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Induction of interferon-α by immune complexes or liposomes containing systemic lupus erythematosus autoantigen- and Sjögren's syndrome autoantigen-associated RNA
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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2006 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 54, no 6, 1917-1927 p.Article in journal (Refereed) Published
Abstract [en]


To investigate the ability of systemic lupus erythematosus (SLE) autoantigen– and Sjögren's syndrome (SS) autoantigen–associated U1 small nuclear RNA (U1 snRNA) and hY1RNA to induce interferon-α (IFNα) production.


In vitro–transcribed U1 snRNA or hY1RNA and lipofectin were added to peripheral blood mononuclear cell (PBMC) cultures. Purified U1 snRNP particles and IgG from SLE patients (SLE-IgG) were added to cultures of PBMCs, enriched monocytes, or natural interferon–producing cells (NIPCs); the latter are also known as plasmacytoid dendritic cells (pDC). Cells were double-stained for IFNα and either blood dendritic cell antigen 2 (NIPCs/pDC) or CD14 (monocytes) and then analyzed by flow cytometry. In some experiments, RNase or inhibitors of Fcγ receptor IIa (FcγRIIa) (specific antibodies), endocytosis (chloroquine, bafilomycin A), or Toll-like receptors (TLRs; oligodeoxynucleotide 2088) were used. The produced IFNα was measured by immunoassay.


Lipofected U1 snRNA and hY1RNA both induced IFNα production in monocytes, but not in NIPC/pDC. In contrast, U1 snRNP combined with SLE-IgG induced IFNα production only in NIPCs/pDC, and this response was decreased by RNase treatment or inhibition of the FcγRIIa, the endocytosis pathways, or the TLRs.


Our finding that U1 snRNA and hY1RNA have IFNα-inducing capacity indicates that immune complexes containing such RNA, for example U1 snRNP particles, can be at least partly responsible for the ongoing IFNα production seen in SLE and SS. These results may help to explain the molecular mechanisms behind the pathogenesis of these and other autoimmune diseases in which autoantibodies to RNA- binding proteins occur.

Place, publisher, year, edition, pages
2006. Vol. 54, no 6, 1917-1927 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-94953DOI: 10.1002/art.21893OAI: oai:DiVA.org:uu-94953DiVA: diva2:168986
Available from: 2006-10-13 Created: 2006-10-13 Last updated: 2012-04-01Bibliographically 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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 180
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
urn:nbn:se:uu:diva-7181 (URN)91-554-6675-3 (ISBN)
Public defence
2006-11-03, Sal IX, Universitetshuset, Uppsala, 09:15
Available from: 2006-10-13 Created: 2006-10-13Bibliographically approved

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Lövgren, TanjaEloranta, Maija-LeenaRönnblom, Lars
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