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Eugene C Butcher - One of the best experts on this subject based on the ideXlab platform.
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immune cell trafficking in uterus and early life is dominated by the mucosal Addressin madcam 1 in humans
Gastroenterology, 2001Co-Authors: Marko Salmi, Eugene C Butcher, Kalle Alanen, Seija Grenman, Michael J Briskin, Sirpa JalkanenAbstract:Abstract Background & Aims: In adults, binding of mucosal Addressin cell adhesion molecule 1 (MAdCAM-1) to lymphocyte α4β7 integrin directs cell trafficking to gut, whereas interaction of peripheral node Addressins (PNAd) with lymphocyte L-selectin targets immune cells to peripheral lymph nodes (PLNs). Because nothing is known about these Addressins during human development, we studied the expression and function of MAdCAM-1 (and PNAd for comparison) in fetuses and children. Methods: Series of human tissue samples obtained from fetuses (7–40 weeks), children (2 months–7 years), and adults were immunostained with monoclonal antibodies. The function of the Addressins and their lymphocyte counter-receptors was tested in in vitro binding assays on fetal and adult tissues. Results: Unlike in adults, MAdCAM-1 is widely expressed from embryonic week 7 onwards, and it only gradually becomes polarized to mucosal vessels after birth. In utero MAdCAM-1 functionally governs lymphocyte adhesion to vessels both in the gut and PLNs by binding to α4β7 integrin. The later induction of PNAd gradually starts to dominate the binding of lymphocytes to PLNs during childhood. Conclusions: There are striking age-dependent switches and species-specific variation in the molecular mechanisms of lymphocyte migration. In utero and during early childhood, the mucosal Addressin MAdCAM-1 plays a dominant role in lymphocyte-endothelial cell adhesion at mucosal and nonmucosal sites. GASTROENTEROLOGY 2001;121:853-864
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A developmental switch in lymphocyte homing receptor and endothelial vascular Addressin expression regulates lymphocyte homing and permits CD4+ CD3- cells to colonize lymph nodes.
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Reina E. Mebius, Eugene C Butcher, Sara A. Michie, Philip R. Streeter, Irving L. WeissmanAbstract:Abstract IN adult mice, the dominant adhesion molecules involved in homing to lymph nodes are L-selectin homing receptors on lymphocytes and the peripheral lymph node Addressins on specialized high endothelial venules. Here we show that, from fetal life through the first 24 hr of life, the dominant adhesion molecules are the mucosal Addressin MAdCAM-1 on lymph node high endothelial venules and its counterreceptor, the Peyer's patch homing receptor, integrin alpha 4 beta 7 on circulating cells. Before birth, 40-70% of peripheral blood leukocytes are L-selectin-positive, while only 1-2% expresses alpha 4 beta 7. However, the fetal lymph nodes preferentially attract alpha 4 beta 7-expressing cells, and this can be blocked by fetal administration of anti-MAdCAM-1 antibodies. During fetal and early neonatal life, when only MAdCAM-1 is expressed on high endothelial venules, an unusual subset of CD4 + CD3- cells, exclusively expressing alpha 4 beta 7 as homing receptors, enters the lymph nodes. Beginning 24 hr after birth a developmental switch occurs, and the peripheral node Addressins are upregulated on high endothelial venules in peripheral and mesenteric lymph nodes. This switch in Addressin expression facilitates tissue-selective lymphocyte migration and mediates a sequential entry of different cell populations into the lymph nodes.
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L-selectin and alpha 4 beta 7 integrin homing receptor pathways mediate peripheral lymphocyte traffic to AKR mouse hyperplastic thymus.
