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* Department of Pediatrics, Harvard Medical School, and Gastrointestinal Cell Biology Laboratory, Children’s Hospital, Boston, MA 02115;
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095; and
Division of Immunology and Allergy, Hôpital Orthopédique, Lausanne, Switzerland
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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1 and C2
are required for IgA adherence to mouse Peyer’s patch M cells. This
distinguishes the M cell IgA receptor from CD89 (FcI), which binds
domains C2-C3. Finally, we observed by immunofluorescence
microscopy that some M cells in the human ileum are coated with IgA.
Together these data suggest that mouse, and possibly human, M cells
express an IgA-specific receptor on their apical surfaces that mediates
the transepithelial transport of SIgA from the intestinal lumen to
underlying gut-associated organized lymphoid
tissues. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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There is evidence that neonatal and adult M cells express an IgR on their apical surfaces that functions in the binding and transepithelial transport of Abs from secretions. Roy and Varvayanis (8) first proposed the existence of such a receptor based on their observation that milk-derived IgA accumulated on the apical surfaces of suckling rabbit Peyer’s patch M cells, but not on the apical surfaces of other intestinal epithelial cell types. Endogenous SIgA is also present on the luminal surfaces of M cells in adult rabbit Peyer’s patch and appendix, indicating that the putative IgR is expressed throughout the lifetime of the animal (9, 10). The polymeric IgR (pIgR), which mediates basolateral to apical transport and secretion of polymeric IgA, is absent from the FAE, excluding this molecule as the M cell IgA receptor (11, 12, 13, 14, 15). Weltzin et al. (15) observed that colloidal gold particles coated with IgA injected into the mouse distal ileum adhered exclusively to Peyer’s patch M cells. Furthermore, within minutes after injection IgA colloidal gold particles were detected within M cell cytoplasmic vesicles and in the extracellular space of M cell pockets, raising the possibility that M cells may mediate the transepithelial transport of Ab from the intestinal lumen to the O-MALT.
In this study we demonstrate that murine Peyer’s patch M cells
selectively bind IgA, with or without secretory component (SC), but not
IgG or IgM Abs. IgA binding to M cells is not mediated by known
lectin-like IgRs or by previously described FcRs, including CD89 and
the recently described FcµR (16). Using human IgA
subclasses and recombinant chimeric Igs we provide evidence that the M
cell IgA receptor requires domains C1 and C2 of IgA, further
differentiating it from other known IgRs. Finally, we observed that M
cells in the human ileum are coated with SIgA, raising the possibility
that human M cells, like those in the mouse, may express an
IgA-specific receptor on their apical surfaces that mediates the
transcytosis of SIgA and SIgA-Ag complexes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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FITC- and tetramethylrhodamine isothiocyanate (TRITC)-conjugated streptavidin was obtained from Pierce (Rockford, IL). HRP conjugated to avidin was from Sigma-Aldrich (St. Louis, MO). The lectin Ulex europaeus type I (UEA-1) was obtained from Vector Laboratories (Burlingame, CA). Neoglycoproteins were purchased from EY Laboratories (San Mateo, CA). Paraformaldehyde (16% aqueous solution) and Epon 812-Araldite 502 embedding chemicals were purchased from Electron Microscopy Sciences (Warrington, PA). Mowiol was purchased from Calbiochem (San Diego, CA) and mounting medium containing 1,2-diazobicyclo-(2, 2, 2)-octane (Sigma-Aldrich) was made as described (17).
Igs and Ig labeling
Biotinylated mouse serum IgG was from Pierce. MOPC-315
(mouse IgA,
), TEPC-15 (mouse IgA,
), TEPC-183 (mouse IgM,),
MOPC-104e (mouse IgM,), human colostral IgA, and human serum IgA
were purchased from Sigma-Aldrich. Purified human myeloma IgA1 and IgA2
were from Calbiochem. The generation and purification of recombinant
human IgA1, IgA2 of the m-1 allotype (IgA2 m1), human IgA1 lacking the
hinge region, IgG2, and IgG2 with CH1 of IgA1 have been previously
described (18, 19).
