ARTICLE |
Correspondence to: Matti Korhonen, Hospital for Children and Adolescents, Helsinki University Central Hospital, FIN-00290 Helsinki, Finland. E-mail: matti.korhonen@helsinki.fi
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Summary |
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Extensive remodeling of the extracellular matrix (ECM) occurs in inflammatory tissues. The celiac lesion in the small intestine is characterized by inflammation accompanied by profound morphological alterations. We used immunohistochemistry to determine the distribution of laminin, fibronectin, and tenascin isoforms in small intestinal biopsies of untreated patients with celiac disease. In normal mucosa, the distribution of laminin isoforms defines three epithelial basement membrane (BM) zones. We found that the organization of these zones was maintained in the celiac mucosa. Thus, components of laminin-5 (3 and ß3) were found in the surface epithelial BM, laminin
2 chain was found selectively at crypt bottoms, and laminin
5 chain was the sole
-type chain in middle crypt BMs. Likewise, the distribution of fibronectin and tenascin resembled that of the normal gut. The organization of pericryptal fibroblasts and lamina propria smooth muscle strands, as defined by immunostaining for
-smooth muscle actin, also remained unchanged in the celiac mucosa. Unexpectedly, major ECM changes were not detected in the celiac lesion. (J Histochem Cytochem 48:10111020, 2000)
Key Words: basement membrane, extracellular matrix, immunohistochemistry, human
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Introduction |
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Celiac disease is characterized by abnormalities in both cell-mediated and humoral immunity, precipitated by gluten peptides. Current concepts of the pathogenic process include the activation of lamina propria T-cells (
Profound alterations in extracellular matrix (ECM) molecules and their cell surface receptors have been found in a number of inflammatory processes. The characterization of such alterations is important not only because they reflect the disease processes but because cellECM interactions are regulators of these pathological sequences (
Accompanied by extensive immunopathology, the celiac mucosa displays marked morphological alterations (
In this study we compared the distribution of Ln, Fn, and Tn isoforms and organization of mucosal smooth muscle components in celiac disease and in normal human child and adult small intestinal mucosa by immunohistochemistry.
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Materials and Methods |
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Patients and Controls
Small intestinal biopsy specimens from 13 patients with untreated celiac disease were available for the study. Nine were pediatric patients aged 0.910.3 years. Indications for biopsy were gastrointestinal complaints and/or growth failure, and increased levels of endomysium or reticulin antibodies. Four specimens were from adult healthy hospital personnel aged 39.548.9 years, who were found to have increased levels of endomysium antibodies in a screening study (Kolho et al. unpublished data). All had had minor gastrointestinal complaints and had an increased level of IgA and/or IgG anti-gliadin antibodies. Biopsy specimens from pediatric patients were taken with a CrosbyKugler biopsy device at the level of ligamentum Treitz or distal to it. Adult patients were biopsied with a gastroscope from the distal duodenum. Eleven of the biopsies showed total villous atrophy and two had a villous length of <180 µm. All had an elevated density of intraepithelial lymphocytes and /
1 cells. All 13 patients had a favorable clinical response to a gluten-free diet.
Four controls were specimens from pediatric patients aged 3.213.8 years. They were taken from children with minor gastrointestinal complaints. An additional indication for biopsy was an increased level of IgG anti-gliadin antibodies in three patients. IgAendomysium and IgAgliadin antibodies, mucosal morphology, and density of intraepithelial lymphocytes and /
1 cells were all normal. Four samples of normal adult small intestine were obtained from surgical specimens of the Jorvi Hospital (Espoo, Finland). Both biopsy and surgical samples were immediately frozen in liquid nitrogen and stored at -80C until use.
The patient samples used in this study represented active celiac lesions with typical mucosal morphology and marked infiltration of surface epithelium with both /ß and
/
TCR+ lymphocytes (
Mucosal Histology and Density of Intraepithelial Lymphocytes
MAbs TCR 1 (T Cell Diagnostics; Woburn, MA) and F1 (T Cell Diagnostics) were used at a dilution of 1:100, and anti-Leu4 (anti-CD3; BecktonDickinson, Mountain View, CA) at a dilution of 1:400. Eight-µm cryostat sections were incubated with MAbs and then treated with 0.5% hydrogen peroxide for 20 min to block endogenous peroxidase activity. The bound MAbs were detected with a Vectastain Elite ABC kit (PK-6102; Vector Laboratories, Burlingame, CA). Mucosal histology and the density of intraepithelial lymphocytes were evaluated independently from the other results of the study. The number of stained cells was counted as cells/mm of epithelium with a light microscope through a calibrated graticule (0.053 mm) at x100 magnification (
Ethical Considerations
Biopsy specimens from pediatric patients were taken because of clinical indications. From the adults, informed consent was obtained for the screening study of endomysium antibodies in hospital personnel and subsequently for gastroduodenoscopy. The screening study has been approved by the Ethical committee of the Medical Department of Helsinki University Central Hospital.
