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Specific and nonspecific immune mechanisms in human gut: a comparative study of normal and ulcerative colitis intestine
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
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 [en]
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: urn:nbn:se:umu:diva-73387ISBN: 91-7191-235-5 (print)OAI: oai:DiVA.org:umu-73387DiVA: diva2:631314
Public defence
1996-11-08, Astrid Fagraeussalen (A103), Norrlands universitetssjukhus, Umeå, 10:00
Opponent
Supervisors
Available from: 2013-06-20 Created: 2013-06-20 Last updated: 2013-06-20Bibliographically approved
List of papers
1. Expression of carcinoembryonic antigen and nonspecific cross-reacting 50-kDa antigen in human normal and cancerous colon mucosa: comparative ultrastructural study with monoclonal antibodies
Open this publication in new window or tab >>Expression of carcinoembryonic antigen and nonspecific cross-reacting 50-kDa antigen in human normal and cancerous colon mucosa: comparative ultrastructural study with monoclonal antibodies
1994 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 54, no 12, 3305-3314 p.Article in journal (Refereed) Published
Abstract [en]

The precise localization of carcinoembryonic antigen (CEA) and non-specific cross-reacting 50-kDa antigen (NCA 50) in normal colon mucosa and colon adenocarcinoma was investigated by using an indirect immunoperoxidase electron microscopic technique with specific monoclonal antibodies. In normal adult colon both antigens were localized to microvesicles and filaments of the "fuzzy coat" on the apical surface of the epithelial cells. In addition, NCA 50 was found in the narrow spaces between adjoining microvilli. Mature columnar cells at the free luminal surface contained most of the antigen positive material. CEA and NCA 50 were also detected as intracellular components of goblet cells. In multilayered tumor glands, the cell surface expression of the antigens was dependent on the position of the tumor cell in the gland. The neoplastic cells showed either a predominant apical labeling or a positive staining of almost the entire cell surface. Some of the neoplastic cells contained CEA in so-called "intracellular lumina." In contrast to normal colon epithelial cells most tumor cells synthesized NCA 50 actively. In normal colonic mucosa, unlike in cancerous tissue, CEA and NCA 50 appear to be released via vesicles formed from the microvillous membrane of mature columnar cells. These results are consistent with the hypothesis that CEA and NCA play a role in the nonspecific defense against microorganisms in the large intestine.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-73381 (URN)8205554 (PubMedID)
Available from: 2013-06-20 Created: 2013-06-20 Last updated: 2017-12-06Bibliographically approved
2. Cell- and region-specific expression of biliary glycoprotein and its messenger RNA in normal human colonic mucosa
Open this publication in new window or tab >>Cell- and region-specific expression of biliary glycoprotein and its messenger RNA in normal human colonic mucosa
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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.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-73380 (URN)7606710 (PubMedID)
Available from: 2013-06-20 Created: 2013-06-20 Last updated: 2017-12-06Bibliographically approved
3. Intraepithelial lymphocytes in human gut have lytic potential and a cytokine profile that suggest T helper 1 and cytotoxic functions.
Open this publication in new window or tab >>Intraepithelial lymphocytes in human gut have lytic potential and a cytokine profile that suggest T helper 1 and cytotoxic functions.
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1996 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 157, no 5, 1926-34 p.Article in journal (Refereed) Published
Abstract [en]

The functional properties of intraepithelial lymphocytes (IEL) in normal human jejunum, ileum, and colon were investigated. Cytokine mRNA expression in IEL and enterocytes was determined by reverse transcriptase-PCR and IFN-gamma+ IEL by immunohistochemistry. Polyclonal activators were used to study proliferation and IFN-gamma secretion of IEL, and an anti-CD3-mediated redirected cytotoxicity assay was used to determine the lytic potential of IEL. Freshly isolated IEL at all three gut levels expressed mRNA for IL-1 beta, IL-2, IL-8, IFN-gamma, and TNF-alpha. Approximately 10% of IEL produced IFN-gamma, suggesting that IEL are immunologically active in vivo, performing similar functions along the intestine. IEL could be stimulated further in vitro to express IL-10, TNF-beta, and TGF-beta 1, while no Th2-type cytokines were induced, suggesting suppressive and cytolytic functions for IEL. All three jejunal IEL subpopulations (CD4-CD8-TCR-gamma delta+, CD4+TCR-alpha beta+, CD8+TCR-alpha beta+) expressed the same four cytokines, IL-2, IL-8, IFN-gamma, and TNF-alpha, indicating that CD4+TCR-alpha beta+ IEL are Th1 cells and that TCR-gamma delta+ IEL and CD8+TCR-alpha beta+ IEL include cytotoxic effector cells. Indeed, freshly isolated jejunal IEL displayed cytolytic activity. IEL were induced to proliferation by anti-CD3/TCR complex mAbs and leukoagglutinin, but not by Con A. There was no correlation between the magnitude of the proliferative response and the amounts of secreted IFN-gamma. Enterocytes expressed IL-1 beta and IL-8, and sometimes TNF-alpha. Although jejunal enterocytes express HLA-DR and hsp60, Ag presentation by these cells may induce anergy since their cytokine profile is different from that of classical APCs.

National Category
Immunology
Identifiers
urn:nbn:se:umu:diva-67900 (URN)8757311 (PubMedID)
Available from: 2013-04-07 Created: 2013-04-07 Last updated: 2017-12-06
4. A role for γδ T-cells in the pathogenesis of ulcerative colitis? Quantitative analysis of leukocytes in ulcerative colitis and normal colon.
Open this publication in new window or tab >>A role for γδ T-cells in the pathogenesis of ulcerative colitis? Quantitative analysis of leukocytes in ulcerative colitis and normal colon.
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-73383 (URN)
Available from: 2013-06-20 Created: 2013-06-20 Last updated: 2013-06-20Bibliographically approved
5. Colonic T-lymphocytes in patients with ulcerative colitis do not produce IL-2
Open this publication in new window or tab >>Colonic T-lymphocytes in patients with ulcerative colitis do not produce IL-2
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-73384 (URN)
Available from: 2013-06-20 Created: 2013-06-20 Last updated: 2013-06-20Bibliographically approved
6. Phenotypic characterization of epithelial cells in ulcerative colitis colon
Open this publication in new window or tab >>Phenotypic characterization of epithelial cells in ulcerative colitis colon
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-73385 (URN)
Available from: 2013-06-20 Created: 2013-06-20 Last updated: 2013-06-20Bibliographically approved

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