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- Lövgren, Tanja, 1976-
(författare)
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Endogenous Type I Interferon Inducers in Systemic Autoimmune Diseases
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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