Igs were biotinylated using EZ-link sulfo-NHS-LC-biotin (Pierce) or EZ-link LC-biotin-hydrazide (Pierce) following instructions provided by the manufacturer. Biotinylation was confirmed by dot blot analysis using streptavidin-HRP and an ECL detection kit purchased from Amersham Pharmacia Biotech (Piscataway, NJ). Protein concentrations were determined using the Bio-Rad protein assay reagent (Bio-Rad, Hercules, CA). Biotinylated Igs (0.8–1 mg/ml in PBS) were stored at -80°C until before use.
Mouse polymeric/dimeric IgA was purified from MB.2 hybridoma supernatant by size exclusion chromatography on a Sephacryl S300 column (2.6 x 100 cm2) and conjugated to indocarbocyanine (Cy3) using Fluorolink (Amersham Pharmacia Biotech). Cy3-labeled polymeric/dimeric IgA were mixed with recombinant SC produced in Chinese hamster ovary cells4 to reconstitute SIgA in vitro (20).
Animals
Mice and rats used in this study were housed under conventional specific pathogen-free conditions and were treated in strict compliance with guidelines established by Children’s Hospital (Boston, MA), Harvard Medical School (Boston, MA), and the National Institutes of Health (Bethesda, MD). Female BALB/c mice, 6–8 wk of age, were purchased from Charles River Breeding Laboratories (Wilmington, MA). Asialoglycoprotein receptor (ASGPR)-deficient mice carrying homozygous null mutations in the mouse hepatic lectin-2 subunit of the receptor (21) were purchased from The Jackson Laboratory (Bar Harbor, ME). IgA-deficient mice originally generated by Dr. G. Harriman (Baylor College of Medicine, Houston, TX) (22) were a gift from Dr. J. Nedrud (Case Western Reserve University, Cleveland, OH). Sprague Dawley mice were obtained from Taconic Farms (Germantown, NY).
Ligated ileal loop assays and processing of Peyer’s patch tissues
Mouse ligated ileal loop assays were done as previously described (15). During the procedure mice were maintained under avertin (5 g tri-bromoethanol in 2.5 ml t-amyl alcohol; 200 mg/kg animal weight) anesthesia and kept warm on a 37°C warming pad. Biotinylated Abs were injected into ligated ileal loops at a concentration of 100 µg/ml, unless noted otherwise. M cells were labeled in vivo by coinjection of TRITC-labeled UEA-1 (20 µg/ml). At the completion of the experiment, the mice were sacrificed by cervical dislocation and Peyer’s patches were removed, gently washed in PBS to remove unbound Abs, then immersed in paraformaldehyde (4% w/v in PBS). Whole, fixed Peyer’s patches were labeled with streptavidin-FITC (20 µg/ml) to detect bound biotinylated Igs, then cryosectioned using a Leica cryostat model CM3050 (Leica, Nussloch, Germany). Sections were captured on Superfrost microscope slides (Fisher, Pittsburgh, PA) and coverslips were mounted with using Mowiol. Alternatively, freshly isolated Peyer’s patch tissues were fixed in paraformaldehyde (4% w/v in 0.1 M cacodylate buffer) and embedded in Epon-Araldite, as described previously (23). Epon-Araldite blocks were sectioned using glass knives mounted on a Leica Ultracut E microtome. Semithin plastic sections (0.5–1 µm) were etched with melting solution and labeled with streptavidin-FITC (2 µg/ml) and UEA-1 TRITC (2 µg/ml) (23).
Immunolabeling rat liver and intestinal tissues
Freshly excised rat Peyer’s patch or liver tissue samples were embedded in Tissue-Tek O.C.T. (Sakura FineTek, Torrance, CA) in plastic base molds (Curtin Matheson Scientific, Houston, TX), then snap-frozen in liquid nitrogen-cooled isopentane. Acetone-fixed, frozen sections (5–7 µm) of rat liver or Peyer’s patch were labeled with polyclonal rabbit anti-rat ASGPR antiserum (kindly provided by Dr. D. Alpers, Washington University, St. Louis, MO (24)) or control nonimmune serum, followed by biotinylated goat anti-rabbit IgG (Southern Biotechnology Associates, Birmingham, AL) and streptavidin-FITC.
Immunolabeling human intestinal tissues
Paraffin sections of pediatric ileal biopsies were obtained from the Children’s Hospital Department of Pathology after approval from the Children’s Hospital Internal Review Board. Sections (5 µm) were deparaffinized, blocked for 1 h in PBS containing goat serum (2% v/v), and stained with biotin-labeled, affinity-purified goat anti-human IgA, IgG, or IgM Abs (ICN Pharmaceuticals, Costa Mesa, CA) followed by streptavidin-FITC.
Microscopy
Tissue sections were viewed using a Zeiss Axiophot microscope (Carl Zeiss, Thornwood, NY) equipped for epifluorescence or a Bio-Rad MRC1024 confocal microscope (Bio-Rad). When using the Zeiss Axiophot, images were either photographed using a 35-mm camera and Kodak Elite Chrome 400 film (Kodak, Rochester, NY) or collected electronically using a SPOT digital camera (Diagnostic Instruments, Sterling Heights, CA). When using the MRC1024 confocal microscope, images were collected electronically using software provided by the manufacturer. Electronic images were edited and annotated using Adobe Photoshop (Adobe Systems, Mountain View, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We began by establishing a convenient model for studying the
interaction of Igs with M cells. To confirm IgA binding in this model,
mouse hybridoma IgA TEPC-15 (mouse IgA,) or MOPC-315 (mouse IgA,)
were biotinylated and injected into BALB/c mouse ligated ileal loops
containing Peyer’s patches. After 40 min the Peyer’s patches were
removed, fixed, and frozen or embedded in EPON. Frozen thick sections
or semithin EPON sections were labeled with streptavidin-FITC to detect
biotinylated IgA. Both monoclonal IgA Abs irrespective of L chain
identity bound to the apical surfaces of most M cells within the
Peyer’s patch FAE (Fig. 1
B).
M cells were identified by phase contrast microscopy (Fig. 1A) and by costaining with the lectin UEA-1 (Fig. 1, C and D). Neither monoclonal IgA Ab bound to
adjacent FAE enterocytes or villus enterocytes, although both Abs
occasionally associated with the mucus layer overlying the FAE and
villus epithelium (data not shown).
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A), neither IgG nor IgM
adhered to the FAE (Fig. 2, C and D), even when
these Igs were injected into ligated loops at concentrations exceeding
1 mg/ml. In competitive inhibition assays, adherence of biotinylated
mouse monoclonal IgA to Peyer’s patch M cells was reduced to
undetectable levels by coinjection of 100-fold excess (w/w)
nonbiotinylated IgA, but not by coinjection of equivalent molar excess
of nonbiotinylated IgG or IgM. We considered the possibility that the M
cell IgR may bind IgG or IgM with a lower affinity than IgA, and that
the failure of IgG or IgM to bind to M cells could be due to
competition with endogenous SIgA in the intestinal lumen. To examine
this possibility, Ig binding assays were performed in IgA-deficient
mice (22). In these mice IgA, but not IgM or IgG, adhered
to Peyer’s patch M cells (data not shown). Thus, the inability of IgM
and IgG to bind to M cells is not due to competition with
endogenous SIgA.
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B) and serum IgA (data not shown)
adhered to mouse Peyer’s patch M cells. These data indicated that the
structural features of IgA important for M cell binding are shared
between mouse and human IgA. These data also confirm that IgA, with or
without SC, can bind to M cells because human colostrum contains
primarily SIgA, whereas serum IgA lacks SC. Mouse Peyer’s patch M cells bind and endocytose SIgA
We wished to test whether binding of SIgA to the apical surfaces
of M cells results in Ab transcytosis, as was previously proposed by
Weltzin et al. (15). To visualize IgA directly and with
greater sensitivity, purified mouse monoclonal IgA consisting
exclusively of dimers and higher m.w. polymers was labeled with Cy3 and
associated in vitro with recombinant SC.4
Cy3-labled SIgA Abs were injected into BALB/c mouse ligated ileal loops
and visualized on frozen Peyer’s patch tissue sections by confocal
laser scanning microscopy. Forty minutes after inoculation, Cy3-SIgA
Abs were detected on the apical surfaces of Peyer’s patch M cells and
within M cell intracellular vesicles (Fig. 3, A and B).
