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Induction of interferon-α production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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2004 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 50, no 6, 1861-1872 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To investigate the release of interferon-alpha (IFN alpha)-inducing material by necrotic or apoptotic cells, its properties, and the necessity of autoantibodies from systemic lupus erythematosus (SLE) patients for the interferogenic activity.

METHODS: U937 monocytic leukemia cells or peripheral blood mononuclear cells (PBMCs) were rendered necrotic by freeze-thawing or apoptotic by treatment with ultraviolet light. Cell culture supernatants from these cells and IgG from SLE patients (SLE IgG) were added to cultures of normal PBMCs or purified plasmacytoid dendritic cells (PDCs). The importance of nucleic acids for IFN alpha induction was investigated by RNase and DNase treatment. The IFN alpha levels were measured by immunoassay.

RESULTS: Both necrotic and apoptotic U937 cells released material that, combined with SLE IgG, induced IFN alpha production in PDCs. The release from apoptotic cells occurred with a 16-hour delay, in late apoptosis. Also, normal PBMCs released IFN alpha-inducing material, but only during necrosis. The interferogenic activity of the necrotic material required the presence of RNA, while both RNA and DNA were important in the apoptotic material. In both cases, the presence of SLE IgG was necessary, and its activity correlated with the presence of antibodies to RNA-binding proteins, but not anti-DNA antibodies.

CONCLUSION: Necrotic and late apoptotic cells release material that, combined with SLE IgG, induces production of IFN alpha in PDCs. The IFN alpha inducers probably consist of immune complexes (ICs) containing RNA and possibly DNA as essential interferogenic components. The presence of such interferogenic ICs could explain the ongoing production of IFN alpha in SLE and could be of etiopathogenic importance.

Place, publisher, year, edition, pages
2004. Vol. 50, no 6, 1861-1872 p.
Keyword [en]
Antigen-Antibody Complex/*genetics/immunology, Apoptosis/*immunology, DNA/metabolism, Dendritic Cells/*immunology/metabolism, Deoxyribonucleases/pharmacology, Freezing, Humans, Immunoglobulin G/metabolism, Interferon-alpha/genetics/*metabolism, Leukocytes; Mononuclear/cytology/immunology, Lupus Erythematosus; Systemic/*immunology/metabolism/physiopathology, Necrosis, RNA/metabolism, Research Support; Non-U.S. Gov't, Ribonucleases/pharmacology, U937 Cells, Ultraviolet Rays
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-94951DOI: 10.1002/art.20254OAI: oai:DiVA.org:uu-94951DiVA: diva2:168984
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-LeenaBåve, UllviRönnblom, Lars
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