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Regulation of the type I interferon production in plasmacytoid dendritic cells induced by snRNP-containing immune complexes
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
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Manuscript (Other academic)
Identifiers
URN: urn:nbn:se:uu:diva-94954OAI: oai:DiVA.org:uu-94954DiVA: diva2:168987
Available from: 2006-10-13 Created: 2006-10-13 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Endogenous Type I Interferon Inducers in Systemic Autoimmune Diseases
Open this publication in new window or tab >>Endogenous Type I Interferon Inducers in Systemic Autoimmune Diseases
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Patients with systemic lupus erythematosus (SLE) have elevated levels of interferon (IFN)-α in blood and IFN-α-producing cells in tissues. In the present thesis, we investigate the mechanisms behind the upregulated IFN-α-production in SLE and also show that the IFN-α system is activated in primary Sjögren’s syndrome (pSS), with IFN-α-producing cells in the major affected organ, the salivary glands. The IFN-α is a type I IFN, a family of cytokines counteracting especially viral infections, by acting directly on infected cells, and via many immunomodulatory effects. The latter may also contribute to autoimmune processes.

The type I IFNs are usually produced upon recognition of microbial structures. In SLE, however, DNA-containing immune complexes (ICs) that induce IFN-α production are found. Many autoantibodies in SLE and pSS are directed to nucleic acids or to DNA/RNA-binding proteins. We show that also RNA in complex with autoantibodies from SLE or pSS patients (RNA-IC) induces IFN-α-production. The RNA could be either in the form of RNA-containing material released from apoptotic or necrotic cells or as a pure RNA-containing autoantigen, the U1 small nuclear ribonucleoprotein particle.

The IFN-α-production induced by RNA-IC occurred in plasmacytoid dendritic cells (PDCs), also termed natural IFN-producing cells (NIPCs), via binding to Fcγ-receptor IIa, endocytosis and triggering of Toll-like receptors (TLRs), probably TLR7 and TLR9. The RNA-IC may also have other effects, and we found that they induce prostaglandin E2 (PGE2) production in monocytes and tumor necrosis factor (TNF)-α in both monocytes and NIPC/PDC. The PGE2 downregulated the IFN-α induction in NIPC/PDC, and the IFN-α induction was increased in monocyte-depleted cell cultures.

The findings presented in this thesis aids in the understanding of the mechanisms behind the activated IFN-α system in SLE and other autoimmune diseases, and shows that also pSS is one of these diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 55 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 180
Keyword
Medicine, Systemic lupus erythematosus, Sjögren's syndrome, type I interferon, plasmacytoid dendritic cell, natural interferon-producing cell, immune complex, RNP, Ro/SSA, La/SSB, Medicin
Identifiers
urn:nbn:se:uu:diva-7181 (URN)91-554-6675-3 (ISBN)
Public defence
2006-11-03, Sal IX, Universitetshuset, Uppsala, 09:15
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Available from: 2006-10-13 Created: 2006-10-13Bibliographically approved

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