Intracellular vesicles containing SIgA were located apically, clustered
near the intraepithelial pocket membrane, and along the basolateral
membranes. In some cases, SIgA was present in M cell basal processes
that extend through the basal lamina (Fig. 3C)
(23). These data indicate polymeric SIgA can adhere to M
cell surfaces and be transported across the FAE.
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Two receptors with IgA binding capacity have been
reported on rodent intestinal epithelium in vivo: the pIgR and the
ASGPR. Expression of pIgR is largely restricted to crypt epithelial
cells and is not present on the FAE (11, 12, 13, 14, 15). The ASGPR,
first identified on the sinusoidal membranes of hepatocytes, is a
lectin-like receptor that can bind IgA via oligosaccharide side chains
bearing terminal galactose residues (26, 27). ASGPR has
been detected on the apical surfaces of certain human colonic
epithelial cell lines in vitro (28) and on the luminal
surfaces of rat neonatal (but not adult) enterocytes in vivo
(24), although its function on enterocytes remains
unknown. Because it has been previously reported that rat Peyer’s
patch M cells bind IgA (15), we used available rabbit
anti-rat ASGPR antiserum and immunofluorescence microscopy to
examine whether the ASGPR is expressed on the apical surfaces of M
cells in the FAE of Peyer’s patches. Anti-ASGPR antiserum failed to
label either the villus epithelium or FAE on frozen sections of rat
Peyer’s patch (Fig. 4). The specificity
and activity of the anti-ASGPR antiserum was confirmed on sections
of rat liver where the antiserum labeled hepatocyte sinusoidal
membranes, consistent with the known distribution of ASGPR (Fig. 4).
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We also tested the possibility that IgA may bind via its carbohydrate moieties to other lectin-like receptors on M cells. Although no specific lectins have been identified on M cells, lectin-like receptors are widespread on mammalian cells (29). Mouse IgA contains two N-linked oligosaccharide side chains terminating in mannose, galactose, N-glycolylneuraminic acid, or N-acetylneuraminic acid (30). To test whether IgA oligosaccharides are important for M cell binding, IgA was biotinylated either before or after treatment with sodium periodate to disrupt monosaccharides containing vicinal hydroxyl groups and destroy most carbohydrate epitopes (31). Periodate-treated IgA bound to the M cells in the BALB/c mouse with a pattern identical to untreated IgA (data not shown). To detect the possible presence of lectin-like receptors on M cells, we examined whether other glycoproteins with terminal galactose or mannose residues, including asialofetuin, asialoorosomucoid, BSA-galactose, BSA-mannose, or BSA-glucose, bound to M cells. No binding of any of these glycoproteins (tested at concentrations ranging from 10 to 1000 µg/ml) to M cells was detected in the BALB/c ligated ileal loop assay (data not shown). These data argue against the presence of a lectin-like receptor on the apical surfaces of M cells involved in binding SIgA.
Domains C1 and C2 are important for IgA binding to mouse
Peyer’s patch M cells
Identification of the domains of IgA that are important for M cell
binding could provide clues as to the nature of the IgA receptor. Human
IgA is comprised of two subclasses, IgA1 and IgA2 (32).
The primary difference between the two subclasses is that IgA1 has a
heavily O-glycosylated 16-aa hinge region located between
domains C1 and C2, whereas IgA2 has a 3-aa hinge that is not
glycosylated. Excluding the hinge, the protein sequence of human IgA1
and IgA2 differ in only 14 aa scattered along the polypeptide
(32). To determine whether both classes of human IgA bind
to mouse M cells, purified myeloma IgA1 and IgA2 were biotinylated and
tested in the ligated ileal loop assay. We observed that human IgA2
bound to mouse M cells but human IgA1 did not (Fig. 5, A and B). The
same result was obtained when recombinant human glycosylated IgA1
and IgA2 produced by mouse Sp2/O myeloma cells were tested (data not
shown). This differentiates the M cell IgA receptor from CD89
(FcRI), a receptor on human myeloid-derived cells that recognizes
IgA1 and IgA2 with equal affinity (33).