The American journal of pathology, 1995Co-Authors: Sara A. Michie, Eugene C Butcher, Philip R. Streeter, Robert V. RouseAbstract:Before the development of thymic lymphoma, AKR mice undergo a striking lymphoid hyperplasia of the thymic medulla. We have previously shown that there is a marked increase in traffic of B and T lymphocytes from the periphery into the preneoplastic, hyperplastic thymuses of these mice, in contrast to the scant traffic of such cells to normal thymuses. The traffic of lymphocytes to lymph nodes and Peyer's patches is controlled in part by the interaction of lymphocyte adhesion molecules called homing receptors with their tissue-selective endothelial ligands known as vascular Addressins. We have investigated the roles of homing receptors and vascular Addressins in the traffic of lymphocytes to the AKR hyperplastic thymus. We demonstrate that development of hyperplasia is accompanied by an increase in the number of thymic medullary blood vessels with high endothelial venule morphology and expression of the peripheral node Addressin (PNAd) and the mucosal Addressin (MAdCAM-1). In vitro and in vivo functional assays show that the Addressin/homing receptor pairs PNAd/L-selectin and MAdCAM-1/alpha 4 beta 7 are involved in lymphocyte traffic to the hyperplastic thymus. These results indicate that molecular adhesion mechanisms involved in tissue-selective migration of lymphocytes to peripheral lymph node and to mucosal lymphoid tissues play a role in the recruitment of B and T lymphocytes to the AKR thymus and thus in the pathogenesis of thymic hyperplasia.
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role of alpha 4 integrins in lymphocyte homing to mucosal tissues in vivo
Journal of Immunology, 1994Co-Authors: Alf Hamann, David P Andrew, Dorothee Jablonskiwestrich, Bernhard Holzmann, Eugene C ButcherAbstract:Lymphocyte recirculation through different organs is thought to be regulated by adhesion molecules ("homing receptors") recognizing tissue-specific vascular Addressins on endothelium. Here we show that the alpha 4/beta 7-integrin has a key role in the migration of mouse lymphocytes to mucosal sites. Homing to Peyer's patches but not to peripheral lymph nodes is inhibited by Fab fragments of mAb PS/2 against the alpha 4-integrin chain, by mAb DATK32 recognizing a combinatorial epitope on the alpha 4/beta 7-integrin, and by mAb FIB30 against the beta 7-chain. The Abs significantly reduce homing of lymphocytes to the intestine, as well. The migration of immunoblasts to gut and gut-associated lymphoid tissue also involves the alpha 4/beta 7-integrin heterodimer. Another anti-alpha 4 Ab, R1-2, which blocks lymphocyte binding to Peyer's patches in the Stamper-Woodruff frozen section assay and lymphocyte adhesion to VCAM-1 and fibronectin, has only minor effects on lymphocyte traffic in vivo. Anti-VCAM-1 Ab as well as the fibronectin peptide CS-1 are without influence on the migration to Peyer's patches or intestine, in contrast to Ab against the mucosal Addressin MAdCAM-1. Thus, homing to gut-associated sites is regulated by the alpha 4/beta 7-integrin heterodimer interacting with the vascular Addressin, MAdCAM-1, and not with fibronectin or VCAM-1 as counterstructures. Inhibition of homing to Peyer's patches and intestine by the anti-integrin Abs studied was only partial. L-selectin also participates in the homing of small lymphocytes to mucosal sites, especially Peyer's patches, but does not contribute substantially to the localization of blasts into the intestinal wall. The results support a major, but not exclusive role of the alpha 4/beta 7-integrin in lymphocyte traffic to mucosal sites.
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the human peripheral lymph node vascular Addressin an inducible endothelial antigen involved in lymphocyte homing
American Journal of Pathology, 1993Co-Authors: Sara A. Michie, Eugene C Butcher, Philip R. Streeter, P A Bolt, Louis J PickerAbstract:The extravasation of blood-borne lymphocytes into organized lymphoid tissues and sites of chronic inflammation is directed in part by interactions of lymphocyte surface adhesion molecules, known as homing receptors, with tissue-selective endothelial ligands called vascular Addressins. In mice and humans, lymphocyte L-selectin and the peripheral lymph node Addressin (PNAd) form a homing receptor-endothelial ligand pair involved in lymphocyte traffic to peripheral lymph node (PLN). We have examined the tissue distribution and function of human PNAd, using monoclonal antibody MECA-79 and in vitro assays of L-selectin-dependent lymphocyte binding. We demonstrate that PNAd is expressed by human high endothelial venules (HEV) in lymphoid tissues which support lymphocyte adhesion via a PLN-associated recognition system. MECA-79 inhibits adhesion to these HEV of a cell line that binds predominantly via the PLN-homing receptor, L-selectin, but has no effect on adhesion by a mucosal HEV-binding cell line. Furthermore, MECA-79 blocks binding of human peripheral blood mononuclear cells to both PLN and tonsil HEV, but not significantly to HEV in the appendix. In addition, we demonstrate PNAd induction on venules at chronic inflammatory sites in humans, particularly sites with severe or long-standing chronic inflammatory involvement. These results confirm that PNAd functions as a PLN vascular Addressin in humans, and that in addition to directing normal lymphocyte recirculation to lymph nodes and tonsils, this Addressin likely participates in lymphocyte recruitment to sites of chronic inflammation.
Antonio Di Sabatino - One of the best experts on this subject based on the ideXlab platform.
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increased expression of mucosal Addressin cell adhesion molecule 1 in the duodenum of patients with active celiac disease is associated with depletion of integrin α4β7 positive t cells in blood
Human Pathology, 2009Co-Authors: Antonio Di Sabatino, L Rovedatti, Maria Manuela Rosado, Rita Carsetti, Gino Roberto Corazza, Thomas T MacdonaldAbstract:Mucosal Addressin cell adhesion molecule 1, expressed on gut endothelial cells, in conjunction with integrin alpha(4)beta(7), expressed on lymphocytes, is critical in lymphocyte homing to the gut. The mucosal Addressin cell adhesion molecule 1/integrin alpha(4)beta(7) pathway is involved in the pathogenesis of chronic intestinal inflammation by recruiting lymphocytes into inflamed gut. We explored the duodenal expression of mucosal Addressin cell adhesion molecule 1 and the peripheral T-cell expression of integrin alpha(4)beta(7) in patients with celiac disease. Duodenal biopsies and a peripheral blood sample were collected from 15 celiac patients, before and after 12 months of gluten-free diet, and from 12 control subjects. Treated celiac biopsies were cultured with peptic-tryptic digest of gliadin and/or an anti-interferon alpha neutralizing antibody. Mucosal Addressin cell adhesion molecule 1 was determined by confocal immunofluorescence microscopy and immunoblotting. Integrin beta(7)-positive T cells were analyzed by flow cytometry. Mucosal Addressin cell adhesion molecule 1 expression was significantly higher in active celiac disease than in normal mucosa. After gluten-free diet, a dramatic reduction of mucosal Addressin cell adhesion molecule 1 was also observed. No difference was seen between patients with celiac disease after treatment and controls. Ex vivo peptic-tryptic digest of gliadin challenge induced a marked increase of mucosal Addressin cell adhesion molecule 1 expression. Blocking interferon alpha inhibited the peptic-tryptic digest of gliadin-induced mucosal Addressin cell adhesion molecule 1 overexpression. The percentage of circulating beta(7)-positive T cells was significantly lower in untreated celiac disease in comparison to controls but normalized after gluten-free diet. Mucosal Addressin cell adhesion molecule 1 is strongly up-regulated in active celiac disease dependent on interferon alpha and is associated with peripheral depletion of integrin alpha(4)beta(7)-expressing T cells. We conclude that mucosal Addressin cell adhesion molecule 1 may represent an important determinant for the generation of mucosal damage in celiac disease.
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increased expression of mucosal Addressin cell adhesion molecule 1 in the duodenum of patients with active celiac disease is associated with depletion of integrin α4β7 positive t cells in blood
Human Pathology, 2009Co-Authors: Antonio Di Sabatino, L Rovedatti, Maria Manuela Rosado, Rita Carsetti, Gino Roberto Corazza, Thomas T MacdonaldAbstract:Summary Mucosal Addressin cell adhesion molecule 1, expressed on gut endothelial cells, in conjunction with integrin α 4 β 7 , expressed on lymphocytes, is critical in lymphocyte homing to the gut. The mucosal Addressin cell adhesion molecule 1/integrin α 4 β 7 pathway is involved in the pathogenesis of chronic intestinal inflammation by recruiting lymphocytes into inflamed gut. We explored the duodenal expression of mucosal Addressin cell adhesion molecule 1 and the peripheral T-cell expression of integrin α 4 β 7 in patients with celiac disease. Duodenal biopsies and a peripheral blood sample were collected from 15 celiac patients, before and after 12 months of gluten-free diet, and from 12 control subjects. Treated celiac biopsies were cultured with peptic-tryptic digest of gliadin and/or an anti–interferon α neutralizing antibody. Mucosal Addressin cell adhesion molecule 1 was determined by confocal immunofluorescence microscopy and immunoblotting. Integrin β 7 -positive T cells were analyzed by flow cytometry. Mucosal Addressin cell adhesion molecule 1 expression was significantly higher in active celiac disease than in normal mucosa. After gluten-free diet, a dramatic reduction of mucosal Addressin cell adhesion molecule 1 was also observed. No difference was seen between patients with celiac disease after treatment and controls. Ex vivo peptic-tryptic digest of gliadin challenge induced a marked increase of mucosal Addressin cell adhesion molecule 1 expression. Blocking interferon α inhibited the peptic-tryptic digest of gliadin–induced mucosal Addressin cell adhesion molecule 1 overexpression. The percentage of circulating β 7 -positive T cells was significantly lower in untreated celiac disease in comparison to controls but normalized after gluten-free diet. Mucosal Addressin cell adhesion molecule 1 is strongly up-regulated in active celiac disease dependent on interferon α and is associated with peripheral depletion of integrin α 4 β 7 -expressing T cells. We conclude that mucosal Addressin cell adhesion molecule 1 may represent an important determinant for the generation of mucosal damage in celiac disease.
