficient (pIgR-/-) mice, and both intestinal and hepatic transcytosis of dIgA was severely blocked, resulting in the massive accumulation of dIgA in the serum of pIgR-/- mice. However, a significant amount of IgA was still present in the exocrine fluids of pIgR-/- mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BDF1 and C57BL/6J mice were purchased from Japan Clea (Tokyo, Japan).
Gene targeting by homologous recombination
Mouse pIgR gene was isolated from genomic library of 129/SvJ mouse, and the complete nucleotide sequence was determined (10). Targeting vector was constructed from MscI fragment including exon 2 of pIgR gene. NeoA cassette was inserted into SpeI site of the MscI fragment, and the modified MscI fragment was introduced between NotI and AccI sites of diphtheria toxin A vector. Embryonic stem (ES) cell line, RW4, was purchased from Genome Systems (St. Louis, MO) and cultured on mitomycin C-treated embryonic fibroblasts in DMEM supplemented with 15% FCS and leukemia inhibitory factor (Life Technologies, Gaithersburg, MD) at 103 U/ml. Targeting vector DNA (50 µg) was transfected by electroporation (500 µF, 250 V; Gene Pulsar; Bio-Rad, Hercules, CA) into 1 x 107 RW4 ES cells. Cells were selected in the presence of G418 (250 µg/ml; Life Technologies) and 720 colonies picked up. Screening was conducted by PCR using the following primers: sense, 5'-ATCTCGTCGTGACCCATGGCGATGC-3'; antisense, 5'-CCCAACTGCTGGATGGCTAGCATT-3'.
Southern blot analysis
Genomic DNA was extracted from mouse tail and digested with HindIII or KpnI. After agarose gel electrophoresis, separated DNA was transferred to nylon membrane (Hybond-N+, Amersham, Buckinghamshire, U.K.) and hybridized with probes corresponding to the intron between exons 2 and 3, or the neo gene. Detailed methods of Southern blot analysis were described elsewhere (19).
Northern blot analysis
Northern blot analysis was conducted according to the previous method (19). After total RNA was extracted from various tissues with ISOGEN (Nippongene, Toyama, Japan), 7 µg of RNA was applied into each well and electrophoresed. Separated RNA was transferred to nylon membrane and hybridized with cDNAs corresponding to ß-actin mRNA or full-length mouse pIgR mRNA.
Preparation of rabbit anti-mouse SC IgG
Recombinant mouse SC fused with GST was synthesized as follows. cDNA encoding mouse SC was prepared from mouse pIgR cDNA. SC cDNA inserted into pGEX-5X-3 plasmid (Pharmacia Biotech, Uppsala, Sweden) was transfected in Escherichia coli. GST-SC fusion protein was purified from the inclusion body of transfected E. coli. After rabbit was immunized s.c. with 1 mg of GST-SC fusion protein four times, serum was recovered and IgG fraction purified with Ampure PA kit (Amersham). Ab titer was determined with ELISA by using GST-SC and GST proteins.
Western blot analysis
Intestinal epithelial cells were prepared by shaking intestinal walls in 50 mM EDTA/25 mM HEPES (pH 7.2)/Ca2+- and Mg2+-free HBSS at 37°C for 90 min. They were incubated in 1% Triton X-100/50 mM EDTA/25 mM HEPES (pH 7.2)/Ca2+- and Mg2+-free HBSS including protease inhibitors (1 mM PMSF, 0.2 U/ml aprotinin, 1 µg/ml soybean trypsin inhibitor, 1 µg/ml leupeptin, and 1 µg/ml benzamidin) on ice for 45 min, and soluble materials were collected after centrifuging them at 12,000 rpm for 30 min. Intestinal contents were collected by scraping with forceps after opening the intestinal tract longitudinally. Feces were obtained just after evacuation. Both of them were suspended in PBS including protease inhibitors and the supernatants after centrifugation were obtained. Bile was collected by holding gall bladders with forceps. Each sample was mixed with an equal volume of 0.125 M Tris-HCl (pH 6.8), 4% SDS, 20% glycerol, and 0.002% bromphenol blue and boiled for 5 min. After SDS-PAGE was done, proteins were transferred to polyvinylidene difluoride membrane (Immobilon, Millipore, Bedford, MA) using semidry blotting system (Bio-Rad). To detect pIgR and SC proteins, the membrane was incubated with rabbit anti-mouse SC IgG (1 µg/ml) at room temperature (r.t.) for 3 h, and then treated with peroxidase-conjugated anti-rabbit Igs (Cappel Organon Teknica, Durham, NC) at r.t. for 1.5 h. Thereafter, the membrane was soaked in enhanced chemiluminescence (ECL) reagents and exposed to ECL hyperfilm (Amersham).
