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Plasmacytoid DC promote priming of autoimmune Th17 cells and EAE
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Lobell / Autoimmuna sjukdomar, Autoimmunity)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Autoimmuna sjukdomar (Kämpe))
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Systemisk Autoimmunitet)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Autoimmuna sjukdomar (Kämpe))
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2009 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 39, no 10, 2925-2935 p.Article in journal (Refereed) Published
Abstract [en]

EAE, an animal model for MS, is a Th17 and Th1-cell-mediated autoimmune disease, but the mechanisms leading to priming of encephalitogenic T cells in autoimmune neuroinflammation are poorly understood. To investigate the role of plasmacytoid DC (pDC) in the initiation of autoimmune Th17- and Th1-cell responses and EAE, we depleted pDC with anti-pDC Ag-1 (anti-PDCA1) mAb prior to immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein (MOG). pDC-depleted mice developed less severe clinical and histopathological signs of EAE than control mice, which demonstrates a promoting role for pDC in the initiation of EAE. The levels of type I IFN were much lower in the sera from anti-PDCA1-treated mice. However, neutralization of type I IFN ameliorated the early phase of EAE but did not alter the severity of disease. Thus, only a minor part of the EAE-promoting effect of pDC appears to be mediated by IFN-alpha/beta secretion. The numbers of MOG-specific Th17 cells, but not Th1 cells, were lower in spleen from anti-PDCA1-treated mice compared with controls. In contrast, pDC depletion a week after MOG immunization resulted in more severe clinical signs of EAE. In conclusion, we demonstrate that pDC promote initiation of MOG-induced Th17-cell responses and EAE.

Place, publisher, year, edition, pages
2009. Vol. 39, no 10, 2925-2935 p.
Keyword [en]
Autoimmunity, DC, EAE/MS, T cells, Type I IFN
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-108362DOI: 10.1002/eji.200839179ISI: 000271151000030PubMedID: 19637225OAI: oai:DiVA.org:uu-108362DiVA: diva2:235564
Available from: 2009-09-16 Created: 2009-09-16 Last updated: 2012-08-01Bibliographically approved
In thesis
1. Initiation of Autoimmunity in Experimental Autoimmune Encephalomyelitis
Open this publication in new window or tab >>Initiation of Autoimmunity in Experimental Autoimmune Encephalomyelitis
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The events that trigger an autoimmune disease remain largely unknown. To study these events animal models are necessary because symptoms of autoimmune diseases are preceded by a long asymptomatic period in humans.

Experimental autoimmune encephalomyelitis (EAE) is the best characterized model for cell mediated autoimmunity and an animal model for the human disease multiple sclerosis. EAE is induced in rodents by immunization with myelin antigens (Ags) together with adjuvants. After immunization, T cells are primed in the periphery by Ag presenting cells and subsequently invade the central nervous system where they mediate parenchymal inflammation, resulting in demyelination and clinical symptoms of an ascending paralysis. It is now generally recognised that the main cell type mediating EAE is the T helper type 17 (Th17) cell.

Tolerance to EAE can be attained by DNA vaccination, but how the immune response against the myelin Ags is abrogated after DNA vaccination is not known. By employing short interfering RNA technology, induction of the innate immune signalling molecule interferon (IFN) -β was found to be necessary for the protective effect of DNA vaccination in EAE. In addition, DNA vaccination inhibited subsequent autoimmune Th17 cell responses.

The Toll-like receptors (TLRs) of the innate immune system have evolved to recognise conserved molecular structures on microbes and signalling through them almost exclusively converge on the molecule MyD88. Signalling via MyD88 was found to be required for induction of EAE since mice deficient in this molecule did not develop disease. Upstream signalling via TLR4 and TLR9 had tolerogenic properties.

In studies of Ag presentation in EAE, two major subtypes of dendritic cells (DCs) were examined. Plasmacytoid DCs were found to have a promoting role in the induction of EAE, partly via type 1 IFNs. Myeloid DCs had a redundant role in the induction phase of EAE, neither disease severity nor encephalitogenic Th17 responses were affected by their absence during priming.

These studies further demonstrate that the cells and molecules of the innate immune system exhibit a crucial role in controlling the adaptive immune system which mediates tissue damage in autoimmune diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 54 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 780
Autoimmunity, Cytokines, Dendritic cells, DNA vaccination, EAE, Innate immunity, T helper cells, Toll-like receptors, Type I interferons
National Category
Immunology in the medical area
Research subject
Molecular Medicine
urn:nbn:se:uu:diva-173427 (URN)978-91-554-8385-2 (ISBN)
Public defence
2012-06-12, Enghoffsalen, Akademiska sjukhuset, Ingång 50, bv, Akademiska sjukhuset, SE-751 85, Uppsala, 09:00 (English)
Available from: 2012-05-22 Created: 2012-04-23 Last updated: 2012-08-01Bibliographically approved

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Ardesjö, BritaRönnblom, LarsKämpe, OlleEloranta, Maija-LeenaLobell, Anna
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