David W Pascual - One of the best experts on this subject based on the ideXlab platform.
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mucosal Addressin expression and binding interactions with naive lymphocytes vary among the cranial oral and nasal associated lymphoid tissues
European Journal of Immunology, 2002Co-Authors: Keri L Csencsits, Mark A Jutila, David W PascualAbstract:The head and neck lymph nodes (LN)--or cranial, oral, and nasal-associated lymphoid tissue (CONALT)--help disseminate activated lymphocytes to produce salivary immune responses, especially after intranasal immunization. To elucidate the mechanisms that induce immunity at these sites, we investigated the interactions between Addressins and homing-receptors that allow for lymphocyte binding to high endothelial venules (HEV) of CONALT. In vivo lymphocyte trafficking to CONALT was mediated primarily through interactions between peripheral node Addressin (PNAd) and L-selectin, whereas interactions between mucosal Addressin cell adhesion molecule-1 (MAdCAM-1) and alpha 4 beta 7 played a role in retention in cervical LN (CLN). Upon immunofluorescent staining for PNAd and MAdCAM-1, nearly all HEV in CONALT expressed PNAd, with varying MAdCAM-1 expression among these LN. The parotid gland LN (PRLN) and submaxillary gland LN (SMLN) rely exclusively upon PNAd-L-selectin interactions for naive-lymphocyte binding, whereas the CLN utilize PNAd-L-selectin interactions and MAdCAM-1-alpha 4 beta 7 interactions for binding. Intense staining of non-HEV-expressed vascular cell adhesion molecule-1 (VCAM-1) was observed in PRLN, whereas SMLN and CLN displayed less VCAM-1 but showed intense staining for diffuse MAdCAM-1. This study suggests that though PNAd-L-selectin interactions play an important role in the trafficking of lymphocytes throughout CONALT, varying MAdCAM-1 and VCAM-1 Addressin expression and usage impart important differences among the PRLN, SMLN, and CLN.
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nasal associated lymphoid tissue phenotypic and functional evidence for the primary role of peripheral node Addressin in naive lymphocyte adhesion to high endothelial venules in a mucosal site
Journal of Immunology, 1999Co-Authors: Keri L Csencsits, Mark A Jutila, David W PascualAbstract:Nasal-associated lymphoid tissue (NALT), a mucosal inductive site for the upper respiratory tract, is important for the development of mucosal immunity locally and distally to intranasally introduced Ag. To more fully understand the induction of nasal mucosal immunity, we investigated the Addressins that allow for lymphocyte trafficking to this tissue. To investigate the Addressins responsible for naive lymphocyte binding, immunofluorescent and immunoperoxidase staining of frozen NALT sections were performed using anti-mucosal Addressin cell adhesion molecule-1 (MAdCAM-1), anti-peripheral node Addressin (PNAd), and anti-VCAM-1 mAbs. All NALT high endothelial venules (HEV) expressed PNAd, either associated with MAdCAM-1 or alone, whereas NALT follicular dendritic cells expressed both MAdCAM-1 and VCAM-1. These expression profiles were distinct from those of the gut mucosal inductive site, Peyer’s patches (PP). The functionality of NALT HEV was determined using a Stamper-Woodruff ex vivo assay. The anti-L-selectin MEL-14 mAb blocked >90% of naive lymphocyte binding to NALT HEV, whereas the anti-MAdCAM-1 mAb, which blocks almost all naive lymphocyte binding to PP, minimally blocked binding to NALT HEV. NALT lymphocytes exhibited a unique L-selectin expression profile, differing from both PP and peripheral lymph nodes. Finally, NALT HEV were found in increased amounts in the B cell zones, unlike PP HEV. These results suggest that NALT is distinct from the intestinal PP, that initial naive lymphocyte binding to NALT HEV involves predominantly L-selectin and PNAd rather than α 4 β 7 -MAdCAM-1 interactions, and that MAdCAM-1 and VCAM-1 expressed by NALT follicular dendritic cells may play an important role in lymphocyte recruitment and retention.