Immunohistochemical analysis
Jejunum and colon were removed, trimmed of fat and connective tissue, buried in an embedding compound (TISSU MOUNT, Chiba Medical, Sohka, Japan), and snap-frozen on dry ice and ethanol. To detect pIgR protein, each section (5-µm thickness) was fixed with cold acetone for 10 min and thereafter with cold chloroform for 10 min, treated with 0.1% H2O2 at r.t. for 30 min, and then stained with rabbit anti-mouse SC IgG (10 µg/ml) at r.t. for 1.5 h. After washing with PBS, each section was incubated with peroxidase-conjugated anti-rabbit Igs at r.t. for 1 h. To detect IgA+ cells, each section was incubated with biotinylated anti-IgA mAb (1 µg/ml, R5–140, PharMingen, San Diego, CA) at r.t. for 1.5 h, and then incubated with peroxidase-conjugated streptavidin (Nichirei, Tokyo, Japan) at r.t. for 1 h. Thereafter, sections were immersed in 100 ml of 0.1 M phosphate buffer (pH 7.2) containing 10 mg of 3,3'-diaminobenzidine (Sigma, St. Louis, MO) and 65 mg of NaN3 at 37°C for 10 min. Each section was counterstained with 1% methyl green solution.
Measurement of Igs by ELISA
Concentration of IgA, IgM, IgG, and IgE was determined by ELISA. Immunoplates (Nunc, Roskilde, Denmark) were coated by adding 100 µl of anti-mouse IgA, anti-mouse IgM, anti-mouse IgG (all from Cappel Organon Teknica), or anti-mouse IgE (PharMingen) dissolved in 0.05 M sodium carbonate buffer (pH 9.6) and incubated at 4°C overnight. Each well was washed and blocked with 100 µl of 1% BSA/0.05% Triton X-100/PBS. After washing, 100 µl of samples were added and the plate was incubated at 37°C for 1.5 h. Thereafter, unbound materials were washed away and 100 µl of peroxidase-conjugated anti-mouse IgA, anti-mouse IgM, anti-mouse IgG (all from Cappel Organon Teknica), or biotin-conjugated anti-mouse IgE (Serotec, Oxford, U.K.) solutions in 1% BSA/0.05% Triton X-100/PBS was added. To detect biotin-conjugated anti-mouse IgE, peroxidase-conjugated streptavidin (Molecular Probes, Eugene, OR) was added. After the plate was incubated at 37°C for 1 h and washed, 100 µl of o-phenylenediamine solution (0.04% w/v) in 0.075 M citrate buffer (pH 5.0) was added and the plate was allowed to stand at 37°C for 10 min. After 50 µl of 2.5 M H2SO4 was added into each well to stop the reaction, the absorbance at 492 nm was measured using a Titertek Multiskan Plus MKII (Flow Laboratory, Lugano, Switzerland).
