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Dysregulated mucosal immune responses in microscopic colitis patients
Örebro University, School of Medical Sciences.ORCID iD: 0000-0002-9635-0341
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC) is a common cause of chronic watery diarrhea. The diagnosis relies on typical histopathological changes observed upon microscopic examination. The studies in this thesis investigated innate and adaptive immune responses in the colonic mucosa of MC patients, also comparing patients with active disease (CC and LC) and histopathologically in remission (CC/LC-HR). We first analyzed expression of interleukin-1/Toll-like receptor (IL-1/TLR) signaling regulators in MC patients (Paper I). Our results showed enhanced IRAK-M, microRNA-146a, -155 and -21 expressions, whereas IL-37 gene expression was reduced in CC and LC patients as compared to non-inflamed controls. These results suggest different pathophysiological mechanisms in MC patients. The mixed inflammatory cell infiltrations seen in the lamina propria of MC patients might be a result of dysregulated expression of chemotactic mediators. In Paper II, we showed that MC patients display mainly an increased expression of chemokines and chemokine receptors in active disease as compared to noninflamed controls. In Paper III, we examined if the decreased IL-37 expression seen in Paper I could mediate the upregulation of chemokines seen in Paper II. We showed that a relatively small reduction in the ability of epithelial cells to produce IL-37 results in mainly increased chemokine expressions in a pattern similar to the findings in Paper II. In order to understand the nature of infiltrating T cells commonly observed in MC patients, we analyzed the T cell receptor (TCR) β chains in colonic biopsies of MC patients (Paper IV). Our results showed significant differences in TCRβ repertoire, which suggests selectively expanded T cell clones in active MC and histopathologically in remission patients. Altogether, these results i) increase the knowledge of MC pathogenesis by showing changes in TLR signaling regulators, enhanced chemokine and their receptor expressions involved in a mixed immune cell infiltrations and selectively expanded T cell clones in CC and LC patients, as well as in histopathological remission ii) might potentially increase the possibility of more target-specific therapies based on IL-37 induction, chemokines or chemokine receptor inhibitions, or hindering T cell infiltration according to TCR clonality.

Place, publisher, year, edition, pages
Örebro: Örebro university , 2016. , p. 102
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 132
Keyword [en]
Microscopic colitis, collagenous colitis, lymphocytic colitis, TLR, chemokine, chemokine receptor, IL-37, TCR
National Category
Immunology in the medical area Other Basic Medicine
Research subject
Immunology; Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-47390ISBN: 978-91-7529-118-5 (print)OAI: oai:DiVA.org:oru-47390DiVA, id: diva2:893689
Public defence
2016-03-04, Campus USÖ, Örebro universitet, hörsal C2, Södra Grev Rosengatan, Örebro, 09:00 (English)
Opponent
Supervisors
Available from: 2016-01-13 Created: 2016-01-13 Last updated: 2018-01-10Bibliographically approved
List of papers
1. Differential expression of interleukin-1/Toll-like receptor signaling regulators in microscopic and ulcerative colitis
Open this publication in new window or tab >>Differential expression of interleukin-1/Toll-like receptor signaling regulators in microscopic and ulcerative colitis
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2014 (English)In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 20, no 34, p. 12249-12259Article in journal (Refereed) Published
Abstract [en]

AIM: To investigate Toll-like receptor (TLR) signaling regulators in microscopic and ulcerative colitis patients.

METHODS: Total RNA and microRNA were isolated from fresh frozen colonic biopsies of non-inflamed controls and patients with active or in-remission collagenous colitis (CC), lymphocytic colitis (LC), or ulcerative colitis (UC). We compared expressions of interleukin-1 receptor-associated kinase (IRAK)-2, IRAK-M, interleukin (IL)-37, microRNA (miR)-146a, miR-155, and miR-21 using quantitative real time reverse transcription polymerase chain reaction.

