| 1. |
- Petersson McIntyre, Magdalena, 1968, et al.
(författare)
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Hur konsumtionen digitaliseras : Texter från forskningsprojektet Digcon - Digitaliseringen av konsumtionskulturen
- 2019
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Digital teknik håller radikalt på att förändra vår konsumtionskultur. Appar, QR-koder och ständigt mer avancerade mobiltelefoner, samt de digitala spår användningen av dem lämnar efter sig skapar nya konsumtionsbeteenden, nya metoder för marknadsföring och försäljning av produkter, men också nya metoder för forskare att studera konsumtionsmönster. De omformar även vilka vi är som konsumenter. Att forska om den här omvandlingen innebär att undersöka tekniken i sig, de som tillverkar den, de som marknadsför den liksom de som använder den. I forskningsprojektet Digcon – Digitaliseringen av konsumtionskulturen, har forskare från Sverige och Frankrike undersökt olika aspekter av digitalisering och konsumtion. Vilka betydelser har digitala verktyg och apparater i människors vardagsliv och hur förändrar de konsumtionsmönster? Hur påverkar digitaliseringen vad det innebär att vara konsument och hur en konsument uppfattas vara. Hur omformas förståelser av kön, till exempel genom uppkomsten av modebloggar och modeappar? Vilka möjligheter till etisk konsumtion skapas genom digital teknik och vilken etik är det som skapas? I den här rapporten har vi samlat populärvetenskapliga texter från forskningsprojektet. Digcon bedrivs vid Centrum för konsumtionsvetenskap och Centre for retailing, Handelshögskolan vid Göteborgs universitet, Handelshögskolan i Stockholm och Université Tolouse II, Frankrike.
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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. |
- Cochoy, Franck, 1964, et al.
(författare)
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Digitalizing consumption: Introduction
- 2017
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Ingår i: Cochoy, Franck, Hagberg, Johan, Petersson McIntyre, Magdalena & Sörum, Niklas. (2017). Digitalizing Consumption: How devices shape consumer culture. - : Routledge. - 9781138124899 ; , s. 1-19
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Bokkapitel (refereegranskat)
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| 4. |
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Digitalizing Consumption: How Devices Shape Consumer Culture
- 2017
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Samlingsverk (redaktörskap) (övrigt vetenskapligt/konstnärligt)abstract
- Contemporary consumer society is increasingly saturated by digital technology, and the devices that deliver this are increasingly transforming consumption patterns. Social media, smartphones, mobile apps and digital retailing merge with traditional consumption spheres, supported by digital devices which further encourage consumers to communicate and influence other consumers to consume. Through a wide range of empirical studies which analyse the impact of digital devices, this volume explores the digitization of consumption and shows how consumer culture and consumption practices are fundamentally intertwined and mediated by digital devices. Exploring the development of new consumer cultures, leading international scholars from sociology, marketing and ethnology examine the effects on practices of consumption and marketing, through topics including big data, digital traces, streaming services, wearables, and social media’s impact on ethical consumption. Digitalizing Consumption makes an important contribution to practice-based approaches to consumption, particularly the use of market devices in consumers’ everyday consumer life, and will be of interest to scholars of marketing, cultural studies, consumer research, organization and management.
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| 5. |
- Elmqvist, Niklas, 1977, et al.
(författare)
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3DVN: A Mixed Reality Platform for Mobile Navigation Assistance
- 2006
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- We present 3DVN, a Mixed Reality platform for navigation assistance in indoor environments. Built on top of a PC-based wearable computer running the Windows operating system, the platform provides a multimodal user interface for navigating in existing physical buildings, including wireless networking, data glove gestural input, voice communication, head-mounted display, and a 3DOF head tracker. Local positioning is performed using a software-only positioning engine making use of WLAN features for accurately pinpointing the mobile device in three dimensions. The 3DVN system has been implemented as a proof-of-concept of a navigation guidance support device for visitors, and has been field-tested with human subjects in the student center of our university. Informal evaluation of subject ratings indicate a strong interest for the new system, both for guests as well as people familiar with the campus and the building.
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| 6. |
- Elmqvist, Niklas, 1977, et al.
