Altered immune system glycosylation causes colitis in alpha1,2-fucosyltransferase transgenic mice

Steven J Brown, Ashley M Miller, Peter J Cowan, John L Slavin, William R Connell, Gregory Thomas Charles Moore, Sally Bell, P Ross Elliot, Paul V Desmond, Anthony JF d'Apice

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Abstract

Altered glycosylation of the mucosal barrier has been proposed as a primary defect in the pathogenesis of IBD. Glycosylation defects however may also have a profound influence on immune function. Mice transgenic for human alpha1,2-fucosyl-transferase (hFUT1) have widespread disturbances in cell surface glycosylation and spontaneously develop colitis. The aims of this study were to characterize colitis in hFUT1 mice and to determine whether glycosylation-induced changes of the mucosal barrier or the immune system were critical for its pathogenesis. METHODS: The pathologic features of hFUT1 transgenic mice were characterized. The mucosal barrier was assessed by lectin binding and permeability studies. T-cells and the thymus were assessed by FACS analysis and histology. To isolate the hFUT1 mucosal barrier from the hFUT1 immune system, bone marrow chimeras were generated. RESULTS: Seventy percent of hFUT1 mice raised in SPF conditions developed histologic evidence of colitis. The mucosal barrier demonstrated altered glycosylation but intestinal permeability was preserved. HFUT1 mice were profoundly lymphopenic, with aberrant T-cell markers and thymic medullary hypoplasia. Reconstitution with wild type bone marrow restored thymic morphology and prevented colitis in hFUT1 mice. CONCLUSION: Altered glycosylation in hFUT1 mice has a profound influence on T-cell development and this defect, rather than a mucosal barrier defect, is crucial for the development of colitis
Original languageEnglish
Pages (from-to)546 - 556
Number of pages11
JournalInflammatory Bowel Diseases
Volume10
Issue number5
DOIs
Publication statusPublished - 2004

Cite this

Brown, Steven J ; Miller, Ashley M ; Cowan, Peter J ; Slavin, John L ; Connell, William R ; Moore, Gregory Thomas Charles ; Bell, Sally ; Elliot, P Ross ; Desmond, Paul V ; d'Apice, Anthony JF. / Altered immune system glycosylation causes colitis in alpha1,2-fucosyltransferase transgenic mice. In: Inflammatory Bowel Diseases. 2004 ; Vol. 10, No. 5. pp. 546 - 556.
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title = "Altered immune system glycosylation causes colitis in alpha1,2-fucosyltransferase transgenic mice",
abstract = "Altered glycosylation of the mucosal barrier has been proposed as a primary defect in the pathogenesis of IBD. Glycosylation defects however may also have a profound influence on immune function. Mice transgenic for human alpha1,2-fucosyl-transferase (hFUT1) have widespread disturbances in cell surface glycosylation and spontaneously develop colitis. The aims of this study were to characterize colitis in hFUT1 mice and to determine whether glycosylation-induced changes of the mucosal barrier or the immune system were critical for its pathogenesis. METHODS: The pathologic features of hFUT1 transgenic mice were characterized. The mucosal barrier was assessed by lectin binding and permeability studies. T-cells and the thymus were assessed by FACS analysis and histology. To isolate the hFUT1 mucosal barrier from the hFUT1 immune system, bone marrow chimeras were generated. RESULTS: Seventy percent of hFUT1 mice raised in SPF conditions developed histologic evidence of colitis. The mucosal barrier demonstrated altered glycosylation but intestinal permeability was preserved. HFUT1 mice were profoundly lymphopenic, with aberrant T-cell markers and thymic medullary hypoplasia. Reconstitution with wild type bone marrow restored thymic morphology and prevented colitis in hFUT1 mice. CONCLUSION: Altered glycosylation in hFUT1 mice has a profound influence on T-cell development and this defect, rather than a mucosal barrier defect, is crucial for the development of colitis",
author = "Brown, {Steven J} and Miller, {Ashley M} and Cowan, {Peter J} and Slavin, {John L} and Connell, {William R} and Moore, {Gregory Thomas Charles} and Sally Bell and Elliot, {P Ross} and Desmond, {Paul V} and d'Apice, {Anthony JF}",
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Brown, SJ, Miller, AM, Cowan, PJ, Slavin, JL, Connell, WR, Moore, GTC, Bell, S, Elliot, PR, Desmond, PV & d'Apice, AJF 2004, 'Altered immune system glycosylation causes colitis in alpha1,2-fucosyltransferase transgenic mice', Inflammatory Bowel Diseases, vol. 10, no. 5, pp. 546 - 556. https://doi.org/10.1097/00054725-200409000-00008

