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Initiation of Autoimmunity in Experimental Autoimmune Encephalomyelitis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. (Autoimmunitet)
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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 780
Keyword [en]
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
Identifiers
URN: urn:nbn:se:uu:diva-173427ISBN: 978-91-554-8385-2 (print)OAI: oai:DiVA.org:uu-173427DiVA: diva2:517517
Public defence
2012-06-12, Enghoffsalen, Akademiska sjukhuset, Ingång 50, bv, Akademiska sjukhuset, SE-751 85, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2012-05-22 Created: 2012-04-23 Last updated: 2012-08-01Bibliographically approved
List of papers
1. Impaired autoimmune T helper 17 cell responses following DNA vaccination against rat experimental autoimmune encephalomyelitis
Open this publication in new window or tab >>Impaired autoimmune T helper 17 cell responses following DNA vaccination against rat experimental autoimmune encephalomyelitis
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2008 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 3, no 11, e3682- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: We have previously shown that vaccination with DNA encoding the encephalitogenic peptide myelin oligodendrocyte glycoprotein (MOG)(91-108) (pMOG) suppresses MOG(91-108)-induced rat Experimental Autoimmune Encephalomyelitis (EAE), a model for human Multiple Sclerosis (MS). The suppressive effect of pMOG is dependent on inclusion of CpG DNA in the plasmid backbone and is associated with early induction of Interferon (IFN)-beta. PRINCIPAL FINDINGS: In this study we examined the mechanisms underlying pMOG-induced protection. We found that in the DNA vaccinated cohort proinflammatory Interleukin (IL)-17 and IL-21 responses were dramatically reduced compared to in the control group, but that the expression of Foxp3 and Tumor Growth Factor (TGF)-beta1, which are associated with regulatory T cells, was not enhanced. Moreover, genes associated with Type I IFNs were upregulated. To delineate the role of IFN-beta in the protective mechanism we employed short interfering RNA (siRNA) to IFN-beta in the DNA vaccine. SiRNA to IFN-beta completely abrogated the protective effects of the vaccine, demonstrating that a local early elaboration of IFN-beta is important for EAE protection. IL-17 responses comparable to those in control rats developed in rats injected with the IFN-beta-silencing DNA vaccine. CONCLUSIONS: We herein demonstrate that DNA vaccination protects from proinflammatory Th17 cell responses during induction of EAE. The mechanism involves IFN-beta as IL-17 responses are rescued by silencing of IFN-beta during DNA vaccination.

Place, publisher, year, edition, pages
PLoS, 2008
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-102743 (URN)10.1371/journal.pone.0003682 (DOI)000265165500005 ()18997868 (PubMedID)1932-6203 (Electronic) (ISBN)
Available from: 2009-05-12 Created: 2009-05-11 Last updated: 2012-08-01Bibliographically approved
2. Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis
Open this publication in new window or tab >>Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis
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2008 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 38, no 2, 565-575 p.Article in journal (Refereed) Published
Abstract [en]

Innate immune mechanisms essential for priming encephalitogenic T cells in autoimmune neuroinflammation are poorly understood. Experimental autoimmune encephalomyelitis (EAE) is a IL-17-producing Th (Th17) cell-mediated autoimmune disease and an animal model of multiple sclerosis. To investigate how upstream TLR signals influence autoimmune T cell responses, we studied the role of individual TLR and MyD88, the common TLR adaptor molecule, in the initiation of innate and adaptive immune responses in EAE. Wild type (WT) C57BL/6, TLR-deficient and MyD88-deficient mice were immunized with myelin oligodendrocyte glycoprotein (MOG) in CFA. MyD88(-/-) mice were completely EAE resistant. Purified splenic myeloid DC (mDC) from MyD88(-/-) mice expressed much less IL-6 and IL-23, and serum and T cell IL-17 were absent. TLR4(-/-) and TLR9(-/-) mice surprisingly exhibited more severe EAE symptoms than WT mice. IL-6 and IL-23 expression by mDC and Th17 responses were higher in TLR4(-/-) mice, suggesting a regulatory role of TLR4 in priming Th17 cells. IL-6 expression by splenocytes was higher in TLR9(-/-) mice. Our data suggest that MyD88 mediates the induction of mDC IL-6 and IL-23 responses after MOG immunization, which in turn drives IL-17-producing encephalitogenic Th17 cell activation. Importantly, we demonstrate that TLR4 and TLR9 regulate disease severity in MOG-induced EAE.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-13139 (URN)10.1002/eji.200737187 (DOI)000253326100025 ()18203139 (PubMedID)
Available from: 2008-01-21 Created: 2008-01-21 Last updated: 2017-12-11Bibliographically approved
3. Plasmacytoid DC promote priming of autoimmune Th17 cells and EAE
Open this publication in new window or tab >>Plasmacytoid DC promote priming of autoimmune Th17 cells and EAE
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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.

Keyword
Autoimmunity, DC, EAE/MS, T cells, Type I IFN
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-108362 (URN)10.1002/eji.200839179 (DOI)000271151000030 ()19637225 (PubMedID)
Available from: 2009-09-16 Created: 2009-09-16 Last updated: 2017-12-13Bibliographically approved
4. Conditional DC depletion does not affect priming of encephalitogenic Th cells in EAE
Open this publication in new window or tab >>Conditional DC depletion does not affect priming of encephalitogenic Th cells in EAE
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2012 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 42, no 10, 2555-2563 p.Article in journal (Refereed) Published
Abstract [en]

EAE, an animal model for multiple sclerosis, is a Th17- and Th1-cell-mediated auto-immune disease, but the mechanisms leading to priming of encephalitogenicTcells in autoimmune neuroinflammation are poorly understood. To investigate the role of dendritic cells (DCs) in the initiation of autoimmuneTh17- andTh1-cell responses andEAE, we used mice transgenic for a simian diphtheria toxin receptor (DTR) expressed under the control of the murineCD11c promoter (CD11c-DTRmice onC57BL/6 background).EAEwas induced by immunization with myelin oligodendrocyte glycoprotein (MOG) protein in CFA. DCs were depleted on the day before and 8 days afterMOG immunization. The mean clinicalEAEscore was only mildly reduced inDC-depleted mice when DCs were ablated beforeEAEinduction. The frequency of activatedTh cells was not altered, andMOG-inducedTh17 orTh1-cell responses were not altered, in the spleens ofDC-depleted mice. Similar results were obtained ifDCswere ablated the first 10 days afterMOGimmunization with repeatedDCdepletions. Unexpectedly, transient depletion of DCs did not affect priming or differentiation of MOG-inducedTh17 andTh1-cell responses or the incidence ofEAE. Thus, the mechansim of priming ofTh cells inEAEremains to be elucidated.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-173266 (URN)10.1002/eji.201142239 (DOI)000309610200004 ()22806332 (PubMedID)
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2012-04-23 Created: 2012-04-21 Last updated: 2017-12-07Bibliographically approved

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