Statistical analysis
Significance of the difference between groups was evaluated by Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As translation of pIgR protein starts from the initiation codon in
exon 2 of pIgR gene, we tried to delete the exon 2 for generation of
pIgR-deficient (pIgR-/-) mice. To construct a
targeting vector, exon 2 and the surrounding introns in the
MscI fragment of pIgR gene was replaced by neoA cassette and
combined with diphtheria toxin A vector (Fig. 1
A). DNA of the targeting
vector was introduced by electroporation into RW4 cells, and the cells
surviving in the presence of G418 were picked up. Three independent
targeted clones were identified among 720 clones, and by aggregating ES
cells of one targeted clone and BDF1 eight-cell morulae, a chimeric
male mouse having a mutated germline was born. Heterozygous mice were
generated and backcrossed with C57BL/6J mice twice (N2). Homozygous
mice were produced by intercrossing heterozygous mice. All the
experiments were conducted using littermates of N2 generation.
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B). From crosses between heterozygous mice,
pIgR+/+, pIgR+/-, and
pIgR-/- mice were born at the expected ratio
(23%, 49%, and 28%, respectively) and nearly the same number of male
and female pIgR-/- mice were born (44% and
56%, respectively), indicating that disruption of the pIgR gene in
mice is not lethal. Expression of truncated pIgR mRNA in pIgR-/- mice
We checked by Northern blot analysis whether aberrant mRNA is
transcribed from the mutated pIgR gene. Total RNAs were extracted from
spleens, livers, small intestines, and large intestines from
pIgR+/+, pIgR+/-, and
pIgR-/- mice, separated by agarose gel
electrophoresis, and hybridized to pIgR or ß-actin cDNAs. pIgR mRNA
with the size of 3.9 kb was expressed in the livers, small intestines,
and large intestines of pIgR+/+ and
pIgR+/- mice. mRNA hybridized to pIgR cDNA was
also detected at the size of 3.9 kb in the liver and intestines of
pIgR-/- mice, although the intensity of pIgR
signal was 5- to 10-fold less in pIgR-/- mice
than pIgR+/+ mice. In contrast, RNAs in the
spleens did not contain pIgR mRNA irrespective of mouse genotypes. On
the other hand, ß-actin mRNA was detected in the above tissues of
pIgR+/+, pIgR+/-, and
pIgR-/- mice to the same extent (Fig. 2). These results demonstrate that
replacement of exon 2 of pIgR gene with the neo gene results
in either decreased transcription or stability of pIgR mRNA, as a small
amount of truncated pIgR mRNA is present in
pIgR-/- mice.
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We examined by Western blot analysis whether pIgR protein is
absent in pIgR-/- mice. pIgR protein with a
molecular mass of 120 kDa and 100 kDa was detected in the extracts of
intestinal epithelial cells (IEC) of pIgR+/+ and
pIgR+/- mice, but the extract of IEC from
pIgR-/- mice did not contain pIgR protein at
the detectable level. Moreover, SC protein was detected as a single
band at 94 kDa in the bile samples from pIgR+/+
and pIgR+/- mice, but SC protein was absent in
the bile of pIgR-/- mice. Likewise, SC protein
was under the detectable level in the intestinal content of
pIgR-/- mice whereas SC protein was readily
ascertained as a doublet of 80 kDa and 68 kDa in the intestinal
secretion of pIgR+/+ and
pIgR+/- mice (Fig. 3). Because a band at 52 kDa in the
intestinal secretions was detected by both rabbit anti-mouse SC IgG
and normal rabbit IgG (data not shown), we regarded the band as
nonspecific staining. It is noteworthy that the amount of pIgR or SC
proteins in pIgR+/- mice was consistently less
than that in pIgR+/+ mice.
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). These results suggest that
inactivation of synthesis of pIgR protein does not interrupt the
development of IgA-producing cells and support that decreased or absent
expression of pIgR would result in the accumulation of IgA in the
lamina propria.
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The above results show that pIgR-/- mice do not express pIgR protein in the intestinal and hepatic tissues. Therefore, if pIgR-mediated transcytosis is the predominant pathway for the transport of dIgA, it is expected that dIgA produced by plasma cells in the intestinal lamina propria or present in serum is not secreted and circulates in the blood of pIgR-/- mice. To address this issue, we measured Ig concentration in the sera of pIgR+/+, pIgR+/-, and pIgR-/- mice.
