| 1. |
- Berggren, Olof, et al.
(författare)
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B lymphocytes enhance the interferon-α production by plasmacytoid dendritic cells
- 2012
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 64:10, s. 3409-3419
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:Type I interferon (IFN) system and B cells are activated in many autoimmune diseases, e.g. systemic lupus erythematosus (SLE). IFNα produced by plasmacytoid dendritic cells (pDC) stimulate several B cell functions, including autoantibody production. However, not much is known how B cells influence the pDC function. We therefore investigated the regulatory effect of B cells on IFNα production by pDC.METHODS:PDC and B cells from healthy blood donor PBMC were stimulated with RNA-containing immune complexes (RNA-IC) consisting of U1 snRNP and IgG from SLE patients, herpes simplex virus (HSV) or oligonucleotide ODN2216, alone or in co-cultures. IFNα, several other cytokines and pDC or B cell-associated surface molecules were analyzed by immunoassays or flow cytometry.RESULTS:B cells enhanced the IFNα production by pDC up to 47-fold, and the effect was most pronounced for pDC stimulated with RNA-IC. Anti-CD31 antibody reduced the RNA-IC-induced IFNα production by 80%, but not when ODN2216 was used as IFN-inducer. Supernatants from ODN2216-stimulated B cells promoted IFNα production by pDC, while supernatants from RNA-IC-stimulated B cells did not.CONCLUSION: Our results reveal a novel B cell function, enhancing the type I IFN production by pDC. Since B cells are activated by type I IFN, this pDC-B cell cross-talk might be of fundamental importance in the etiopathogenesis of SLE, and contribute to a chronic immune activation in SLE and other systemic rheumatic diseases.
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| 2. |
- Berggren, Olof, et al.
(författare)
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Plasmacytoid dendritic cells and RNA-containing immune complexes drive expansion of peripheral B cell subsets with an SLE-like phenotype
- 2017
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 12:8
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Tidskriftsartikel (refereegranskat)abstract
- Background Hyperactive B cells and a continuous interferon (IFN)-alpha production by plasmacytoid dendritic cells (pDCs) play a key role in systemic lupus erythematosus (SLE). We asked whether the interaction between B cells and pDCs stimulated with RNA-containing immune complexes affects peripheral B cell subsets. Methods B cells and pDCs were isolated from blood of healthy individuals and stimulated with immune complexes consisting of SLE-IgG and U1snRNP (RNA-IC). Expression of cell surface molecules as well as IL-6 and IL-10 production were determined by flow cytometry and immunoassays. Gene expression profiles were determined by a NanoString nCounter expression array. Results We found a remarkable increase of double negative CD27-IgD-B cells, from 7% within fresh CD19+B cells to 37% in the RNA-IC-stimulated co-cultures of B cells and pDCs, comparable to the frequency of double negative B cells in SLE patients. Gene expression analysis of the double negative CD27-IgD -and the CD27 + IgD-memory B cells revealed that twenty-one genes were differentially expressed between the two B cell subsets (>= 2-fold, p< 0.001). The, IL21R, IL4R, CCL4, CCL3, CD83 and the IKAROS Family Zinc Finger 2 (IKZ2) showed higher expression in the double negative CD27-IgD-B cells. Conclusion The interactions between B cells and pDCs together with RNA-containing IC led to an expansion of B cells with similar phenotype as seen in SLE, suggesting that the pDC-B cell crosstalk contributes to the autoimmune feed-forward loop in SLE.
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| 3. |
- Hagberg, Niklas, et al.