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1
and C2. To test this we used recombinant IgA1 molecule lacking the
hinge (IgA1
hinge) that was otherwise fully glycosylated
(18). In the BALB/c ligated ileal loop assay, IgA1hinge
adhered to the apical surfaces of Peyer’s patch M cells (Fig. 5, C–F). Furthermore, a recombinant Ig containing C1 of
IgA2 fused to the IgG2 hinge and C
2 and C3 domains did not bind
(Fig. 6), indicating that the IgA C1
domain alone is not sufficient to mediate Ig binding to M cells. Taken
together these results suggest that the IgA-M cell interaction requires
both C1 and C2 domains in a well-defined spatial conformation,
and that the inability of human IgA1 to bind to mouse M cells is due to
the extended hinge.
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In adult and neonatal rabbit Peyer’s patches and appendices,
endogenous SIgA can be detected on the apical surfaces of M cells by
immunohistochemistry (8, 9, 10). To determine whether
endogenous SIgA is present on the apical surfaces of human M cells,
paraffin sections of normal pediatric terminal ileum containing
organized lymphoid follicles were stained with affinity-purified, goat
anti-human IgA Abs. Anti-IgA Abs labeled plasma cells in the lamina
propria (Fig. 7A) and
occasionally in lymphoid follicles (data not shown). Anti-IgA Abs also
stained some (but not all) M cell membranes in biopsies from three
different individuals (Fig. 7, B and C). M
cells were identified by morphological criteria. Affinity-purified
anti-IgM Abs or irrelevant control Abs did not label M cells (data
not shown). These results suggest that human M cells, like those in
rabbits and rodents, express a receptor for IgA.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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At least four physiologically relevant receptors with IgA binding
capability have been described on either intestinal epithelium or
intestinal epithelial cell lines. These receptors include pIgR, ASGPR,
-1,4-galactosyl transferase, and an as-yet-unidentified IgA receptor
described on the colonic carcinoma cell line HT-29 (34).
Through direct and indirect evidence presented in this paper, we can
exclude all of these proteins as being the IgA receptor on Peyer’s
patch M cells. For example, ASGPR was not detectable on the FAE by
immunofluorescence microscopy, and IgA bound to Peyer’s patch M cells
in ASGPR-deficient mice. -1,4-galactosyl transferase recognizes IgA,
IgG, and IgM Abs (albeit with varying affinity) (35),
while we have shown in this study that the IgR on M cells is selective
for IgA. Finally, the novel IgA receptor on HT-29 cells is unable to
bind SIgA (34), whereas the M cell receptor binds IgA with
or without associated SC (15). Generally, IgA receptors
are classified into two groups: those that bind IgA via its
oligosaccharide side chains and those that bind IgA via Fc domains
(36). The observation that periodate treatment of IgA or
biotinylation of IgA on carbohydrate moieties did not affect binding to
M cells suggests that the receptor on M cells may recognize the
polypeptide backbone of the H chains rather than oligosaccharide
side chains.
We observed that human IgA2 but not IgA1 bound to mouse
Peyer’s patch M cells. This finding is not physiologically relevant
for mice that have only one class of IgA. Rather, this result provides
new information about the domains of IgA that may be important for
receptor recognition. The primary difference between the two human IgA
subclasses is that IgA1 has a heavily O-glycosylated 16-aa
hinge region located between domains C1 and C2, whereas IgA2 has
a 3-aa hinge that is not glycosylated (32). Indeed,
recombinant IgA1 lacking the hinge region bound to M cells. Considering
that C1 alone was not sufficient to mediate Ig binding to M cells,
we propose that the M cell IgA receptor spans the IgA hinge region and
makes contact with both C1 and C2 domains. This further
distinguishes the M cell receptor from CD89 (FcRI), which recognizes
the C terminus of C2 and N terminus of C3 (37, 38).
We postulate that the extended hinge of IgA1 may interfere with binding
by altering the spatial arrangement between C1 and C2 relative to
each other such that the M cell receptor cannot simultaneously contact
both domains. Alternatively, the O-linked oligosaccharide
side chains branching from the IgA1 hinge (32) could
potentially mask adjacent amino acids on C1 or C2 that are
important for receptor recognition.
