The Role of Plasmacytoid Dendritic Cells and Natural Killer Cells in Systemic Lupus Erythematosus
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Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 963 The Role of Plasmacytoid Dendritic Cells and Natural Killer Cells in Systemic Lupus Erythematosus NIKLAS HAGBERG ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-554-8837-6 UPPSALA urn:nbn:se:uu:diva-213674 2014 Dissertation presented at Uppsala University to be publicly examined in Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, Friday, 21 February 2014 at 09:15 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in English. Faculty examiner: Professor George Tsokos (Harvard Medical School, Beth Israel Deaconess Medical Center). Abstract Hagberg, N. 2014. The Role of Plasmacytoid Dendritic Cells and Natural Killer Cells in Systemic Lupus Erythematosus. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 963. 73 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-8837-6. 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. Keywords: Systemic lupus erythematosus, plasmacytoid dendritic cells, natural killer cells, type I interferon, immune complex, SLAM receptors, autoantibodies, CD94/NKG2A, CD94/ NKG2C Niklas Hagberg, Department of Medical Sciences, Rheumatology, Akademiska sjukhuset, Uppsala University, SE-75185 Uppsala, Sweden. © Niklas Hagberg 2014 ISSN 1651-6206 ISBN 978-91-554-8837-6 urn:nbn:se:uu:diva-213674 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-213674) List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Hagberg N, Berggren O, Leonard D, Weber G, Bryceson YT, Alm GV, Eloranta ML, Rönnblom L. (2011) IFN-α production by plasmacytoid dendritic cells stimulated with RNA- containing immune complexes is promoted by NK cells via MIP-1β and LFA-1. Journal of Immunology, 186(9):5085-94. II Hagberg N, Theorell J, Schlums H, Eloranta ML, Bryceson YT, Rönnblom L. (2013) Systemic lupus erythematosus im- mune complexes increase the expression of SLAM family members CD319 (CRACC) and CD229 (LY-9) on plasmacy- toid dendritic cells and CD319 on CD56dim NK cells. Journal of Immunology, 191(6):2989-98. III Hagberg N, Theorell J, Pascal V, Eloranta ML, Bryceson YT, Rönnblom L. (2013) Anti-NKG2A autoantibodies in a patient with systemic lupus erythematosus. Rheumatology (Oxford), 52(10):1818-1823. IV Hagberg N, Theorell J, Hjorton K, Eloranta ML, Bryceson YT, Rönnblom L. Autoantibodies to the CD94/NKG2A and CD94/NKG2C receptors in patients with systemic lupus ery- thematosus. Manuscript in preparation. Reprints were made with permission from the respective publishers. Related Papers Berggren O, Hagberg N, Weber G, Alm GV, Rönnblom L, Eloranta ML. (2012) B lymphocytes enhance interferon-α production by plasmacytoid dendritic cells. Arthritis and Rheumatism, 64(10):3409-3419. Wang C, Sandling JK, Hagberg N, Berggren O, Sigurdsson S, Karlberg O, Rönnblom L, Eloranta ML, Syvänen AC. (2013) Genome-wide profiling of target genes for the systemic lupus erythematosus-associated transcription factors IRF5 and STAT4. Annals of the Rheumatic Diseases, 72(1):96-103. Contents Introduction ..................................................................................................... 9 Systemic lupus erythematosus.................................................................... 9 Clinical presentation and epidemiology ................................................ 9 Etiology ............................................................................................... 11 Pathogenesis ........................................................................................ 14 The interferons ......................................................................................... 18 The type I interferon system ................................................................ 18 The type I interferon system in SLE .................................................... 22 Regulation of IFN-α production .......................................................... 24 Natural killer cells .................................................................................... 26 Natural killer cells in SLE ................................................................... 28 Present investigations .................................................................................... 29 Aims of the thesis ..................................................................................... 29 Materials and methods ............................................................................. 30 Results and discussion .............................................................................. 32 Study I .................................................................................................. 32 Study II ................................................................................................ 34 Study III ............................................................................................... 36 Study IV ............................................................................................... 37 Concluding remarks ................................................................................. 39 Sammanfattning på svenska .......................................................................... 42 Acknowledgements ....................................................................................... 45 References ..................................................................................................... 47 Abbreviations ACR American College of Rheumatology ADCC Antibody-dependent cellular cytotoxicity ANA Anti-nuclear antibody BAFF B cell activating factor BCR B cell receptor BDCA Blood dendritic cell antigen BTK Bruton’s tyrosine kinase CRACC CD2-like receptor activating cytotoxic cells DC Dendritic cell dsDNA Double-stranded DNA EAT-2 Ewing’s sarcoma-activated transcript 2 GAS Interferon gamma-activated site HSV Herpes simplex virus IC Immune complex IFN Interferon IFNAR Interferon alpha receptor IFNGR Interferon gamma receptor IFNLR Interferon lambda receptor Ig Immunoglobulin IL Interleukin ILT Immunoglobulin-like transcript IRAK Interleukin-1 receptor-associated kinase IRF Interferon regulatory factor ISGF Interferon-stimulated gene factor ISRE Interferon-stimulated response element ITAM Immunoreceptor tyrosine-based activation motif ITIM Immunoreceptor tyrosine-based inhibitory motif JAK Janus kinase KIR Killer cell immunoglobulin-like receptor LAIR Leukocyte-associated immunoglobulin-like receptor LAMP Lysosomal-associated membrane protein LFA Lymphocyte function-associated antigen MAPK Mitogen-activated protein kinase MHC Major histocompatibility complex MIP Macrophage inflammatory protein MS Multiple sclerosis MyD88 Myeloid differentiation factor 88 NET Neutrophil extracellular trap NFκB Nuclear factor-κB NIPC Natural interferon producing cell NK Natural killer NZBxW New Zealand Black/White ODN Oligodeoxynucleotide PAMP Pathogen-associated molecular pattern PBMC Peripheral blood mononuclear cell pDC Plasmacytoid dendritic cell pSS Primary Sjögren’s syndrome RA Rheumatoid