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IFN-α Production by Plasmacytoid Dendritic Cells Stimulated with RNA-Containing Immune Complexes Is Promoted by NK Cells via MIP-1β and LFA-1
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Rheumatology, Systemic Autoimmmune Diseases)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Rheumatology, Systemic Autoimmmune Diseases)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Rheumatology, Systemic Autoimmmune Diseases)
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2011 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 186, no 9, 5085-5094 p.Article in journal (Refereed) Published
Abstract [en]

Several systemic autoimmune diseases display a prominent IFN signature. This is caused by a continuous IFN-α production by plasmacytoid dendritic cells (pDCs), which are activated by immune complexes (ICs) containing nucleic acid. The IFN-α production by pDCs stimulated with RNA-containing IC (RNA-IC) consisting of anti-RNP autoantibodies and U1 small nuclear ribonucleoprotein particles was recently shown to be inhibited by monocytes, but enhanced by NK cells. The inhibitory effect of monocytes was mediated by TNF-α, PGE2, and reactive oxygen species, but the mechanisms for the NK cell-mediated increase in IFN-α production remained unclear. In this study, we investigated the mechanisms whereby NK cells increase the RNA-IC–induced IFN-α production by pDCs. Furthermore, NK cells from patients with systemic lupus erythematosus (SLE) were evaluated for their capacity to promote IFN-α production. We found that CD56dim NK cells could increase IFN-α production >1000-fold after RNA-IC activation, whereas CD56bright NK cells required costimulation by IL-12 and IL-18 to promote IFN-α production. NK cells produced MIP-1α, MIP-1β, RANTES, IFN-γ, and TNF-α via RNA-IC–mediated FcγRIIIA activation. The IFN-α production in pDCs was promoted by NK cells via MIP-1β secretion and LFA-mediated cell–cell contact. Moreover, NK cells from SLE patients displayed a reduced capacity to promote the RNA-IC–induced IFN-α production, which could be restored by exogenous IL-12 and IL-18. Thus, different molecular mechanisms can mediate the NK cell-dependent increase in IFN-α production by RNA-IC–stimulated pDCs, and our study suggests that the possibility to therapeutically target the NK–pDC axis in IFN-α–driven autoimmune diseases such as SLE should be investigated.

Place, publisher, year, edition, pages
2011. Vol. 186, no 9, 5085-5094 p.
Keyword [en]
interferon, plasmacytoid dendritic cells, MIP-1beta, NK cells
National Category
Rheumatology and Autoimmunity
Research subject
Medicine
Identifiers
URN: urn:nbn:se:uu:diva-150274DOI: 10.4049/jimmunol.1003349ISI: 000289679600011PubMedID: 21430220OAI: oai:DiVA.org:uu-150274DiVA: diva2:406926
Available from: 2011-03-29 Created: 2011-03-29 Last updated: 2017-12-11Bibliographically approved
In thesis
1. The Role of Plasmacytoid Dendritic Cells and Natural Killer Cells in Systemic Lupus Erythematosus
Open this publication in new window or tab >>The Role of Plasmacytoid Dendritic Cells and Natural Killer Cells in Systemic Lupus Erythematosus
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 963
Keyword
Systemic lupus erythematosus, plasmacytoid dendritic cells, natural killer cells, type I interferon, immune complex, SLAM receptors, autoantibodies, CD94/NKG2A, CD94/NKG2C
National Category
Rheumatology and Autoimmunity
Research subject
Medical Science; Immunology
Identifiers
urn:nbn:se:uu:diva-213674 (URN)978-91-554-8837-6 (ISBN)
Public defence
2014-02-21, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Funder
Swedish Research Council, A0258801Knut and Alice Wallenberg Foundation, 2011.0073Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2014-01-28 Created: 2014-01-02 Last updated: 2014-02-10
2. Regulation of Type I Interferon Production in Plasmacytoid Dendritic Cells: Effect of Genetic Factors and Interactions with NK Cells and B Cells
Open this publication in new window or tab >>Regulation of Type I Interferon Production in Plasmacytoid Dendritic Cells: Effect of Genetic Factors and Interactions with NK Cells and B Cells
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1083
Keyword
Systemic lupus erythemtosus, IFN-alpha, autoimmunity, immune complex, single nuclear polymorphisms
National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-246526 (URN)978-91-554-9203-8 (ISBN)
Public defence
2015-05-08, Fåhraeussalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-04-14 Created: 2015-03-09 Last updated: 2015-04-17

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Hagberg, NiklasBerggren, OlofLeonard, DagEloranta, Maija-LeenaRönnblom, Lars

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