Concentration of serum IgA was 40,370 µg/ml in
pIgR+/+ mice and much higher in
pIgR-/- mice (4360 ± 560 µg/ml at an
age of 9–10 wk; 6360 ± 2830 µg/ml at an age of 19 wk). Serum
IgA level of pIgR+/- mice was the intermediate
between those of age-matched pIgR+/+ and
pIgR-/- mice. In contrast, serum IgM level was
comparable irrespective of genotypes. The amount of serum IgG was
almost comparable among pIgR+/+,
pIgR+/-, and pIgR-/-
mice, although serum IgG in pIgR-/- mice at an
age of 19 wk was slightly more than age-matched
pIgR+/+ mice. Likewise, serum IgE levels of
pIgR+/+, pIgR+/-, and
pIgR-/- mice were not significantly different,
but the averaged value of serum IgE level in older
pIgR-/- mice (19-wk-old) was slightly higher
than that of age-matched pIgR+/+ mice (Fig. 5).
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).
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Accumulation of dimeric IgA in the blood circulation of pIgR-/- mice
The above results demonstrate that hepatic and intestinal
transcytosis of IgA is severely blocked in
pIgR-/- mice. As a majority of IgA in the
intestinal lamina propria is dIgA, Western blot analysis of serum IgA
was conducted under nonreducing condition to see the origin of serum
IgA in pIgR-/- mice. Comparing that monomeric
IgA (mIgA; 130 kDa) and dIgA (280 kDa) were comparably detected in the
serum of pIgR+/+ mice, the serum of
pIgR-/- mice contained a huge amount of dIgA
(280 kDa) and an additional IgA molecule with a molecular mass of 350
kDa. Interestingly, the amount of dIgA in the serum of
pIgR+/- mice was between those of
pIgR+/+ and pIgR-/- mice.
Under reducing condition, IgA heavy chains with a molecular mass of
77 kDa were detected in all the serum samples from
pIgR+/+, pIgR+/-, and
pIgR-/- mice. The amount and composition of
serum proteins in pIgR+/+,
pIgR+/-, and pIgR-/-
mice were almost comparable when polyacrylamide gel was stained with
Coomassie brilliant blue (data not shown). On the other hand, mIgA (130
kDa), dIgA (280 kDa), and sIgA (350 kDa) were readily
detected in the bile of pIgR+/+ and
pIgR+/- mice, but the bile of
pIgR-/- mice included only a small amount of
IgA. Again, the amount of biliary dIgA in
pIgR+/- mice was the intermediate between those
of pIgR+/+ and pIgR-/-
mice (Fig. 7).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In contrast to the remarkable reduction of sIgA in pIgR-/- mice, IgM levels in sera and external secretion were not different between pIgR+/+ and pIgR-/- mice. Together with the previous finding that SC binds to IgA but does poorly to IgM in rat (21), our results suggest that pIgR-mediated transcytosis may not be critical for the secretion of IgM.
Northern blot analysis of RNA from the intestines revealed the
expression of mRNA of 3.9 kb hybridized to pIgR cDNA in
pIgR-/- mice. As our targeting strategy was
aimed at deleting exon 2 of pIgR gene, exon 1 and the region from exons
3 to 11 remain intact in pIgR-/- mice. Using
RT-PCR analysis, the truncated pIgR mRNA including exon 1 and the
downstream from exon 3 but excluding exon 2 was detected in
pIgR-/- mice (data not shown). Although the
size of this truncated pIgR mRNA was estimated to be 3764 bp, it cannot
be separated from the intact pIgR mRNA (3863 bp) in the agarose gel
electrophoresis. Expression of aberrant mRNA in gene-knockout mice has
been already reported, although those aberrant mRNAs did not encode
functional proteins (22, 23). In
pIgR-/- mice, the truncated pIgR mRNA may be
translated into pIgR protein lacking the exon 2-encoded peptide. If
such an aberrant pIgR protein is produced in
pIgR-/- mice, the molecule is thought to lack
the signal peptide and start at the second initiation codon, Met 45
(6). However, we could not detect pIgR protein in
pIgR-/- mice by Western blot and
immunohistochemical analyses. Nevertheless, the bile and intestinal
secretion of pIgR-/- mice contained a
significant amount of IgA. These results support that other pathways
than pIgR-mediated transcytosis such as asialoglycoprotein
receptor-mediated endocytosis (16), CD89 (Fc
receptor)-mediated binding (24), or intercellular
diffusion may work for the transport of dIgA. However, we cannot
exclude the possibility that the amount of an aberrant pIgR protein
produced in pIgR-/- mice is too small to be
detected by Western blot and immunohistochemical analyses but
sufficient for the transport of dIgA.