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nasal associated lymphoid tissue phenotypic and functional evidence for the primary role of peripheral node Addressin in naive lymphocyte adhesion to high endothelial venules in a mucosal site
Journal of Immunology, 1999Co-Authors: Keri L Csencsits, Mark A Jutila, David W PascualAbstract:Nasal-associated lymphoid tissue (NALT), a mucosal inductive site for the upper respiratory tract, is important for the development of mucosal immunity locally and distally to intranasally introduced Ag. To more fully understand the induction of nasal mucosal immunity, we investigated the Addressins that allow for lymphocyte trafficking to this tissue. To investigate the Addressins responsible for naive lymphocyte binding, immunofluorescent and immunoperoxidase staining of frozen NALT sections were performed using anti-mucosal Addressin cell adhesion molecule-1 (MAdCAM-1), anti-peripheral node Addressin (PNAd), and anti-VCAM-1 mAbs. All NALT high endothelial venules (HEV) expressed PNAd, either associated with MAdCAM-1 or alone, whereas NALT follicular dendritic cells expressed both MAdCAM-1 and VCAM-1. These expression profiles were distinct from those of the gut mucosal inductive site, Peyer's patches (PP). The functionality of NALT HEV was determined using a Stamper-Woodruff ex vivo assay. The anti-L-selectin MEL-14 mAb blocked >90% of naive lymphocyte binding to NALT HEV, whereas the anti-MAdCAM-1 mAb, which blocks almost all naive lymphocyte binding to PP, minimally blocked binding to NALT HEV. NALT lymphocytes exhibited a unique L-selectin expression profile, differing from both PP and peripheral lymph nodes. Finally, NALT HEV were found in increased amounts in the B cell zones, unlike PP HEV. These results suggest that NALT is distinct from the intestinal PP, that initial naive lymphocyte binding to NALT HEV involves predominantly L-selectin and PNAd rather than alpha4beta7-MAdCAM-1 interactions, and that MAdCAM-1 and VCAM-1 expressed by NALT follicular dendritic cells may play an important role in lymphocyte recruitment and retention.
Thomas T Macdonald - One of the best experts on this subject based on the ideXlab platform.
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increased expression of mucosal Addressin cell adhesion molecule 1 in the duodenum of patients with active celiac disease is associated with depletion of integrin α4β7 positive t cells in blood
Human Pathology, 2009Co-Authors: Antonio Di Sabatino, L Rovedatti, Maria Manuela Rosado, Rita Carsetti, Gino Roberto Corazza, Thomas T MacdonaldAbstract:Mucosal Addressin cell adhesion molecule 1, expressed on gut endothelial cells, in conjunction with integrin alpha(4)beta(7), expressed on lymphocytes, is critical in lymphocyte homing to the gut. The mucosal Addressin cell adhesion molecule 1/integrin alpha(4)beta(7) pathway is involved in the pathogenesis of chronic intestinal inflammation by recruiting lymphocytes into inflamed gut. We explored the duodenal expression of mucosal Addressin cell adhesion molecule 1 and the peripheral T-cell expression of integrin alpha(4)beta(7) in patients with celiac disease. Duodenal biopsies and a peripheral blood sample were collected from 15 celiac patients, before and after 12 months of gluten-free diet, and from 12 control subjects. Treated celiac biopsies were cultured with peptic-tryptic digest of gliadin and/or an anti-interferon alpha neutralizing antibody. Mucosal Addressin cell adhesion molecule 1 was determined by confocal immunofluorescence microscopy and immunoblotting. Integrin beta(7)-positive T cells were analyzed by flow cytometry. Mucosal Addressin cell adhesion molecule 1 expression was significantly higher in active celiac disease than in normal mucosa. After gluten-free diet, a dramatic reduction of mucosal Addressin cell adhesion molecule 1 was also observed. No difference was seen between patients with celiac disease after treatment and controls. Ex vivo peptic-tryptic digest of gliadin challenge induced a marked increase of mucosal Addressin cell adhesion molecule 1 expression. Blocking interferon alpha inhibited the peptic-tryptic digest of gliadin-induced mucosal Addressin cell adhesion molecule 1 overexpression. The percentage of circulating beta(7)-positive T cells was significantly lower in untreated celiac disease in comparison to controls but normalized after gluten-free diet. Mucosal Addressin cell adhesion molecule 1 is strongly up-regulated in active celiac disease dependent on interferon alpha and is associated with peripheral depletion of integrin alpha(4)beta(7)-expressing T cells. We conclude that mucosal Addressin cell adhesion molecule 1 may represent an important determinant for the generation of mucosal damage in celiac disease.
