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Microscopic colitis patients demonstrate a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile
Örebro University, School of Health and Medical Sciences.
Örebro University, School of Health and Medical Sciences.
Örebro University, School of Health and Medical Sciences. Örebro University Hospital.
School of Health and Medical Sciences, Örebro University, Örebro, Sweden; Region Örebro County, Örebro, Sweden.
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2013 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 55, no 3-4, p. 355-364Article in journal (Refereed) Published
Abstract [en]

Background:

Microscopic colitis (MC) is a chronic inflammatory bowel disorder of unknown aetiology comprising collagenous colitis (CC) and lymphocytic colitis (LC). Data on the local cytokine profile in MC is limited. This study investigated the T helper (Th) cell and cytotoxic T lymphocyte (CTL) mucosal cytokine profile at messenger and protein levels in MC patients.

Methods:

Mucosal biopsies from CC (n = 10), LC (n = 5), and CC or LC patients in histopathological remission (CC-HR, n = 4), (LC-HR, n = 6), ulcerative colitis (UC, n = 3) and controls (n = 10) were analysed by real-time PCR and Luminex for expression/production of IL-1 beta, -4, -5, -6, -10, -12, -17, -21, -22, -23, IFN-gamma, TNF-alpha, T-bet and RORC2.

Results:

Mucosal mRNA but not protein levels of IFN-gamma and IL-12 were significantly up regulated in CC, LC as well as UC patients compared to controls. Transcription of the Th1 transcription factor T-bet was significantly enhanced in CC but not LC patients. mRNA levels for IL-17A, IL-21, IL-22 and IL-6 were significantly up regulated in CC and LC patients compared to controls, albeit less than in UC patients. Significantly enhanced IL-21 protein levels were noted in both CC and LC patients. IL-6 protein and IL-1 beta mRNA levels were increased in CC and UC but not LC patients. Increased mucosal mRNA levels of IFN-gamma, IL-21 and IL-22 were correlated with higher clinical activity, recorded as the number of bowel movements per day, in MC patients.

Although at lower magnitude, IL-23A mRNA was upregulated in CC and LC, whereas TNF-alpha protein was increased in CC, LC as well as in UC patients.

Neither mRNA nor protein levels of IL-4, IL-5 or IL-10 were significantly changed in any of the colitis groups. LC-HR and especially CC-HR patients had normalized mRNA and protein levels of the above cytokines compared to LC and CC patients. No significant differences were found between LC and CC in cytokine expression/production.

Conclusion:

LC and CC patients demonstrate a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile.

Place, publisher, year, edition, pages
2013. Vol. 55, no 3-4, p. 355-364
Keywords [en]
T cells, Mucosal cytokines, Microscopic colitis, Collagenous colitis, Lymphocytic colitis
National Category
Immunology in the medical area
Research subject
Medicine
Identifiers
URN: urn:nbn:se:oru:diva-29849DOI: 10.1016/j.molimm.2013.03.007ISI: 000319540200020OAI: oai:DiVA.org:oru-29849DiVA, id: diva2:634111
Available from: 2013-06-28 Created: 2013-06-28 Last updated: 2018-05-19Bibliographically approved
In thesis
1. Adaptive immune response in the intestinal mucosa of microscopic colitis patients
Open this publication in new window or tab >>Adaptive immune response in the intestinal mucosa of microscopic colitis patients
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Microscopic colitis (MC) is a chronic diarrhoeal disease of unknown aetiology, comprising collagenous colitis (CC) and lymphocytic colitis (LC). The nature of the adaptive local immune responses in the mucosa of MC patients is however far from elucidated. The present study investigates phenotypic and functional characteristics of the adaptive local immune responses in the colonic mucosa of these patients.

Our immunohistochemistry and flow cytometry studies (Paper I & II) demonstrated increased frequencies of CD8+ T cells in the colonic epithelium and lamina propria of both LC and CC patients compared to controls, whereas the frequencies of CD4+ T cells were unaltered or reduced. Our flow cytometry data revealed increased local activation of both CD4+ and CD8+ T cells in the lamina propria as well as the intraepithelial compartment of CC and LC patients compared to controls, demonstrated as increased proportions of these cells expressing the active/memory marker CD45RO and the proliferation marker Ki67.

Analysis of recent thymic emigrants by measuring T cell receptor excision circle (TREC) levels in the colonic mucosa of CC and LC patients revealed reduced TRECs levels in these patients compared to controls (Paper III). These results suggests that the observed increased numbers of T cells in the mucosa of CC and LC patients is due to the expansion of local resident T cells rather than direct recruitment of recent thymic emigrants to the mucosa.

Molecular analysis of T helper (Th) cell and cytotoxic T lymphocyte (Tc) mucosal cytokines at messenger and protein levels in the colonic biopsies from CC and LC patients demonstrated a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile and revealed significant differences in the mucosal cytokine levels in CC and LC patients compared to controls (Paper IV).

Finally, we have set up an in vitro model to investigate how the colonic milieu affects the activation and differentiation of T lymphocytes (Paper V). Our preliminary data indicate increased production of both pro inflammatory and antiinflammatory cytokines by peripheral blood T cells in the presence of soluble factors from the inflamed colonic mucosa of CC patients compared to controls.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2013. p. 83
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 84
Keywords
Microscopic colitis, collagenous colitis, lymphocytic colitis, intraepithelial lymphocytes, lamina propria lymphocytes, T cell receptor excision circle, T helper cells, cytotoxic T lymphocyte and mucosal cytokines
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-27894 (URN)978-91-7668-929-5 (ISBN)
Public defence
2013-05-24, Hörsal P2, Prismahuset, Örebro universitet, Fakultetsgatan 1, Örebro, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-03-18 Created: 2013-03-11 Last updated: 2017-10-17Bibliographically approved

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