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Gunaltay, S., Repsilber, D., Helenius, G., Nyhlin, N., Bohr, J., Hultgren, O. & Hultgren Hörnquist, E. (2017). Oligoclonal T-cell Receptor Repertoire in Colonic Biopsies of Patients with Microscopic Colitis and Ulcerative Colitis. Inflammatory Bowel Diseases, 23(6), 932-945
Open this publication in new window or tab >>Oligoclonal T-cell Receptor Repertoire in Colonic Biopsies of Patients with Microscopic Colitis and Ulcerative Colitis
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2017 (English)In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 23, no 6, p. 932-945Article in journal (Refereed) Published
Abstract [en]

Background: Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC), is a type of variation of inflammatory bowel diseases. Local T-cell infiltration in the mucosa plays a major role in MC immunopathology.

Methods: To understand diversity and clonality of infiltrating T cells, we analyzed the T-cell receptor beta (TCR beta) chains in colonic biopsies of MC, ulcerative colitis (UC), and their remission counterparts (CC/LC-HR [histological remission] or UC-R [remission]) compared with patients with non-inflamed colons using next-generation sequencing.

Results: Compared with controls and patients with CC, patients with LC had significantly lower diversity with significantly lower evenness and richness in TCRVb-Jb gene segments. Similarly, patients with LC-HR had lower diversity because of significantly lower TCRVb-Jb clone richness. Patients with UC and UC-R showed significantly higher diversity and richness. Univariate and multivariate analyses were performed to identify TCRVb-Jb gene segments differentiating disease types from controls or their remission counterparts. Patients with LC were discriminated from controls by 12 clones and from patients with CC by 8 clones. Neither univariate nor multivariate analyses showed significance for patients with CC or CC-HR compared with controls. Patients with UC and UC-R had 16 and 14 discriminating clones, respectively, compared with controls.

Conclusions: Altogether, patients with MC and UC showed an oligoclonal TCRb distribution. TCRVb-Jb clone types and their diversity were distinctive between patients with CC and LC, as well as for patients with UC, suggesting different pathophysiological mechanisms according to disease type and stage. This study suggests that CC and LC are different entities because of differences in immunoregulatory responses, as mirrored by their T-cell repertoire.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2017
Keywords
collagenous colitis, lymphocytic colitis, next-generation sequencing, ulcerative colitis, T-cell repertoire analysis
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-59319 (URN)10.1097/MIB.0000000000001127 (DOI)000405609200014 ()28498152 (PubMedID)2-s2.0-85019705487 (Scopus ID)
Note

Funding Agencies:

Swedish Society of Medicine (Bengt Ihre Foundation)  SLS-176271/2011  98031/2010 

Örebro University Hospital Research Foundation (Nyckelfonden)  

Research Committee, Örebro County Council  

Örebro University 

Available from: 2017-08-25 Created: 2017-08-25 Last updated: 2018-09-04Bibliographically approved
Jayaprakash, K., Demirel, I., Gunaltay, S., Khalaf, H. & Bengtsson, T. (2017). PKC, ERK/p38 MAP kinases and NF-B targeted signalling play a role in the expression and release of IL-1β  and CXCL8 in Porphyromonas gingivalis-infected THP1 cells. Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), 125(7), 623-633
Open this publication in new window or tab >>PKC, ERK/p38 MAP kinases and NF-B targeted signalling play a role in the expression and release of IL-1β  and CXCL8 in Porphyromonas gingivalis-infected THP1 cells
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2017 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 125, no 7, p. 623-633Article in journal (Refereed) Published
Abstract [en]