(författare)
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Anti-NKG2A autoantibodies in a patient with systemic lupus erythematosus
- 2013
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Ingår i: Rheumatology. - : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 52:10, s. 1818-1823
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesTo characterize a novel anti-NKG2A autoantibody detected in a patient with SLE during a severe flare, and in a cross-sectional study investigate the occurrence of such autoantibodies in patients with SLE and primary SS (pSS).MethodsSerum or IgG from patients with SLE, pSS and healthy volunteers were assayed for blocking of anti-NKG2A or HLA-E binding to peripheral blood mononuclear cells or CD94/NKG2A- and CD94/NKG2C-transfected Ba/F3 cells. The anti-NKG2A autoantibodies were evaluated for effect on NK cell degranulation in response to HLA-E-transfected K562 cells. IFN-α was determined by an immunoassay and disease activity by the SLEDAI score.ResultsAnti-NKG2A autoantibodies, which blocked binding of HLA-E tetramers to CD94/NKG2A-transfected cells and impaired NKG2A-mediated inhibition of NK cell activation, were observed in a patient with SLE. The presence of anti-NKG2A autoantibodies was associated with high SLE disease activity (SLEDAI score 14 and 16) and increased serum IFN-α. Of 94 SLE, 60 pSS and 30 healthy donor sera, only the index patient serum contained anti-NKG2A autoantibodies.ConclusionThe presence of autoantibodies targeting NKG2A is a rare event, but when such autoantibodies occur they may promote excessive NK cell function. This can contribute to the pathogenesis by increasing the killing of cells and the release of autoantigens. Our findings highlight the possible importance of NK cells in the SLE disease process.
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| 4. |
- Hagberg, Niklas, 1977-, et al.
(författare)
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Autoantibodies to the CD94/NKG2A and CD94/NKG2C receptors in patients with systemic lupus erythematosus
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Objectives: To investigate the occurrence and function of autoantibodies (autoabs) targeting the CD94/NKG2A, CD94/NKG2C or NKG2D receptors in patients with systemic lupus erythematosus (SLE).Method: Murine Ba/F3 cells transfected with CD94/NKG2A, CD94/NKG2C or NKG2D, and untransfected cells were incubated with sera from 203 patients with SLE and 90 healthy individuals. Binding of immunoglobulin (Ig) to the cells was determined by flow cytometry. Autoabs were characterized with regard to isotype, subclass, λ/κ exclusion and interference with HLA-E-binding. IgG were evaluated for effect on NK cell degranulation in response to HLA-E-transfected K562 target cells, as well as their capacity to induce antibody-dependent cellular cytotoxicity (ADCC). The frequency and phenotype of NK cells from these patients were determined by flow cytometry and the exons encoding NKG2A (KLRC1), NKG2C (KLRC2) and CD94 (KLRD1) were sequenced. The titers of anti-CD94/NKG2A and -CD94/NKG2C autoabs were determined in longitudinally sampled sera and correlated to disease activity (SLEDAI score) and severity (SLICC/ACR damage index).Results: Seven patients with autoabs targeting the CD94/NKG2A receptor were identified. Two of these patients’ autoabs also recognized the CD94/NKG2C receptor. IgG from six of the patients interfered with the binding of HLA-E to CD94/NKG2A, whereas IgG from one patient increased this binding. Of the two patients with anti-CD94/NKG2C autoabs, IgG from one patient blocked, and IgG from the other patient stabilized the binding of HLA-E to CD94/NKG2C. Anti-CD94/NKG2A autoabs abrogated the HLA-E-mediated inhibition of NK cell cytotoxicity by CD94/NKG2A+ NK cells, whereas anti-CD94/NKG2C autoabs interfered with the HLA-E-mediated increased cytotoxicity of CD94/NKG2C+ NK cells. Furthermore, these autoabs induced ADCC of CD94/NKG2A- and CD94/NKG2C-expressing target cells. No uncommon non-synonymous sequence variations were found in the genes encoding NKG2A, NKG2C or CD94. The titers of anti-CD94/NKG2A and -CD94/NKG2C autoabs were associated to the SLEDAI score.Conclusions: Autoabs targeting the CD94/NKG2A or the CD94/NKG2C receptor are found in a subset of patients with SLE. These autoabs affects the cytotoxicity of NK cells, mediate ADCC in vitro and their titers are associated to the disease activity and a more severe SLE phenotype. Consequently, anti-CD94/NKG2A and anti-CD94/NKG2C autoabs may contribute to the pathogenesis of SLE and our findings highlight the possible importance of NK cells in the SLE disease process.
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| 5. |
- Hagberg, Niklas, et al.
