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Maintained thymic output of conventional and regulatory T cells during human pregnancy
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
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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. Vol. 143, no 2, p. 771-775.e7
National Category
Respiratory Medicine and Allergy
Identifiers
URN: urn:nbn:se:liu:diva-154564DOI: 10.1016/j.jaci.2018.09.023ISI: 000457718700037PubMedID: 30312712Scopus ID: 2-s2.0-85058386317OAI: oai:DiVA.org:liu-154564DiVA, id: diva2:1290505
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
In thesis
1. Effects of Pregnancy and Hormones on T cell Immune Regulation in Multiple Sclerosis
Open this publication in new window or tab >>Effects of Pregnancy and Hormones on T cell Immune Regulation in Multiple Sclerosis
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:nbn:se:liu:diva-161091 (URN)10.3384/diss.diva-161091 (DOI)9789179299934 (ISBN)
Public defence
2019-11-08, Berzeliussalen, Building 463, Campus US, Linköping, 09:00 (Swedish)
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Supervisors
Available from: 2019-10-22 Created: 2019-10-22 Last updated: 2019-10-22Bibliographically approved

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Hellberg, SandraBhai Mehta, RatneshForsberg, AnnaBerg, GöranBrynhildsen, JanJenmalm, MariaErnerudh, Jan
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Division of Neuro and Inflammation ScienceFaculty of Medicine and Health SciencesDivision of Children's and Women's healthDepartment of Gynaecology and Obstetrics in LinköpingDepartment of Clinical Immunology and Transfusion Medicine
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