Altered immune system glycosylation causes colitis in alpha1,2-fucosyltransferase transgenic mice. / Brown, Steven J; Miller, Ashley M; Cowan, Peter J; Slavin, John L; Connell, William R; Moore, Gregory Thomas Charles; Bell, Sally; Elliot, P Ross; Desmond, Paul V; d'Apice, Anthony JF.

In: Inflammatory Bowel Diseases, Vol. 10, No. 5, 2004, p. 546 - 556.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Altered immune system glycosylation causes colitis in alpha1,2-fucosyltransferase transgenic mice

AU - Brown, Steven J

AU - Miller, Ashley M

AU - Cowan, Peter J

AU - Slavin, John L

AU - Connell, William R

AU - Moore, Gregory Thomas Charles

AU - Bell, Sally

AU - Elliot, P Ross

AU - Desmond, Paul V

AU - d'Apice, Anthony JF

PY - 2004

Y1 - 2004

N2 - Altered glycosylation of the mucosal barrier has been proposed as a primary defect in the pathogenesis of IBD. Glycosylation defects however may also have a profound influence on immune function. Mice transgenic for human alpha1,2-fucosyl-transferase (hFUT1) have widespread disturbances in cell surface glycosylation and spontaneously develop colitis. The aims of this study were to characterize colitis in hFUT1 mice and to determine whether glycosylation-induced changes of the mucosal barrier or the immune system were critical for its pathogenesis. METHODS: The pathologic features of hFUT1 transgenic mice were characterized. The mucosal barrier was assessed by lectin binding and permeability studies. T-cells and the thymus were assessed by FACS analysis and histology. To isolate the hFUT1 mucosal barrier from the hFUT1 immune system, bone marrow chimeras were generated. RESULTS: Seventy percent of hFUT1 mice raised in SPF conditions developed histologic evidence of colitis. The mucosal barrier demonstrated altered glycosylation but intestinal permeability was preserved. HFUT1 mice were profoundly lymphopenic, with aberrant T-cell markers and thymic medullary hypoplasia. Reconstitution with wild type bone marrow restored thymic morphology and prevented colitis in hFUT1 mice. CONCLUSION: Altered glycosylation in hFUT1 mice has a profound influence on T-cell development and this defect, rather than a mucosal barrier defect, is crucial for the development of colitis

AB - Altered glycosylation of the mucosal barrier has been proposed as a primary defect in the pathogenesis of IBD. Glycosylation defects however may also have a profound influence on immune function. Mice transgenic for human alpha1,2-fucosyl-transferase (hFUT1) have widespread disturbances in cell surface glycosylation and spontaneously develop colitis. The aims of this study were to characterize colitis in hFUT1 mice and to determine whether glycosylation-induced changes of the mucosal barrier or the immune system were critical for its pathogenesis. METHODS: The pathologic features of hFUT1 transgenic mice were characterized. The mucosal barrier was assessed by lectin binding and permeability studies. T-cells and the thymus were assessed by FACS analysis and histology. To isolate the hFUT1 mucosal barrier from the hFUT1 immune system, bone marrow chimeras were generated. RESULTS: Seventy percent of hFUT1 mice raised in SPF conditions developed histologic evidence of colitis. The mucosal barrier demonstrated altered glycosylation but intestinal permeability was preserved. HFUT1 mice were profoundly lymphopenic, with aberrant T-cell markers and thymic medullary hypoplasia. Reconstitution with wild type bone marrow restored thymic morphology and prevented colitis in hFUT1 mice. CONCLUSION: Altered glycosylation in hFUT1 mice has a profound influence on T-cell development and this defect, rather than a mucosal barrier defect, is crucial for the development of colitis

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U2 - 10.1097/00054725-200409000-00008

DO - 10.1097/00054725-200409000-00008

M3 - Article

VL - 10

SP - 546

EP - 556

JO - Inflammatory Bowel Diseases

JF - Inflammatory Bowel Diseases

SN - 1078-0998

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