(författare)
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Functional Anti-CD94/NKG2A and Anti-CD94/NKG2C Autoantibodies in Patients With Systemic Lupus Erythematosus
- 2015
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Ingår i: ARTHRITIS & RHEUMATOLOGY. - : Wiley. - 2326-5191 .- 2326-5205. ; 67:4, s. 1000-1011
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Recently we serendipitously identified a patient with systemic lupus erythematosus (SLE) who was positive for autoantibodies to CD94/natural killer receptor group 2A (NKG2A). The present study was undertaken to investigate the occurrence and function of autoantibodies targeting lectin-like NK cell receptors in SLE. Methods. Sera from 203 SLE patients and 90 healthy individuals were analyzed, by flow cytometry, for Ig binding to Ba/F3 cells transfected with CD94/NKG2A, CD94/NKG2C, or NKG2D. Autoantibodies identified were characterized with regard to interference with HLA-E binding, effect on NK cell activation in response to HLA-E-transfected K562 cells, and capacity to facilitate antibody-dependent cell-mediated cytotoxicity (ADCC). Levels of autoantibodies were determined in longitudinally sampled sera, and correlations with disease activity (SLE Disease Activity Index 2000) and severity (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) were investigated. Results. Anti-CD94/NKG2A autoantibodies were identified in 7 SLE patients. The autoantibodies from 6 patients inhibited binding of HLA-E to CD94/NKG2A, whereas those from the seventh patient augmented this binding. Autoantibodies from 2 patients also reacted with the activating receptor CD94/NKG2C, with inhibition of the binding of HLA-E to CD94/NKG2C observed in 1 case and enhancement of this binding in the other. None of the sera contained anti-NKG2D autoantibodies. The levels of anti-CD94/NKG2A and anti-CD94/NKG2C autoantibodies correlated with disease activity and with a more severe SLE phenotype. Mechanistically, anti-CD94/NKG2A and anti-CD94/NKG2C autoantibodies both interfered with HLA-E-mediated regulation of NK cell activation and facilitated the elimination of target cells expressing CD94/NKG2A or CD94/NKG2C through ADCC. Conclusion. Anti-CD94/NKG2A and anti-CD94/NKG2C autoantibodies occur in a subset of patients with clinically active SLE. Given their capacity to deplete certain NK cell subsets and interfere with particular NK cell function, such autoantibodies may promote the pathogenesis of SLE.
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| 6. |
- Hagberg, Niklas, et al.
(författare)
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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
- 2011
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 186:9, s. 5085-5094
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Hagberg, Niklas, 1977-, et al.
(författare)
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Immunogenetics in systemic lupus erythematosus : Transitioning from genetic associations to cellular effects
- 2020
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 92:4, s. e12894-
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Systemic lupus erythematosus (SLE) is a heterogeneous rheumatic autoimmune disease. Genetic studies have identified up to 100 SLE risk loci. Many of these encode proteins of importance in the immune system, but the cellular and molecular mechanisms underlying these associations are still elusive. In this review, we will highlight some of the SLE risk loci where mechanistic insights have been achieved recently by linking genetic risk polymorphisms to cellular or molecular phenotypes important for the disease process.
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| 8. |
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| 9. |
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| 10. |
- Hagberg, Niklas, et al.
(författare)
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Systemic lupus erythematosus : a disease with a dysregulated type I interferon system
- 2015
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 82:3, s. 199-207
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Forskningsöversikt (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease characterized by the loss of tolerance to nuclear antigens, immune complex formation and inflammation in multiple organs. The disease is very heterogeneous and most clinicians consider SLE as a group of diseases with similar features where the pathogenesis is driven by a combination of genetic and environmental factors. One of the most prominent features, shared by the majority of SLE patients, is a continuous activation of the type I interferon (IFN) system, which manifests as increased serum levels of IFNα and/or an increased expression of type I IFN induced genes, a so called type I IFN-signature. The mechanisms behind this IFN-signature have partly been clarified during recent years, although the exact function of the IFN regulated genes in the disease process is unclear. In this review we will describe the type I IFN system and its regulation and summarize the numerous findings implicating an important ethiopathogenic role of a dysregulated type I IFN system in SLE. Furthermore, strategies to therapeutically target the type I IFN system that are currently evaluated preclinically and in clinical trials will be mentioned.
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