Porphyromonas gingivalis is a keystone pathogen in periodontitis and is gaining importance in cardiovascular pathogenesis. Protease-activated receptors (PARs), toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD) on monocytes recognize the structural components on P. gingivalis, inducing inflammatory intermediates. Here, we elucidate the modulation of PARs, TLRs, NODs, and the role of MAPK and NF-B in IL-1 and CXCL8 release. THP1 cells were stimulated with P. gingivalis wild-type W50 and its isogenic gingipain mutants: Rgp mutant E8 and Kgp mutant K1A. We observed modulation of PARs, TLRs, NOD, IL-1 and CXCL8 expression by P. gingivalis. Gingipains hydrolyse IL-1 and CXCL8, which is more evident for IL-1 accumulation at 24 h. Inhibition of PKC (protein kinase C), p38 and ERK (extracellular signal-regulated kinases) partially reduced P. gingivalis-induced IL-1 at 6 h, whereas PKC and ERK reduced CXCL8 at both 6 and 24 h. Following NF-B inhibition, P. gingivalis-induced IL-1 and CXCL8 were completely suppressed to basal levels. Overall, TLRs, PARs and NOD possibly act in synergy with PKC, MAPK ERK/p38 and NF-B in P. gingivalis-induced IL-1 and CXCL8 release from THP1 cells. These pro-inflammatory cytokines could affect leucocytes in circulation and exacerbate other vascular inflammatory conditions such as atherosclerosis.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
Keywords
THP1 cells, Porphyromonas gingivalis, chemokine ligand 8, interleukin-1, protease-activated receptors
National Category
Immunology in the medical area Microbiology in the medical area Cancer and Oncology
Identifiers
urn:nbn:se:oru:diva-58945 (URN)10.1111/apm.12701 (DOI)000403476400003 ()28493507 (PubMedID)2-s2.0-85019056141 (Scopus ID)
Funder
Swedish Heart Lung FoundationKnowledge Foundation
Note

Funding Agency:

Foundation of Olle Engkvist

Available from: 2017-08-18 Created: 2017-08-18 Last updated: 2018-01-13Bibliographically approved
Günaltay, S., Ghiboub, M., Hultgren, O. & Hultgren Hörnquist, E. (2017). Reduced IL-37 Production Increases Spontaneous Chemokine Expressions in Colon Epithelial Cells. Digestive Diseases and Sciences, 62(5), 1204-1215
Open this publication in new window or tab >>Reduced IL-37 Production Increases Spontaneous Chemokine Expressions in Colon Epithelial Cells
2017 (English)In: Digestive Diseases and Sciences, ISSN 0163-2116, E-ISSN 1573-2568, Vol. 62, no 5, p. 1204-1215Article in journal (Refereed) Published
Abstract [en]

Background and Aim: Microscopic colitis, comprising collagenous colitis and lymphocytic colitis, is a common cause of chronic diarrhea. Previously, we showed enhanced chemokine productions in microscopic colitis patients, indicating dysregulated immune cell chemotaxis in the immunopathogenesis. We also showed decreased mRNA of IL-37, mainly regarded as an anti-inflammatory cytokine, in the colonic mucosa of these patients, potentially an important factor for the chronicity of the colitis. Our aim in this study was to understand the possible role of IL-37 in chemokine production using a cell line model.

Methods: A colon epithelial cell line, T84, was stimulated with the TLR5 ligand flagellin. IL-37 protein production was reduced 20% using the CRISPR/Cas9 system, and the changes in chemokine mRNA and protein expressions were compared to cells transfected with empty plasmid.

Results: The 20% reduction in IL-37 protein levels spontaneously increased CCL5, CXCL8, CXCL10, and CXCL11 mRNA and protein expressions. CCL2 mRNA and protein levels were enhanced upon TLR5 stimulation. CCL3, CCL20, and CX3CL1 mRNA expressions were increased either spontaneously or following TLR5 stimulation, whereas CCL4 and CCL22 mRNA expressions were significantly decreased.

Conclusions: Even a minor decrease in the ability of colon epithelial cells to produce IL-37 results in altered chemokine expression, mainly an increase in the production of several chemokines. Our results indicate that a decreased IL-37 expression by colon epithelial cells may be an important factor for increasing the recruitment of immune cells and subsequently developing microscopic colitis.