(författare)
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3DVN: A Mixed Reality Platform for Mobile Navigation Assistance
- 2007
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Ingår i: ACM CHI2007 Workshop on Mobile Spatial Interaction. ; , s. 1-4
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Konferensbidrag (refereegranskat)abstract
- We present 3DVN, a Mixed Reality platform for navigation assistance in indoor environments. Built on top of a PC-based wearable computer running the Windows operating system, the platform provides a multimodal user interface to navigate existing physical buildings, including wireless networking, data glove gestural input, voice communication, head-mounted display, and a 3DOF head tracker. Local positioning is performed using a software-only WLAN-based engine to accurately pinpoint the mobile device in three dimensions. We use this system as a platform for a simple theoretical framework for classifying interaction for mobile navigation assistance. Informal qualitative evaluation of our system seems to conform to predictions derived from our framework and shows the need for a rich set of interaction components for successful mobile navigation.
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| 7. |
- Hagberg, Johan, 1973, et al.
(författare)
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Konsumtionsrapporten 2022
- 2022
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- I Konsumtionsrapporten 2022 sammanfattas och analyseras konsumtionen i Sverige under 2021 och merparten av 2022. I den första delen, ”Hushållens konsumtion” ges en översikt över den privata konsumtionen i Sverige, hur den har förändrats i såväl kortare som längre perspektiv samt hushållens framtidstro avseende sin egen och Sveriges ekonomi. I andra delen, ”Detaljhandeln” beskrivs försäljning och utveckling inom detaljhandeln under 2021 och inledningen av 2022 med fokus på olika delbranscher, kanaler och platser, e-handeln respektive den butiksbaserade detaljhandeln. Den andra delen avslutas med handelns framtidsförväntningar. Den tredje delen ”Framtidsutsikter” tar avstamp i konsumenters och handelns framtidsförväntningar från de två första delarna och fördjupar analysen av framtidsutsikter utifrån publicerade prognoser och uttalanden från ekonomiska bedömare. Årets rapport innehåller tre fördjupningsdelar som var en och analyserar aktuella teman inom konsumtion. Under lång tid har det skett en ökad digitalisering av konsumtionen och inte minst under pandemin har många konsumtionsbeteenden förskjutits mot en allt större användning av internet och olika digitala gränssnitt som till exempel webshopar, social media och strömningstjänster. I takt med detta har det också väckts många frågor som berör säkerhet och personlig integritet online. I den första av fördjupningsdelarna analyserar Jeanette Carlsson Hauff konsumenters upplevda fördelar och risker avseende digital integritet vid användning av olika digitala tjänster. I den andra fördjupningsdelen visar Niklas Sörum på konsumenters olika förhållningssätt till datainsamling och datadriven marknadsföring. Andra konsumtionsbeteenden som aktualiserats under de senaste åren är olika typer av reaktioner på eller förberedelser inför kriser i termer av bunkring, hamstring och prepping. I den tredje delen analyserar och diskuterar Elias Mellander olika exempel på kriskonsumtion och hemberedskap.
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| 8. |
- Hagberg, Johan, 1973, et al.
(författare)
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Konsumtionsrapporten 2024
- 2024
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- I Konsumtionsrapporten 2024 sammanfattas och analyseras konsumtionen i Sverige under 2023. I den första delen, ”Hushållens konsumtion” ges en översikt över den privata konsumtionen i Sverige och hur den förändrats. Här beskrivs även hållbarhetsaspekter på konsumtionen samt hushållens framtidsförväntningar på den egna ekonomin. I andra delen, ”Detaljhandeln” beskrivs försäljning och utveckling inom detaljhandeln under 2023 med fokus på olika delbranscher, kanaler och platser, inom e-handeln respektive den butiksbaserade detaljhandeln. Den andra delen avslutas med handelns framtidsförväntningar. Årets Konsumtionsrapport innehåller två fördjupningsdelar som var en och analyserar aktuella teman inom konsumtion. I den första av fördjupningsdelarna diskuterar Magdalena Petersson McIntyre och Emma Björner lyxkonsumtionens utveckling, status, hållbarhet och moral. I den andra fördjupningsdelen belyser Karin M. Ekström kulturkonsumtion med fokus på konstutställningar.
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| 9. |
- 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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| 10. |
- 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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| 11. |
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| 12. |
- Hagberg, Niklas, 1977-
(författare)
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The Role of Plasmacytoid Dendritic Cells and Natural Killer Cells in Systemic Lupus Erythematosus
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 13. |
- Hagberg, Niklas, 1977-, et al.
