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


CONCLUSIONS
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.
Immunology Research Centre, St. Vincent's Hospital, Fitzroy, Victoria 3056, Australia.
Steven J
SJ
Brown
Ashley M
AM
Miller
Peter J
PJ
Cowan
John
J
Slavin
William R
WR
Connell
Gregory T
GT
Moore
Sally
S
Bell
P Ross
PR
Elliott
Paul V
PV
Desmond
Anthony J F
AJ
d'Apice
D000818:Animals; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology*; D005260:Female; D005647:Fucosyltransferases / Q000235:genetics* / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000097631:Galactoside 2-alpha-L-fucosyltransferase
D005647:Fucosyltransferases; D000097631:Galactoside 2-alpha-L-fucosyltransferase