RESULTS: IRAK-M expression was increased in LC patients with active disease in histopathological remission (LC-HR; P = 0.02) and UC patients (P = 0.01), but no differences in IRAK-2 expression were detected compared to controls. miR-146a, -155 and -21 expressions were increased in LC-HR (P = 0.04, 0.07, and 0.004) and UC (P = 0.02, 0.04 and 0.03) patients. miR-146a and miR-21 expressions were significantly enhanced in UC patients compared to UC remission (UC-R; P = 0.01 and 0.04). Likewise, active CC patients showed significantly increased expression of miR-155 (P = 0.003) and miR-21 (P = 0.006). IL-37 expression was decreased in both CC (P = 0.03) and LC (P = 0.04) patients with a similar trend in UC patients but not statistically significant, whilst it was increased in UC-R patients compared to controls (P = 0.02) and active UC (P = 0.001).

CONCLUSION: The identification of differentially expressed miRNAs, IL-37, and IRAK-M suggests different pathophysiologic mechanisms in various disease stages in LC, CC, and UC. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

Place, publisher, year, edition, pages
WJG Press, 2014
Keyword
Interleukin-37, MicroRNA, Lymphocytic colitis, Collagenous colitis, Ulcerative colitis
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-37676 (URN)10.3748/wjg.v20.i34.12249 (DOI)000341719100033 ()2-s2.0-84909606787 (Scopus ID)
Note

Funding Agencies:

Research Committee of Örebro County Council

Örebro University

Available from: 2014-10-13 Created: 2014-10-13 Last updated: 2017-12-05Bibliographically approved
2. Enhanced levels of chemokines and their receptors in the colon of microscopic colitis patients indicate mixed immune cell recruitment
Open this publication in new window or tab >>Enhanced levels of chemokines and their receptors in the colon of microscopic colitis patients indicate mixed immune cell recruitment
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2015 (English)In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 132458Article in journal (Refereed) Published
Abstract [en]

Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC), is a common cause of chronic diarrhea. Various immune cell infiltrations in the epithelium and lamina propria are seen in MC immunopathology. We compared gene and protein expressions of different immune cell attracting chemokines and their receptors in colon biopsies from MC patients in active disease or histopathological remission (CC/LC-HR) with controls, using qRT-PCR and Luminex, respectively. CC and LC patients with active disease demonstrated a mixed chemokine profile with significantly enhanced gene and/or protein expressions of the chemokines CCL2, CCL3, CCL4, CCL5, CCL7, CCL22, CXCL8, CXCL9, CXCL10, CXCL11, and CX(3)CL1 and the receptors CCR2, CCR3, CCR4, CXCR1, CXCR2, and CX(3)CR1. Enhanced chemokine/chemokine receptor gene and protein levels in LC-HR patients were similar to LC patients, whereas CC-HR patients demonstrated almost normalized levels. These findings expand the current understanding of the involvement of various immune cells in MC immunopathology and endorse chemokines as potential diagnostic markers as well as therapeutic candidates. Moreover, this study further supports the hypothesis that CC and LC are two different entities due to differences in their immunoregulatory responses.

National Category
Cell and Molecular Biology Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:oru:diva-44605 (URN)10.1155/2015/132458 (DOI)000353128700001 ()2-s2.0-84928473938 (Scopus ID)
Note

Funding Agencies:

Örebro University Hospital Research Foundation (Nyckelfonden)

Research Committee, Orebro County Council

Örebro University

Available from: 2015-05-12 Created: 2015-05-12 Last updated: 2018-01-11Bibliographically approved
3. Reduced Il-37 production increases the spontaneous chemokine expressions in colon epithelial cells
Open this publication in new window or tab >>Reduced Il-37 production increases the spontaneous chemokine expressions in colon epithelial cells
(English)Manuscript (preprint) (Other academic)
National Category
Other Basic Medicine
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-47897 (URN)
Available from: 2016-02-02 Created: 2016-02-02 Last updated: 2018-01-10Bibliographically approved
4. Oligoclonal T cell receptor repertoire in colonic biopsies of microscopic and ulcerative colitis patients
Open this publication in new window or tab >>Oligoclonal T cell receptor repertoire in colonic biopsies of microscopic and ulcerative colitis patients
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(English)Manuscript (preprint) (Other academic)
National Category
Other Basic Medicine
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-47898 (URN)
Available from: 2016-02-02 Created: 2016-02-02 Last updated: 2018-01-10Bibliographically approved

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