Antibodies
The following MAbs were used to localize ECM proteins: Ln 2 chain (clone 5H2) (
3 (BM-2) (
5 (4C7) (
1 (2E8) (
-smooth muscle actin (1A4; Sigma Chemical, St Louis, MO) (
1 chain (
Indirect Immunofluorescence Microscopy
Frozen sections were cut at 5 µm and fixed in acetone at -20C for 10 min. The sections were then exposed to the primary and subsequently to the secondary antibodies at room temperature for 30 min. The secondary antibodies were fluorescein isothiocyanate-coupled goat anti-mouse IgG, fluorescein isothiocyanate-coupled goat anti-rat IgG, and tetramethylrhodamine-coupled goat anti-rabbit IgG sera (all from Jackson Immunoresearch; West Grove, CA). Controls were carried out omitting the primary antibodies. The sections were embedded in sodium-veronal/glycerol buffer (1:1; pH 8.4), or Mowiol in the case of lectins, and viewed with a Leitz Aristoplan microscope using appropriate filters. Intensity of the immunoreaction was evaluated on a 4-point scale: -, negative; +, weak; ++, moderate; +++, strong.
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Results |
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The results are summarized in Table 1 and Table 2 and in Fig 5.
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Laminins in Epithelial BMs in Celiac Mucosa
Immunoreactivity for Ln 5 (Fig 1a), ß1 (Fig 1b), and
1 (Fig 4a) chains, components of Ln-10, was detected in a linear formation along BMs of surface epithelium and the full length of the crypts. Immunoreactivity for Ln
5 chain was weaker along the crypt than the surface epithelial BMs. MAb to Ln
2 (Fig 1c) reacted selectively with BM surrounding crypt bottoms, excluding middle and upper crypt and surface epithelial BMs. Immunoreactivity for Ln
1 (Fig 1d) or ß2 chains (not shown) was not detected in the epithelial BM or lamina propria. Occasional subepithelial myofibroblasts, also immunoreactive for
-actinin and desmin, reacted with Ln
3,
5, ß1 (Fig 1b), and
1 MAbs.
MAbs detecting Ln ß3 and 3 chains (Fig 2a and Fig 2b) and the antiserum against Ln-5 (Ln
3ß3
2; Fig 2c and Fig 2d) reacted distinctly with the BM of surface epithelium, with weak immunoreactivity sometimes extending to upper crypt BMs. In tangential sections, the immunoreactivity was often spotty (Fig 2b). In double immunostaining experiments, there was no overlap of the proliferative cell compartment, as defined by immunoreaction for the MAb Ki-67, and the distribution of Ln-5 (Fig 2c and Fig 2d). In two of the 13 samples, weak immunoreactivity using Ln-5 antiserum and Ln
3 and ß3 chain MAbs was detected in crypt BMs, including crypt bottoms, in addition to the surface epithelial BM.
Fibronectins and Tenascins in Celiac Mucosa
An MAb recognizing EDA-Fn (Fig 3a) reacted with crypt BMs but inconsistently with upper crypt and surface epithelial BM regions. In addition, a weak fibrillar meshwork was seen throughout the lamina propria mesenchyme. The EDB-Fn and Onc-Fn MAbs (not shown) detected sparse weakly immunoreactive cells in the lamina propria but otherwise failed to react with epithelial BMs or the lamina propria stroma.
Both anti-Tn MAbs (Fig 3b and Fig 3c) reacted distinctly with the BM zone of surface epithelium as well as upper crypts, but failed to reveal immunoreactivity in the stroma of lamina propria. No distinct differences in the distribution of the different Tn splicing isoforms were noted.
Mucosal Smooth Muscle, Pericryptal Fibroblasts, and Capillaries
Ln ß1 (Fig 1b) and 1 (Fig 4a and Fig 4b) chain MAbs reacted with strand-like formations within the lamina propria mesenchyme in the celiac patient samples. These strands also reacted with desmin antiserum (Fig 4a4d) and with an MAb to
-smooth muscle actin (Fig 4e), but not with UEA-I lectin (not shown) that detects endothelial cells, indicating that the strands contain smooth muscle and are distinct from capillaries. In normal small intestine, smooth muscle strands extending from the muscularis mucosae into the villous mesenchyme reacted similarly (Fig 4e and Fig 4f), suggesting that the strands were corresponding structures. Immunoreactivity for Ln
1,
2,
3,
5 (Fig 4c and Fig 4d), ß2, or ß3 chains was not found in the strands. Slight immunoreactivity for
-smooth muscle actin located at the epithelialmesenchymal interface extended all the way from crypt bottoms to the surface epithelium, identifying pericryptal fibroblasts (Fig 4e and Fig 4f). Muscularis mucosae displayed distinct immunoreactivity for Ln
5 (Fig 4c and Fig 4d), ß1 (Fig 1b), ß2 (not shown), and
1 (Fig 4a and Fig 4b) chains as well for EDA-Fn (Fig 3a) and both Tn MAbs (Fig 3b and Fig 3c). However, antibodies against Ln
1,
3 and ß3 chains and against EDB- and Onc-Fn did not react, and Ln
2 (Fig 1c) chain MAb revealed only scattered immunoreactivity in muscularis mucosae.
