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Regulation of Type ...
Regulation of Type I Interferon Production in Plasmacytoid Dendritic Cells : Effect of Genetic Factors and Interactions with NK Cells and B Cells
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- Berggren, Olof (författare)
- Uppsala universitet,Reumatologi
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- Eloranta, Maija-Leena, Associate Professor (preses)
- Uppsala universitet,Reumatologi
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- Heegaard, Niels, Professor (opponent)
- Department of Autoimmunology & Biomarkers, Statens Serum Institut, Copenhagen, Denmark
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(creator_code:org_t)
- ISBN 9789155492038
- Uppsala : Acta Universitatis Upsaliensis, 2015
- Engelska 59 s.
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Serie: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 1083
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Abstract
Ämnesord
Stäng
- The type I interferon (IFN) system plays a central role in the etiopathogenesis of many autoimmune diseases, e.g. systemic lupus erythematosus (SLE). Activation of the type I IFN system in SLE is promoted by endogenous nucleic acid-containing immune complexes (ICs) which stimulate plasmacytoid dendritic cells (pDCs). This thesis focuses on the regulation of IFN-α production in pDCs, by interactions with B cells and natural killer (NK) cells, and by genetic factors.In Study I, RNA-IC-stimulated CD56dim NK cells were found to be activated via FcγRIIIa and enhanced the IFN-α production by pDCs. The enhancing effect of the NK cells was mediated via both soluble factors, such as the cytokine MIP-1β, and in a cell-cell contact mediated manner via the adhesion molecule LFA-1. In Study II, B cells enhanced the IFN-α production by pDCs via cell-cell contact or soluble factors, depending on the stimuli. The cell-cell contact-mediated enhancement, when the cells were stimulated with RNA-IC, was abolished by blocking the cell adhesion molecule CD31. B cells stimulated with the oligonucleotide ODN2216 enhanced the IFN-α production via soluble factors. In Study III, gene variants related to autoimmune or inflammatory diseases were analyzed for the association to the IFN-α production by pDCs, alone or in coculture with NK or B cells. Depending on cell combination, 18-86 SNPs (p < 0.001) were associated with the IFN-α production. Several of the SNPs showed novel associations to the type I IFN system, while some loci have been described earlier for their association with SLE, e.g. IL10 and PXK. In Study IV, several B cell populations were affected by cocultivation with pDCs and stimulation with RNA-IC. The frequency of CD24hiCD38hi B cells of regulatory character was increased in the pDC-B cell cocultures. However, RNA-IC-stimulation only induced modest levels of IL-10. A remarkably increased frequency of double negative CD27-IgD- B cells was found in the RNA-IC-stimulated cocultures of pDCs and B cells.In conclusion, the findings in the present thesis reveal novel mechanisms behind the regulation of the type I IFN system which could be important targets in autoimmune diseases with constantly activated pDCs.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)
Nyckelord
- Systemic lupus erythemtosus
- IFN-alpha
- autoimmunity
- immune complex
- single nuclear polymorphisms
- Medicinsk vetenskap
- Medical Science
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