Although the data presented in this paper suggest that the protein
responsible for binding SIgA on the apical surfaces of M cells is novel
and distinct from previously described human and murine FcRs, this
conclusion is premature in the absence of the additional molecular
information. For example, a recently described FcµR has been shown
by in situ hybridization and RT-PCR to be expressed at high levels in
the small intestine (16, 39). Although the expression of
this receptor was originally thought to be restricted to B cells and
macrophages, it has been now been reported to be present on mesangial
cells (40). In light of these studies we cannot exclude
the possibility that an alternative form of this receptor (which binds
IgA but not IgM) could be expressed on M cells. Future studies in this
laboratory will be aimed at identifying the M cell IgA receptor using
molecular genetic and biochemical techniques.
The function of the IgA receptor on M cells may be to
mediate the delivery of SIgA from the intestinal lumen to underlying
O-MALT. Consistent with this, we observed that SIgA applied to the
apical surfaces of M cells accumulated within vesicles clustered near
the intraepithelial pocket membranes. Presumably these vesicles were
released into the pocket. SIgA also accumulated in M cell basolateral
processes that have been proposed to make direct contact with
subepithelial leukocytes (23). Following M cell
transcytosis, SIgA-Ag complexes could be sampled by pocket B
lymphocytes (6) and/or subepithelial dendritic cells
(7). Brandtzaeg et al. (41) have hypothesized
that memory B cells in the M cell pocket present luminal Ags to
neighboring resident T cells, promoting T cell survival and B cell
differentiation. Human and murine mature B cells express an FcµR
that can mediate endocytosis of both IgA- and IgM-immune complexes
(39), although it has not been determined whether B cells
within the M cell pocket express this receptor. SIgA-immune complexes
could also interact with dendritic cells that form a dense
network below the FAE and occasionally migrate into the M cell
pocket (7). In vitro, human monocyte-derived DC can bind
and internalize SIgA (42, 43).
In this report we detected IgA on the apical surfaces of M cells in the human pediatric ileum, suggesting that human M cells, like those in the rabbit and mouse, bind and endocytose SIgA. This could have implications for understanding the regulation of mucosal immune responses in humans and potential applications for the development of oral vaccine delivery strategies. In humans a significant proportion of the intestinal microflora is coated with SIgA (44). This raises the possibility that M cells may "sample" IgA-coated commensal bacteria, promoting the maintenance of anticommensal immune responses that could control the luminal microflora and clear microorganisms from the mucosa (2). There is current interest in targeting vaccines to the apical surfaces of M cells in the human small intestine, colon, and rectum. In mice, exogenous IgA has been used as an Ag delivery vehicle, apparently promoting the sampling of oral or rectal vaccines by M cells and more efficient delivery to the mucosal immune system (45, 46). A better understanding of the interaction of SIgA with M cells and the resulting immune response is needed to assess the feasibility of such a vaccine strategy in humans.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Nicholas J. Mantis, Gastrointestinal Cell Biology Laboratory, Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115. E-mail address: nicholas.mantis{at}tch.harvard.edu
3 Abbreviations used in this paper: SIgA, secretory IgA; UEA-1, Ulex europaeus type I; TRITC, tetramethylrhodamine isothiocyanate; O-MALT, organized mucosa-associated lymphoid tissue; FAE, follicle-associated epithelium; pIgR, polymeric IgR; SC, secretory component; ASGPR, asialoglycoprotein receptor; Cy3, indocarbocyanine.
4 A. Phalipon, A. Cardona, L. Edelman, J.-P. Kraehenbuhl, P. Sansonetti, and B. Corthésy. Secretory component: a new role in secretory IgA-mediated immune exclusion in vivo. Submitted for publication.
Received for publication April 12, 2002. Accepted for publication June 3, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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+, and double negative Peyer’s patch dendritic cells. J. Immunol. 166:4884. receptors. P. L. Ogra, and J. Mestecky, and M. Lamm, and W. Strober, and J. Bienenstock, and J. R. McGhee, eds. Mucosal Immunology 213. Academic, San Diego.
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/µ receptor by human mesangial cells: a candidate receptor for immune complex deposition in IgA nephropathy. Biochem. Biophys. Res. Commun. 290:438.[Medline]
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