Place, publisher, year, edition, pages
Springer, 2017
Keywords
IL-37, Chemokines, CRISPR/Cas9
National Category
Immunology Gastroenterology and Hepatology
Identifiers
urn:nbn:se:oru:diva-54389 (URN)10.1007/s10620-016-4422-9 (DOI)000399814900016 ()28044228 (PubMedID)2-s2.0-85007553244 (Scopus ID)
Note

Funding Agencies:

Swedish Society of Medicine (Bengt Ihre Foundation)  SLS-176271/2011  98031/2010 

Örebro University Hospital Research Foundation (Nyckelfonden)  

Örebro County Council Research Committee  

Örebro University 

Available from: 2017-02-07 Created: 2017-01-10 Last updated: 2018-07-30Bibliographically approved
Günaltay, S. (2016). Dysregulated mucosal immune responses in microscopic colitis patients. (Doctoral dissertation). Örebro: Örebro university
Open this publication in new window or tab >>Dysregulated mucosal immune responses in microscopic colitis patients
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
Keywords
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:nbn:se:oru:diva-47390 (URN)978-91-7529-118-5 (ISBN)
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
Gunaltay, S., Kumawat, A. K., Nyhlin, N., Bohr, J., Tysk, C., Hultgren, O. & Hultgren-Hörnquist, E. (2015). Enhanced levels of chemokines and their receptors in the colon of microscopic colitis patients indicate mixed immune cell recruitment. Mediators of Inflammation, Article ID 132458.
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: 2018-06-30Bibliographically approved
Günaltay, S., Nyhlin, N., Kumawat, A. K., Tysk, C., Bohr, J., Hultgren, O. & Hultgren-Hörnquist, E. (2014). Differential expression of interleukin-1/Toll-like receptor signaling regulators in microscopic and ulcerative colitis. World Journal of Gastroenterology, 20(34), 12249-12259
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
Keywords
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: 2019-03-26Bibliographically approved
Gunaltay, S., Ghiboub, M., Hultgren, O. & Hultgren-Hörnquist, E. (2014). The role of IL-37 on cytokine responses downstream of TLR4 and TLR5 signalling in intestinal epithelial cells. Immunology, 143, 94-95
Open this publication in new window or tab >>The role of IL-37 on cytokine responses downstream of TLR4 and TLR5 signalling in intestinal epithelial cells
2014 (English)In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 143, p. 94-95Article in journal, Meeting abstract (Other academic) Published
National Category
Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:oru:diva-40157 (URN)000345702600261 ()
Available from: 2015-01-08 Created: 2015-01-07 Last updated: 2018-02-07Bibliographically approved
Gunaltay, S., Nyhlin, N., Kumawat, A., Tysk, C., Bohr, J., Hultgren, O. & Hultgren-Hörnquist, E. (2013). IL-1/TLR signaling inhibitors in microscopic and ulcerative colitis: Immunopathogenic markers of active disease and remission. Paper presented at Annual Congress of the British-Society-for-Immunology, DEC 02-05, 2013, Liverpool, ENGLAND. Immunology, 140, 167-167
Open this publication in new window or tab >>IL-1/TLR signaling inhibitors in microscopic and ulcerative colitis: Immunopathogenic markers of active disease and remission
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2013 (English)In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 140, p. 167-167Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Wiley-Blackwell, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:oru:diva-32911 (URN)000327487700438 ()
Conference
Annual Congress of the British-Society-for-Immunology, DEC 02-05, 2013, Liverpool, ENGLAND
Available from: 2014-01-03 Created: 2014-01-03 Last updated: 2019-03-26Bibliographically approved
Gunaltay, S., Nyhlin, N., Kumawat, A., Bohr, J., Tysk, C., Hultgren, O. & Hultgren-Hörnquist, E. (2013). Increased expression of T cell recruiting chemokines in the colonic mucosa of microscopic colitis patients. Paper presented at Annual Congress of the British-Society-for-Immunology, DEC 02-05, 2013, Liverpool, ENGLAND. Immunology, 140, 135-135
Open this publication in new window or tab >>Increased expression of T cell recruiting chemokines in the colonic mucosa of microscopic colitis patients
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2013 (English)In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 140, p. 135-135Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Wiley-Blackwell, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:oru:diva-32910 (URN)000327487700348 ()
Conference
Annual Congress of the British-Society-for-Immunology, DEC 02-05, 2013, Liverpool, ENGLAND
Available from: 2014-01-03 Created: 2014-01-03 Last updated: 2019-03-26Bibliographically approved
Günaltay, S., Repsilber, D., Helenius, G., Nyhlin, N., Bohr, J. & Hultgren-Hörnquist, E.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
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-9635-0341

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