Capillaries of lamina propria, identified by double labeling with UEA-I, displayed immunoreactivity for components of Ln-10: Ln 5 (Fig 1a and Fig 4c), ß1 (Fig 1b), and
1 (Fig 4a), but not for
1,
2,
3, ß2, or ß3 chains.
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Discussion |
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Extensive remodeling of the ECM, detectable by immunohistochemistry, is often found in inflammatory lesions, e.g., in inflammatory bowel disease (
The morphology of the celiac lesion is characterized by crypt hyperplasia and villous atrophy, coupled with an increase in the volume of lamina propria (
This study addresses the question of whether ECM alterations can be detected in the celiac lesion by immunohistochemistry. One pertinent limitation of this kind of study is that it gives us only a snapshot of a dynamic process of ECM turnover. However, immunohistochemical changes can be detected in the other above-mentioned inflammatory lesions, and we expected to find likewise in the celiac mucosa. Given the multitude of known ECM molecules, another obvious limitation is that they cannot all be covered in a single study. Here we chose to investigate the distribution of Lns, Fn, and Tn because they are all differentially expressed along the cryptvillous axis in the normal gut, and have been suggested to influence enterocyte differentiation (see above). Another family of ECM molecules that requires further study in this context is that of the collagen IV isoforms. Their expression has been shown to be regulated independently of laminins in both normal and neoplastic gut (
The main finding of this study is that untreated celiac intestinal mucosa displays a surprisingly normal distribution of ECM molecules.
It should be noted that MAb 4C7, formerly believed to recognize the Ln 1 chain, was recently shown to recognize the human Ln
5 polypeptide (
-type chain are therefore found ubiquitously throughout normal and celiac intestinal epithelial BM. In accordance with earlier studies using in situ hybridization suggesting sparse distribution of the Ln
1 mRNA in many tissues (
1 protein in normal or celiac small intestinal mucosa.
The Epithelial Basement Membrane
In the normal small intestinal epithelium, the exclusive localization of specific Ln isoforms defines three zones within the epithelial BM of the cryptvillous axis (3 and ß3 chains, components of Ln-5. (II) The middle and upper crypt BMs contain
5 as their sole
-type chain, lacking both
2 and
3. (III) The
2 chain is found exclusively at the crypt bottoms. These three zones were also identified in the celiac epithelium (Table 1; Fig 5). The BM at the bottom of the crypts was characterized by immunoreactivity for Ln
2, implying the presence of Ln-2 (
2ß1
1), and BM of surface epithelium was defined as homologous to that of normal villous epithelium by its immunoreactivity for
3 and ß3, components of Ln-5. The expansion of the crypt compartment that occurs in the celiac lesion (
The celiac mucosa is characterized by hypertrophy of crypts and expansion of the proliferative cell compartment. However, by double immunostaining using MAb Ki-67 we showed that the proliferative cell compartment did not extend to the surface epithelial BM zone that contains Ln-5. In addition, the organization of the celiac epithelium resembles that of the normal gut (3 and ß3 chains and Ln-5 was detected also in crypt BMs.
Normal gut mucosa displays a striking gradient of increasing Tn expression from crypt bottom to villous tip, apparently involved in cell shedding at the villous tip (
The specialization of the intestinal BM along the cryptvillous axis is believed to reflect and modulate enterocyte differentiation (
Lamina Propria
Two other aspects of lamina propria tissue architecture merit mention: the smooth muscle scaffolding of small intestinal villi and the pericryptal fibroblastic sheath. In celiac mucosa, we detected abundant strands of desmin and -smooth muscle actin-positive cells extending from the muscularis mucosae towards the mucosal surface, similar to the smooth muscle bundles of normal villi (
1 chains, but the
-type chain could not be identified using
1,
2,
3, or
5 antibodies. The Ln
4 chain, which has been found in murine intestinal mesenchyme and specifically in mucosal smooth muscle (
-type chain also found in human intestine.
In the normal gut, a pericryptal fibroblastic sheath envelops crypts, extending to the villous tips at the epithelialmesenchymal interface. It has been suggested that these cells control epithelial cell proliferation and immunological functions (-smooth muscle actin, remains intact in the celiac mucosa.
In summary, we found that the spatially restricted distribution of Lns, Fn, and Tn along the cryptvillous axis and the organization of the lamina propria smooth muscle scaffolding and of the pericryptal fibroblastic sheath resemble those seen in normal intestinal mucosa. Surprisingly, our results suggest that despite the profound changes in morphology coupled with the active immunopathological processes, major ECM changes do not occur in celiac disease.
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Acknowledgments |
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We are indebted to Eva Engvall, Sen-itiroh Hakomori, Joshua Sanes, and Luciano Zardi for kind gifts of antibodies. The skillful technical assistance of Hannu Kamppinen, Reijo Karppinen, Marja-Leena Piironen, Sirkku Kristianssen, and Outi Rauanheimo is acknowledged.
Received for publication August 6, 1999; accepted March 1, 2000.
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