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increased expression of mucosal Addressin cell adhesion molecule 1 in the duodenum of patients with active celiac disease is associated with depletion of integrin α4β7 positive t cells in blood
Human Pathology, 2009Co-Authors: Antonio Di Sabatino, L Rovedatti, Maria Manuela Rosado, Rita Carsetti, Gino Roberto Corazza, Thomas T MacdonaldAbstract:Summary Mucosal Addressin cell adhesion molecule 1, expressed on gut endothelial cells, in conjunction with integrin α 4 β 7 , expressed on lymphocytes, is critical in lymphocyte homing to the gut. The mucosal Addressin cell adhesion molecule 1/integrin α 4 β 7 pathway is involved in the pathogenesis of chronic intestinal inflammation by recruiting lymphocytes into inflamed gut. We explored the duodenal expression of mucosal Addressin cell adhesion molecule 1 and the peripheral T-cell expression of integrin α 4 β 7 in patients with celiac disease. Duodenal biopsies and a peripheral blood sample were collected from 15 celiac patients, before and after 12 months of gluten-free diet, and from 12 control subjects. Treated celiac biopsies were cultured with peptic-tryptic digest of gliadin and/or an anti–interferon α neutralizing antibody. Mucosal Addressin cell adhesion molecule 1 was determined by confocal immunofluorescence microscopy and immunoblotting. Integrin β 7 -positive T cells were analyzed by flow cytometry. Mucosal Addressin cell adhesion molecule 1 expression was significantly higher in active celiac disease than in normal mucosa. After gluten-free diet, a dramatic reduction of mucosal Addressin cell adhesion molecule 1 was also observed. No difference was seen between patients with celiac disease after treatment and controls. Ex vivo peptic-tryptic digest of gliadin challenge induced a marked increase of mucosal Addressin cell adhesion molecule 1 expression. Blocking interferon α inhibited the peptic-tryptic digest of gliadin–induced mucosal Addressin cell adhesion molecule 1 overexpression. The percentage of circulating β 7 -positive T cells was significantly lower in untreated celiac disease in comparison to controls but normalized after gluten-free diet. Mucosal Addressin cell adhesion molecule 1 is strongly up-regulated in active celiac disease dependent on interferon α and is associated with peripheral depletion of integrin α 4 β 7 -expressing T cells. We conclude that mucosal Addressin cell adhesion molecule 1 may represent an important determinant for the generation of mucosal damage in celiac disease.
L Rovedatti - One of the best experts on this subject based on the ideXlab platform.
