Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Effects of Pregnancy and Hormones on T cell Immune Regulation in Multiple Sclerosis
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Multiple sclerosis (MS) is characterized by a dysregulated immune system leading to chronic inflammation in the central nervous system. Despite increasing number of treatments, many patients continue to deteriorate. A better understanding of the underlying disease mechanisms involved in driving disease is a pre-requisite for finding new biomarkers and new treatment targets. The improvement of MS during pregnancy, comparable to the beneficial effects of the most effective treatment, suggests that the transient and physiological immune tolerance established during pregnancy could serve as a model for successful immune regulation. Most likely the immune-endocrine alterations that take place during pregnancy to accommodate the presence of the semi-allogenic fetus contribute to the observed disease improvement.

The aim of this thesis was to characterize the dysregulated immune system in MS and define potential factors and mechanisms established during pregnancy that could be involved in the pregnancy-induced effects in MS, focusing on CD4+ T cells as one of the main drivers in immunity and in the MS pathogenesis. Using a network-based modular approach based on gene expression profiling, we could show that CD4+ T cells from patients with MS displayed an altered dynamic gene response to activation, in line with a dysregulated immune system in MS. The resulting gene module disclosed cell activation and chemotaxis as central components in the deviating response, results that form a basis for further studies on its modulation during pregnancy. Moreover, a combination of secreted proteins (OPN+CXCL1-3+CXCL10-CCL2), identified from the module, could be used to separate patients and controls, predict disease activity after 2 years and discriminate between high and low responders to treatment, highlighting their potential use as biomarkers for predicting disease activity and response to treatment.

The pregnancy hormone progesterone (P4), a potential factor involved in the pregnancy-induced amelioration of MS, was found to significantly dampen CD4+ T cell activation. Further detailed transcriptomic profiling revealed that P4 almost exclusively down-regulated immune-related pathways in activated T cells, several related to or downstream of T cell activation such as JAKSTAT signaling, T cell receptor signaling and cytokine-cytokine receptor interaction. In particular, P4 significantly affected genes of relevance to diseases known to be modulated during pregnancy, where genes associated to MS were most significantly affected, supporting a role for P4 in the pregnancy-induced immunomodulation. By using another approach, the role of thymus in T cell regulation during pregnancy was assessed. Two established measures of thymic output, CD31 expression and TREC content, were used and showed that thymic output of T cells is maintained during human pregnancy, or even possibly increased in terms of regulatory T cells.

This thesis further supports a pivotal role for CD4+ T cells and T cell activation in the MS pathogenesis and adds to the knowledge of how they could be involved in driving disease. We identified a novel strategy for capturing central aspects of the deviating response to T cell activation that could be translated into potentially clinically relevant biomarkers. Further, P4 is emerging as a promising candidate for the pregnancy-induced immunomodulation that could be of importance as a future treatment option. Lastly, maintained thymic output of T cells during human pregnancy challenges the rodent-based dogma of an inactive thymus during pregnancy. Thymic dysfunction has been reported not only in MS but also in rheumatoid arthritis, another inflammatory disease that improves during pregnancy, which highlights a potential role for thymus in immune regulation that could be involved in the pregnancy-induced amelioration.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2019. , p. 118
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1705
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:liu:diva-161091DOI: 10.3384/diss.diva-161091ISBN: 9789179299934 (print)OAI: oai:DiVA.org:liu-161091DiVA, id: diva2:1362989
Public defence
2019-11-08, Berzeliussalen, Building 463, Campus US, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2019-10-22 Created: 2019-10-22 Last updated: 2019-10-22Bibliographically approved
List of papers
1. Dynamic Response Genes in CD4+T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis
Open this publication in new window or tab >>Dynamic Response Genes in CD4+T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis
Show others...
2016 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 16, no 11, p. 2928-2939Article in journal (Refereed) Published
Abstract [en]

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS and has a varying disease course as well as variable response to treatment. Biomarkers may therefore aid personalized treatment. We tested whether in vitro activation of MS patient-derived CD4+ T cells could reveal potential biomarkers. The dynamic gene expression response to activation was dysregulated in patient-derived CD4+ T cells. By integrating our findings with genome-wide association studies, we constructed a highly connected MS gene module, disclosing cell activation and chemotaxis as central components. Changes in several module genes were associated with differences in protein levels, which were measurable in cerebrospinal fluid and were used to classify patients from control individuals. In addition, these measurements could predict disease activity after 2 years and distinguish low and high responders to treatment in two additional, independent cohorts. While further validation is needed in larger cohorts prior to clinical implementation, we have uncovered a set of potentially promising biomarkers.

Place, publisher, year, edition, pages
CELL PRESS, 2016
National Category
Hematology
Identifiers
urn:nbn:se:liu:diva-132056 (URN)10.1016/j.celrep.2016.08.036 (DOI)000383882300014 ()27626663 (PubMedID)
Note

Funding Agencies|Swedish Research Council [K2013-61X-22310-01-4, K2013-61X-07488-28-5, 2015-03495]; Medical Research Council of Southeast Sweden (FORSS); Swedish Foundation for MS Research; NEURO Sweden; Centre for Industrial IT (CENIIT); Ake Wiberg Foundation; Knut and Alice Wallenberg Foundation; Swedish Brain Foundation; AFA foundation; Margareta af Ugglas foundation; Swedish Society for Medical Research; Biogen; Novartis; Genzyme; Merck; Allmiral; Biogen Idec

Available from: 2016-10-18 Created: 2016-10-17 Last updated: 2019-10-22
2. Maintained thymic output of conventional and regulatory T cells during human pregnancy
Open this publication in new window or tab >>Maintained thymic output of conventional and regulatory T cells during human pregnancy
Show others...
2019 (English)In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 143, no 2, p. 771-775.e7Article in journal, Letter (Other academic) Published
Abstract [en]

n/a

Place, publisher, year, edition, pages
Philadelphia, United States: Mosby, Inc., 2019
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:liu:diva-154564 (URN)10.1016/j.jaci.2018.09.023 (DOI)000457718700037 ()30312712 (PubMedID)2-s2.0-85058386317 (Scopus ID)
Note

Funding Agencies|Swedish Research Council [K2013-61X-22310-01-4]; Medical Research Council of Southeast Sweden [FORSS-315121, FORSS-161101]

Available from: 2019-02-20 Created: 2019-02-20 Last updated: 2019-10-22Bibliographically approved

Open Access in DiVA

fulltext(7863 kB)64 downloads
File information
File name FULLTEXT01.pdfFile size 7863 kBChecksum SHA-512
6db1c275a69fa2810fb7ce4bb14fb5cd1fa2c811c188a3c7e1d22dbb56f0e632fdd23f13d86b59648af20b4a0c9ccfdca9786431c7487e72dfd875b9c8d54608
Type fulltextMimetype application/pdf
Order online >>

Other links

Publisher's full text

Search in DiVA

By author/editor
Hellberg, Sandra
By organisation
Division of Neuro and Inflammation ScienceFaculty of Medicine and Health Sciences
Immunology in the medical area

Search outside of DiVA

GoogleGoogle Scholar
Total: 64 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
isbn
urn-nbn

Altmetric score

doi
isbn
urn-nbn
Total: 81 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf