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The Combination of Apoptotic U937 Cells and Lupus IgG Is a Potent IFN-α Inducer
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
2000 In: The Journal of Immunology, Vol. 165, 3519-3526 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2000. Vol. 165, 3519-3526 p.
URN: urn:nbn:se:uu:diva-90440OAI: oai:DiVA.org:uu-90440DiVA: diva2:162796
Available from: 2003-05-08 Created: 2003-05-08Bibliographically approved
In thesis
1. Mechanisms of Interferon-α Induction in Systemic Lupus Erythematosus
Open this publication in new window or tab >>Mechanisms of Interferon-α Induction in Systemic Lupus Erythematosus
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Patients with systemic lupus erythematosus (SLE) have an activated type I interferon (IFN) system with an ongoing IFN-α synthesis. This may be caused by circulating immune complexes, consisting of anti-DNA antibodies (Abs) and DNA, with IFN-α inducing capacity. Produced IFN-α may be crucial in the pathogenesis, because this cytokine can break tolerance and promote autoimmunity.

In the present thesis, possible mechanisms of the IFN-α production in SLE were studied. To investigate whether IFN-α inducing material could be derived from apoptotic cells, IgG from SLE patients (SLE-IgG) were combined with apoptotic cells. This combination induced high IFN-α production in normal peripheral blood mononuclear cells (PBMC). The IFN-α induction was associated to presence of anti-RNP Abs, but not to anti-dsDNA Abs, indicating that two inducers could be active in SLE, one containing DNA and the other RNA.

Apoptotic cells and SLE-IgG exclusively activated the natural interferon producing cells (NIPC) and the IFN-α response was enhanced by type I IFN and inhibited by IL-10 and TNF-α. The IFN-α induction was dependent on FcγRII, because blocking this receptor reduced IFN-α production and NIPC were found to express FcγRIIa.

To further elucidate the role of different autoantibodies in the IFN-α induction, sera from patients with Sjögren´s syndrome (SS), containing autoantibodies to RNA binding proteins (SSA, SSB, RNP and/or Sm) were investigated. The combination of SS or SLE sera and apoptotic or necrotic cell material induced high IFN-α production in PBMC. RNA, but not DNA, was required for IFN-α induction, indicating that RNA and Abs to RNA-binding proteins form potent IFN-α inducing complexes.

The findings in this thesis can explain central mechanisms for the activation of NIPC in SLE, and perhaps also other autoimmune diseases. This activation is mediated by interferogenic immune complexes, and modulating the NIPC activation may be a novel therapeutic approach in SLE.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 70 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1267
Medicine, Systemic lupus erythematosus, interferon inducer, apoptosis, autoantibodies, natural interferon-alpha producing cell, FcgammaRII, Sjögren´s syndrome, Medicin
National Category
Dermatology and Venereal Diseases
Research subject
urn:nbn:se:uu:diva-3436 (URN)91-554-5643-X (ISBN)
Public defence
2003-05-30, sal IX, Universitetshuset, Uppsala, 09:15
Available from: 2003-05-08 Created: 2003-05-08Bibliographically approved

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