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Cell- and region-specific expression of biliary glycoprotein and its messenger RNA in normal human colonic mucosa
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
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1995 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 55, no 14, 2963-2967 p.Article in journal (Refereed) Published
Abstract [en]

The localization of biliary glycoprotein (BGP) and its mRNA in normal colonic mucosa was studied by immunohistochemistry and in situ hybridization. BGP mRNA was confined to columnar epithelial cells and expressed abundantly in the superficial mature cells and at low levels in differentiating cells in the upper crypts. Epithelial expression of BGP coincided with that of BGP mRNA. Ultrastructurally, BGP was localized to microfilaments of the fuzzy coat of the columnar cells at the luminal surface and the upper crypts. Additionally, BGP was found in cryptal caveolated cells. The results are consistent with primary transcriptional regulation of BGP production and suggest that BGP synthesis is controlled by the degree of cytodifferentiation. The fuzzy-coat localization of BGP implies a role in nonspecific defense mechanisms against pathogens.

Place, publisher, year, edition, pages
1995. Vol. 55, no 14, 2963-2967 p.
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-73380PubMedID: 7606710OAI: oai:DiVA.org:umu-73380DiVA: diva2:631232
Available from: 2013-06-20 Created: 2013-06-20 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Specific and nonspecific immune mechanisms in human gut: a comparative study of normal and ulcerative colitis intestine
Open this publication in new window or tab >>Specific and nonspecific immune mechanisms in human gut: a comparative study of normal and ulcerative colitis intestine
1996 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The intestine, with its large mucosal surface area, digests and absorbs food nutrients and maintains a beneficial microbial flora in the colon. Local protective immune responses against intestinal pathogens ensure the survival of the individual. These immune reactions are both specific and non-specific in nature. The intestinal epithelium is single-layered and constantly renewed with differentiating epithelial cells moving from the crypt to the luminal surface. Intraepithelial lymphocytes (IEL) are interspersed between the epithelial cells. Ulcerative colitis (UC) is a life-threatening chronic inflammation affecting colon.

In this study three molecules belonging to the carcinoembryonic antigen (CEA) family, namely CEA proper, nonspecific cross-reacting antigen 50/90 (NCA 50/90) and biliary glycoprotein (BGP), were found to be specifically localized to the apical surface of colonic epithelial cells. Full expression of these molecules occurs when the cells reach the upper 1/3 of the crypts and are maintained on the mature cells at the luminal surface. Ultrastructurally, CEA, NCA50/90 and BGP are localized to microvesicles and microfilaments of the fuzzy coat/glycocalyx as well as to the microvilli of the epithelial cells. Their unique localization and documented bacterial binding capacities suggest that they have a role in innate immunity.

Functional analysis of IEL in normal jejunum, ileum and colon revealed that IEL are in vivo activated T-lymphocytes expressing mRNA for the cytokines IL-1β, IL-2, IL-8, IFNγ and TNFα and that jejunal IEL have T-cell receptor (TCR)/CD3 dependent cytolytic capacity. As many as 10% of IEL actively produce IFNγ. CD4+TCRαβ+IEL, CD8+TCRαβ+IEL and CD4-CD8-TCRαβ+IEL all had a TH1/cytotoxic cytokine profile. IEL could be further stimulated in vitro to express IL-10, TNFβ and TGFβ1, to proliferate and to secrete IFNγ. Thus, active protection and/or regulation of the epithelium via cell-mediated immune reactions are prominent in the gut.

UC colon was characterized by a marked lymphocyte infiltration in the lamina propria, 10-50 times the normal level. Most lymphocytes were present in follicle-like cell aggregates containing both T- and B-cells. An unexpected finding was that γδT-cells constituted about 15% of the cells in the aggregates. Such cells are only found intraepithelially in normal gut. γδT-cells of both the intestinal- (TCR-Vδ1/Vγ8) and blood type (TCR-Vδ2/Vγ9) were seen. T-cells in UC colon were activated but nonproliferating and had a down-regulated TCR/CD3 complex. RT-PCR and quantitative immunohistochemistry for cytokine mRNA (n=11) and protein respectively, revealed that the T-cells in UC colon did not produce IL-2, in marked contrast to T-cells in normal colon and to ileal T-cells from UC patients. This was a selective defect since TNFα, IFNγ, IL-1β, IL-8 and TGFβ1 were similarly expressed in normal colon. No TH2 cytokines were seen. Lamina propria leukocytes in UC colon expressed IL-6, a cytokine not found in normal colon. The epithelial cells of UC colon were activated expressing MHC class II antigens, heat shock proteins and the co-stimulatory molecule B7.1/CD80.

Our study demonstrates that UC is an immunological disease. The immunopathological picture seen in UC colon probably reflects an inappropriate down-regulation of local immune responses perhaps due to a selective loss of the key cytokine IL-2 in a situation of extreme antigenic stress.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 1996. 95 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 485
Keyword
human intestine, ulcerative colitis, lymphoid aggregates, intraepithelial lymphocytes, lamina propria lymphocytes, γδT-cells, cytokines, IL-2, carcinoembryonic antigen, biliary glycoprotein, epithelial cells, glycocalyx
National Category
Cancer and Oncology Gastroenterology and Hepatology
Identifiers
urn:nbn:se:umu:diva-73387 (URN)91-7191-235-5 (ISBN)
Public defence
1996-11-08, Astrid Fagraeussalen (A103), Norrlands universitetssjukhus, Umeå, 10:00
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Available from: 2013-06-20 Created: 2013-06-20 Last updated: 2013-06-20Bibliographically approved

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