J-/- mice exhibited conspicuously high IgA level in serum accompanied with the significant reduction of biliary and fecal IgA (17). pIgR-/- mice also showed a 40-fold higher IgA level in the serum than pIgR+/+ mice, and biliary and fecal IgA were much reduced in pIgR-/- mice compared with pIgR+/+ mice. These results are consistent with the earlier observation that hepatic transport of dIgA is mediated by covalent binding of J-chain and pIgR. However, IgA levels in intestinal surfaces obtained using absorbent wicks were comparable between J+/+ and J-/- mice (18), whereas intestinal contents of pIgR-/- mice contained much fewer amount of IgA than pIgR+/+ mice. This discrepancy may be explained by the differences of methodology. Another explanation is that J-chain-containing dIgA is mainly transported by pIgR but J-chain-deficient IgA may be secreted in a pIgR-independent pathway in the intestinal epithelia. Because the molecular form of IgA in the serum and milk of J-/- mice is mainly monomer, it is likely that different pathways in the intestine transport J-chain-deficient mIgA and J-chain-containing dIgA.
It is known that the expression of hepatic and intestinal pIgR is strictly regulated during the ontogeny in rat (25, 26). These findings demonstrate that the production of pIgR protein in hepatocytes and IEC gradually increases after birth. We analyzed pIgR expression in mice from gestational day 14 to adult age and found that pIgR mRNA and protein are already expressed in the intestine at gestational day 18 when IgA-producing cells do not colonize the intestinal mucosa yet (data not shown). This result suggests that the production of pIgR protein in IEC precedes the development of intestinal IgA-producing cells in mice and dIgA does not induce the expression of pIgR. On the other hand, as the amount of dIgA in the intestinal contents was roughly correlated with those of pIgR protein in IEC of pIgR+/+, pIgR+/-, and pIgR-/- mice, it is likely that the amount of pIgR expressed in IEC may determine the amount of dIgA transcytosed across the epithelial layer.
IgA nephropathy (IgAN) is caused by the massive deposition of Ag-IgA
immune complex to glomerular mesangium. The concentration of serum IgA
of patients with IgAN is frequently higher than age-matched normal
controls (27), and some of the patients have abnormally
few IgA in the intestinal secretion (28). On the basis of
these findings, primary abnormalities of IgAN may be ascribed to the
impaired pIgR-mediated transport of IgA. This hypothesis is supported
by the fact that some patients with IgAN have deficiency in the
production of J-chain (28).
pIgR-/- mice have increased level of IgA in the
serum due to the interruption of transepithelial transport of dIgA. It
has been already reported that HIGA mice established from breeding of
ddY mice show high serum IgA level (1000 µg/ml) and IgA deposition
in the mesangial area of a glomerulus at an age of 25 wk
(29). Therefore, it is of great importance to see whether
pIgR-/- mice suffer from IgAN in association
with aging.
