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Polymorphonuclear Leukocytes from Individuals Carrying the G329A Mutation in the α1,3-Fucosyltransferase VII Gene (FUT7) Roll on E- and P-Selectins
Linköpings universitet, Institutionen för biomedicin och kirurgi, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för biomedicin och kirurgi, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
Department of Clinical Chemistry and Transfusion Medicine, Institute of Laboratory Medicine, Sahlgrenska University Hospital, Göteborg, Sweden .
Linköpings universitet, Institutionen för biomedicin och kirurgi, Klinisk kemi. Linköpings universitet, Hälsouniversitetet.
2002 (engelsk)Inngår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 169, nr 7, s. 3940-3946Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

We recently identified several individuals carrying a missense mutation (G329A; Arg110-Gln) in the FUT7 gene encoding fucosyltransferase VII. This enzyme is involved in the biosynthesis of the sialyl Lewis x (Lex) epitope on human leukocytes, which has been identified as an important component of leukocyte ligands for E- and P-selectin. No enzyme activity was measurable in expression studies in COS-7 cells using the mutated FUT7 construct. One of the identified individuals carried this mutation homozygously. Flow cytometry analysis of polymorphonuclear leukocytes (PMN) from this individual showed a nearly complete absence of staining with mAbs directed against sialyl Lex and a diminished staining with an E-selectin IgG chimera. However, staining with P-selectin IgG chimera and Abs directed against P-selectin glycoprotein ligand-1 was not affected by the mutation. PMN from the homozygously mutated individual was further analyzed in an in vitro flow chamber assay. The number of rolling PMN and the rolling velocities on both E- and P-selectin were in the range of PMN from nonmutated individuals. FUT4 and FUT7 mRNA was quantified in PMN isolated from individuals carrying the FUT7 mutation. It was found that PMN from both FUT7 homozygously and heterozygously mutated individuals exhibited an elevated expression of FUT4 mRNA compared with PMN from FUT7 nonmutated individuals. The elevated expression of fucosyltransferase IV was reflected as an increased expression of the Lex and CD65s Ags on PMN from these individuals. The significance of the mutation was supported by transfection of BJAB cells.

sted, utgiver, år, opplag, sider
2002. Vol. 169, nr 7, s. 3940-3946
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-24924Lokal ID: 9329OAI: oai:DiVA.org:liu-24924DiVA, id: diva2:245248
Tilgjengelig fra: 2009-10-07 Laget: 2009-10-07 Sist oppdatert: 2017-12-13bibliografisk kontrollert
Inngår i avhandling
1. Carbohydrate dependent adhesion of leukocytes and the role of fucosyltransferase VII
Åpne denne publikasjonen i ny fane eller vindu >>Carbohydrate dependent adhesion of leukocytes and the role of fucosyltransferase VII
2003 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Galectins, E-and P-selectins are carbohydrate-binding proteins that are up regulated at inflammatory lesions. Selectins expressed ou the activated endothelium mediate transient binding to leukocyte ligands that require sequential action of α 2,3-sialyltransferases and a 1,3-fucosyltransferases. ln leukocytes α1,3 fucosyltransferase VII adds fucose to α 2,3- sialylated lactosarnine acceptors in the final step of the biosynthesis of the selectin binding epitope sialyl Lewis x.

The finding of low sialyl Lewis x expression in polymorphonuclear leukocytes from a patient with ulcerative colitis led to the discovery of a missense mutation (G329A) in the human gene coding for α1,3 fucosyltransferase VII, FUT7. Studies including enzymatic and immunochemical analysis oftransfected cell lines and isolated polymorphonuclear leukocytes from patients confirmed that this mutation impair the ability of α1,3 fucosyltransferase VII to synthesize sialyl Lewis x. The frequency of the mutation were measured in a mixed Swedish population and found to be -1 %. One individual carrying the FUT7-G329A mutation homozygously was identified. This individual suffered from ulcer disease, noninsulin-dependent diabetes, osteoporosis, spondyloarthrosis, and Sjögren's syndrome, but the relationship between disease and the mutation is not established.

Studies using an in vitro flow chamber assay showed that transfected B-lymphoma cells and Epstein-Barr virus transformed B cells only transcribing FUT7-G329A were not able to interact with E-selectin during flow whereas polymorphonuclear leukocytes from the FUT7-G329A homozygous individual interacted well with both P- and E selectin during flow. The mRNA level of the fucosyltransferase IV coding gene, FUT4, was found to be elevated in the homozygous individual, which resulted in elevated levels ofthe CD65s epitope. However, transfected B-lymphoma cells and Epstein- Barr virus transformed cells did not show a similar elevation of FUT4 mRNA. In in vitro studies galectin-1 and- 3 were observed to be able to recruit polymorphonuclear leukocytes during flow. This thesis gives further insight into the molecular mechanisms leading to carbohydrate dependent dynamic adhesion between polymorphonuclear leukocytes and lectins during inflammation.

sted, utgiver, år, opplag, sider
Linköping: Linköpings universitet, 2003. s. 41
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 762
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-25551 (URN)9999 (Lokal ID)91-7373-204-4 (ISBN)9999 (Arkivnummer)9999 (OAI)
Disputas
2003-03-28, Berzeliussalen, Universitetssjukhuset, 13:00 (svensk)
Opponent
Tilgjengelig fra: 2009-10-07 Laget: 2009-10-07 Sist oppdatert: 2012-09-24bibliografisk kontrollert

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