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increased expression of mucosal Addressin cell adhesion molecule 1 in the duodenum of patients with active celiac disease is associated with depletion of integrin α4β7 positive t cells in blood
Human Pathology, 2009Co-Authors: Antonio Di Sabatino, L Rovedatti, Maria Manuela Rosado, Rita Carsetti, Gino Roberto Corazza, Thomas T MacdonaldAbstract:Mucosal Addressin cell adhesion molecule 1, expressed on gut endothelial cells, in conjunction with integrin alpha(4)beta(7), expressed on lymphocytes, is critical in lymphocyte homing to the gut. The mucosal Addressin cell adhesion molecule 1/integrin alpha(4)beta(7) pathway is involved in the pathogenesis of chronic intestinal inflammation by recruiting lymphocytes into inflamed gut. We explored the duodenal expression of mucosal Addressin cell adhesion molecule 1 and the peripheral T-cell expression of integrin alpha(4)beta(7) in patients with celiac disease. Duodenal biopsies and a peripheral blood sample were collected from 15 celiac patients, before and after 12 months of gluten-free diet, and from 12 control subjects. Treated celiac biopsies were cultured with peptic-tryptic digest of gliadin and/or an anti-interferon alpha neutralizing antibody. Mucosal Addressin cell adhesion molecule 1 was determined by confocal immunofluorescence microscopy and immunoblotting. Integrin beta(7)-positive T cells were analyzed by flow cytometry. Mucosal Addressin cell adhesion molecule 1 expression was significantly higher in active celiac disease than in normal mucosa. After gluten-free diet, a dramatic reduction of mucosal Addressin cell adhesion molecule 1 was also observed. No difference was seen between patients with celiac disease after treatment and controls. Ex vivo peptic-tryptic digest of gliadin challenge induced a marked increase of mucosal Addressin cell adhesion molecule 1 expression. Blocking interferon alpha inhibited the peptic-tryptic digest of gliadin-induced mucosal Addressin cell adhesion molecule 1 overexpression. The percentage of circulating beta(7)-positive T cells was significantly lower in untreated celiac disease in comparison to controls but normalized after gluten-free diet. Mucosal Addressin cell adhesion molecule 1 is strongly up-regulated in active celiac disease dependent on interferon alpha and is associated with peripheral depletion of integrin alpha(4)beta(7)-expressing T cells. We conclude that mucosal Addressin cell adhesion molecule 1 may represent an important determinant for the generation of mucosal damage in celiac disease.
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increased expression of mucosal Addressin cell adhesion molecule 1 in the duodenum of patients with active celiac disease is associated with depletion of integrin α4β7 positive t cells in blood
Human Pathology, 2009Co-Authors: Antonio Di Sabatino, L Rovedatti, Maria Manuela Rosado, Rita Carsetti, Gino Roberto Corazza, Thomas T MacdonaldAbstract:Summary Mucosal Addressin cell adhesion molecule 1, expressed on gut endothelial cells, in conjunction with integrin α 4 β 7 , expressed on lymphocytes, is critical in lymphocyte homing to the gut. The mucosal Addressin cell adhesion molecule 1/integrin α 4 β 7 pathway is involved in the pathogenesis of chronic intestinal inflammation by recruiting lymphocytes into inflamed gut. We explored the duodenal expression of mucosal Addressin cell adhesion molecule 1 and the peripheral T-cell expression of integrin α 4 β 7 in patients with celiac disease. Duodenal biopsies and a peripheral blood sample were collected from 15 celiac patients, before and after 12 months of gluten-free diet, and from 12 control subjects. Treated celiac biopsies were cultured with peptic-tryptic digest of gliadin and/or an anti–interferon α neutralizing antibody. Mucosal Addressin cell adhesion molecule 1 was determined by confocal immunofluorescence microscopy and immunoblotting. Integrin β 7 -positive T cells were analyzed by flow cytometry. Mucosal Addressin cell adhesion molecule 1 expression was significantly higher in active celiac disease than in normal mucosa. After gluten-free diet, a dramatic reduction of mucosal Addressin cell adhesion molecule 1 was also observed. No difference was seen between patients with celiac disease after treatment and controls. Ex vivo peptic-tryptic digest of gliadin challenge induced a marked increase of mucosal Addressin cell adhesion molecule 1 expression. Blocking interferon α inhibited the peptic-tryptic digest of gliadin–induced mucosal Addressin cell adhesion molecule 1 overexpression. The percentage of circulating β 7 -positive T cells was significantly lower in untreated celiac disease in comparison to controls but normalized after gluten-free diet. Mucosal Addressin cell adhesion molecule 1 is strongly up-regulated in active celiac disease dependent on interferon α and is associated with peripheral depletion of integrin α 4 β 7 -expressing T cells. We conclude that mucosal Addressin cell adhesion molecule 1 may represent an important determinant for the generation of mucosal damage in celiac disease.