(författare)
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The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-γ production in T cells from patients with SLE
- 2018
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 77:7, s. 1070-1077
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Genetic variants in the transcription factor STAT4 are associated with increased susceptibility to systemic lupus erythematosus (SLE) and a more severe disease phenotype. This study aimed to clarify how the SLE-associated intronic STAT4 risk allele rs7574865[T] affects the function of immune cells in SLE.Methods Peripheral blood mononuclear cells (PBMCs) were isolated from 52 genotyped patients with SLE. Phosphorylation of STAT4 (pSTAT4) and STAT1 (pSTAT1) in response to interferon (IFN)-α, IFN-γ or interleukin (IL)-12, total levels of STAT4, STAT1 and T-bet, and frequency of IFN-γ+ cells on IL-12 stimulation were determined by flow cytometry in subsets of immune cells before and after preactivation of cells with phytohaemagglutinin (PHA) and IL-2. Cellular responses and phenotypes were correlated to STAT4 risk allele carriership. Janus kinase inhibitors (JAKi) selective for TYK2 (TYK2i) or JAK2 (JAK2i) were evaluated for inhibition of IL-12 or IFN-γ-induced activation of SLE PBMCs.Results In resting PBMCs, the STAT4 risk allele was neither associated with total levels of STAT4 or STAT1, nor cytokine-induced pSTAT4 or pSTAT1. Following PHA/IL-2 activation, CD8+ T cells from STAT4 risk allele carriers displayed increased levels of STAT4 resulting in increased pSTAT4 in response to IL-12 and IFN-α, and an augmented IL-12-induced IFN-γ production in CD8+ and CD4+ T cells. The TYK2i and the JAK2i efficiently blocked IL-12 and IFN-γ-induced activation of PBMCs from STAT4 risk patients, respectively.Conclusions T cells from patients with SLE carrying the STAT4 risk allele rs7574865[T] display an augmented response to IL-12 and IFN-α. This subset of patients may benefit from JAKi treatment.
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| 14. |
- Hjorton, Karin, et al.
(författare)
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Cytokine production by activated plasmacytoid dendritic cells and natural killer cells is suppressed by an IRAK4 inhibitor
- 2018
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- Background: In systemic lupus erythematosus (SLE), immune complexes (ICs) containing self-derived nucleic acids trigger the synthesis of proinflammatory cytokines by immune cells. We asked how an interleukin (IL)-1 receptor-associated kinase 4 small molecule inhibitor (IRAK4i) affects RNA-IC-induced cytokine production compared with hydroxychloroquine (HCQ).Methods: Plasmacytoid dendritic cells (pDCs) and natural killer (NK) cells were isolated from peripheral blood mononuclear cells (PBMCs) of healthy individuals. PBMCs from SLE patients and healthy individuals were depleted of monocytes. Cells were stimulated with RNA-containing IC (RNA-IC) in the presence or absence of IRAK4i I92 or HCQ, and cytokines were measured by immunoassay or flow cytometry. Transcriptome sequencing was performed on RNA-IC-stimulated pDCs from healthy individuals to assess the effect of IRAK4i and HCQ.Results: In healthy individuals, RNA-IC induced interferon (IFN)-α, tumor necrosis factor (TNF)-α, IL-6, IL-8, IFN-γ, macrophage inflammatory protein (MIP)1-α, and MIP1-β production in pDC and NK cell cocultures. IFN-α production was selective for pDCs, whereas both pDCs and NK cells produced TNF-α. IRAK4i reduced the pDC and NK cell-derived cytokine production by 74–95%. HCQ interfered with cytokine production in pDCs but not in NK cells. In monocyte-depleted PBMCs, IRAK4i blocked cytokine production more efficiently than HCQ. Following RNA-IC activation of pDCs, 975 differentially expressed genes were observed (false discovery rate (FDR) < 0.05), with many connected to cytokine pathways, cell regulation, and apoptosis. IRAK4i altered the expression of a larger number of RNA-IC-induced genes than did HCQ (492 versus 65 genes).Conclusions: The IRAK4i I92 exhibits a broader inhibitory effect than HCQ on proinflammatory pathways triggered by RNA-IC, suggesting IRAK4 inhibition as a therapeutic option in SLE.