Physiological significance of sIgA is now been reevaluated. IgA-/- mice can protect against vaginal infection of herpes simplex virus-type 2 and intranasal infection of influenza virus when previously immunized by those viral vaccines (30, 31). These results suggest that sIgA may not be necessary for Ag-induced immunity in the mucosal tissues. On the other hand, Kaetzel et al. (32) have shown using pIgR cDNA-transfected Madin-Darby canine kidney cells that the immune complex of dIgA and Ag is transported via pIgR-mediated pathway. This result proposes that one of the important roles for pIgR is to eliminate dIgA complexed with the exogenous or self Ags outside the body. Furthermore, IgA Ab is able to neutralize virus intracellularly, giving IgA a role in host protection that has been reserved for cell-mediated immunity (33, 34) From this viewpoint, pIgR-/- mice should be a valuable animal model for analysis of Ag specificity and physiological function of sIgA.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: dIgA, dimeric IgA; pIgA, polymeric IgA; sIgA, secretory IgA; pIgR, polymeric Ig receptor; IgAN, IgA nephropathy; SC, secretory component; IEC, intestinal epithelial cell; r.t., room temperature; ES, embryonic stem.
Received for publication June 30, 1999. Accepted for publication September 2, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-/- mice, but not in TNF--/- mice: role for IFN- in activating apoptosis of hepatocytes. J. Immunol. 159:1418.[Abstract]
receptor (CD89) isoforms generated by alternative splicing that are differentially expressed between blood monocytes and alveolar macrophages. J. Immunol. 156:4442.[Abstract]
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 L. Sait, M. Galic, R. A. Strugnell, and P. H. Janssen Secretory Antibodies Do Not Affect the Composition of the Bacterial Microbiota in the Terminal Ileum of 10-Week-Old Mice Appl. Envir. Microbiol., April 1, 2003; 69(4): 2100 - 2109. [Abstract] [Full Text] [PDF]
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T. K. Uren, F.-E. Johansen, O. L. C. Wijburg, F. Koentgen, P. Brandtzaeg, and R. A. Strugnell Role of the Polymeric Ig Receptor in Mucosal B Cell Homeostasis J. Immunol., March 1, 2003; 170(5): 2531 - 2539. [Abstract] [Full Text] [PDF]
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P. M. Hempen, K. M. Phillips, P. S. Conway, K. H. Sandoval, T. A. Schneeman, H.-J. Wu, and C. S. Kaetzel Transcriptional Regulation of the Human Polymeric Ig Receptor Gene: Analysis of Basal Promoter Elements J. Immunol., August 15, 2002; 169(4): 1912 - 1921. [Abstract] [Full Text] [PDF]
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Y. Asahi, T. Yoshikawa, I. Watanabe, T. Iwasaki, H. Hasegawa, Y. Sato, S.-i. Shimada, M. Nanno, Y. Matsuoka, M. Ohwaki, et al. Protection Against Influenza Virus Infection in Polymeric Ig Receptor Knockout Mice Immunized Intranasally with Adjuvant-Combined Vaccines J. Immunol., March 15, 2002; 168(6): 2930 - 2938. [Abstract] [Full Text] [PDF]
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H. Schjerven, P. Brandtzaeg, and F.-E. Johansen A Novel NF-{kappa}B/Rel Site in Intron 1 Cooperates with Proximal Promoter Elements to Mediate TNF-{alpha}-Induced Transcription of the Human Polymeric Ig Receptor J. Immunol., December 1, 2001; 167(11): 6412 - 6420. [Abstract] [Full Text] [PDF]
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F.-E. Johansen, R. Braathen, and P. Brandtzaeg The J Chain Is Essential for Polymeric Ig Receptor-Mediated Epithelial Transport of IgA J. Immunol., November 1, 2001; 167(9): 5185 - 5192. [Abstract] [Full Text] [PDF]
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 L. Erlandsson, P. Akerblad, C. Vingsbo-Lundberg, E. Kallberg, N. Lycke, and T. Leanderson Joining Chain-Expressing and-Nonexpressing B Cell Populations in the Mouse J. Exp. Med., September 3, 2001; 194(5): 557 - 570. [Abstract] [Full Text] [PDF]
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H. Schjerven, P. Brandtzaeg, and F.-E. Johansen Mechanism of IL-4-Mediated Up-Regulation of the Polymeric Ig Receptor: Role of STAT6 in Cell Type-Specific Delayed Transcriptional Response J. Immunol., October 1, 2000; 165(7): 3898 - 3906. [Abstract] [Full Text] [PDF]
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