The Role of Plasmacytoid Dendritic Cells and Natural Killer Cells in Systemic Lupus Erythematosus
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production, which can eventually lead to immune complex (IC)-mediated organ damage. Due to the stimulation of plasmacytoid dendritic cells (pDC) by nucleic acid-containing ICs (DNA- or RNA-IC), patients with SLE have an ongoing interferon (IFN)-α production. IFN-α induces a general activation of the immune system that may initiate or propagate an autoimmune process if not properly regulated. Previous studies have shown that natural killer (NK) cells potently enhance the IFN-α production by pDCs.
In study I, the mechanisms behind the NK cell-mediated increased IFN-α production by RNA-IC-stimulated pDCs were investigated. ICs triggered CD56dim NK cells via FcγRIIIA to the secretion of cytokines (e.g. MIP-1β) that promoted IFN-α production. Additionally, an LFA-1-dependent cell-cell interaction between pDCs and NK cells strongly contributed to the increased production of IFN-α. In study II, the RNA-IC-induced regulation of surface molecules on pDCs and NK cells was investigated. The expression of CD319 and CD229, which are two SLAM family receptors genetically associated with SLE, was induced on pDCs and NK cells by RNA-IC. IFN-α-producing pDCs displayed an increased expression of CD319 and CD229, whereas pDCs from patients with SLE had a decreased expression of CD319. In study III, we serendipitously identified an SLE patient harboring autoantibodies to the NK cell receptor CD94/NKG2A. In study IV, sera from 203 patients with SLE were analyzed for autoantibodies to the CD94/NKG2A, CD94/NKG2C and NKG2D receptors. Seven patients harbored anti-CD94/NKG2A autoantibodies, and two of these patient’s autoantibodies also reacted with CD94/NKG2C. Anti-CD94/NKG2A and anti-CD94/NKG2C autoantibodies both interfered with the HLA-E-mediated regulation of NK cell cytotoxicity, and facilitated the elimination of target cells expressing these receptors. Furthermore, these autoantibodies were found in a group of severely diseased SLE patients and their titers closely followed disease activity.
In conclusion, this thesis provides insights to molecular mechanisms whereby NK cells regulate the IFN-α production, it further links the SLAM receptors to SLE, and it describes novel autoantibodies to receptors regulating NK cell cytotoxicity. Together these findings strengthen the assumption that NK cells are involved in the pathogenesis of SLE.
Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. , 73 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 963
Systemic lupus erythematosus, plasmacytoid dendritic cells, natural killer cells, type I interferon, immune complex, SLAM receptors, autoantibodies, CD94/NKG2A, CD94/NKG2C
Rheumatology and Autoimmunity
Research subject Medical Science; Immunology
IdentifiersURN: urn:nbn:se:uu:diva-213674ISBN: 978-91-554-8837-6OAI: oai:DiVA.org:uu-213674DiVA: diva2:684301
2014-02-21, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Tsokos, George, Professor
Rönnblom, Lars, ProfessorEloranta, Maija-Leena, Associate Professor
FunderSwedish Research Council, A0258801Knut and Alice Wallenberg Foundation, 2011.0073Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
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