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| 15. |
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| 16. |
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| 17. |
- Hjorton, Karin, 1974-, et al.
(författare)
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The regulation and pharmacological modulation of immune complex induced type III IFN production by plasmacytoid dendritic cells
- 2020
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivePatients with systemic lupus erythematosus (SLE) have an ongoing interferon (IFN) production due to an activation of plasmacytoid dendritic cells (pDCs), which can be triggered to type I IFN synthesis by RNA containing immune complexes (RNA-IC). Considering emerging data suggesting a role of type III IFN in the SLE disease process, we asked if RNA-IC can induce type III IFN production in pDC and how this production can be regulated.MethodsPeripheral blood mononuclear cells (PBMCs) or immune cell subsets were isolated from healthy blood donors or SLE patients and stimulated with IC containing U1 snRNP and SLE-IgG (RNA-IC). Hydroxychloroquine (HCQ) and an interleukin receptor 1-associated kinase 4 inhibitor (IRAK4i) were added to cell cultures. Cytokine mRNA levels were determined with a microarray and protein levels with immunoassays. Single-cell RNA sequencing of pDCs using ddSEQ technology was performed.ResultsType III IFN mRNA and protein was induced in RNA-IC-stimulated pDC-NK and pDC-B cell co-cultures. A subset of activated pDCs (3%) expressed both type III and type I IFN mRNA. IFN-λ2, IFN-α2b, interleukin (IL)-3, IL-6, or granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced IFN-λ1/3 production 2–5-fold. HCQ and an IRAK4i blocked the RNA-IC-triggered IFN-λ1/3 production (p < 0.01). IFN-α2b and GM-CSF increased the proportion of SLE patients producing IFN-λ1/3 in response to RNA-IC from 11 to 33%.ConclusionsType III IFN production is triggered by RNA-IC in pDCs in a TLR-MyD88-dependent manner, enhanced by NK and B cells as well as several pro-inflammatory cytokines. These results support a contributing role for both type I and type III IFNs in SLE, which needs to be considered when targeting the IFN system in this disease.
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| 18. |
- Lundtoft, Christian, et al.
(författare)
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Function of multiple sclerosis-protective HLA class I alleles revealed by genome-wide protein-quantitative trait loci mapping of interferon signalling
- 2020
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 16:10
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Tidskriftsartikel (refereegranskat)abstract
- Interferons (IFNs) are cytokines that are central to the host defence against viruses and other microorganisms. If not properly regulated, IFNs may contribute to the pathogenesis of inflammatory autoimmune, or infectious diseases. To identify genetic polymorphisms regulating the IFN system we performed an unbiased genome-wide protein-quantitative trait loci (pQTL) mapping of cell-type specific type I and type II IFN receptor levels and their responses in immune cells from 303 healthy individuals. Seven genome-wide significant (p < 5.0E-8) pQTLs were identified. Two independent SNPs that tagged the multiple sclerosis (MS)-protective HLA class I alleles A*02/A*68 and B*44, respectively, were associated with increased levels of IFNAR2 in B and T cells, with the most prominent effect in IgD–CD27+ memory B cells. The increased IFNAR2 levels in B cells were replicated in cells from an independent set of healthy individuals and in MS patients. Despite increased IFNAR2 levels, B and T cells carrying the MS-protective alleles displayed a reduced response to type I IFN stimulation. Expression and methylation-QTL analysis demonstrated increased mRNA expression of the pseudogene HLA-J in B cells carrying the MS-protective class I alleles, possibly driven via methylation-dependent transcriptional regulation. Together these data suggest that the MS-protective effects of HLA class I alleles are unrelated to their antigen-presenting function, and propose a previously unappreciated function of type I IFN signalling in B and T cells in MS immune-pathogenesis.Author summaryGenetic association studies have been very successful in identifying disease-associated single nucleotide polymorphisms (SNPs), but it has been challenging to define the molecular mechanisms underlying these associations. As interferons (IFNs) have a central role in the immune system, we hypothesized that some of the SNPs associated to immune-mediated diseases would affect the IFN system. By combining genetic data with characterization of interferon receptor levels and their responses on the protein level in immune cells from 303 genotyped healthy individuals, we show that two SNPs tagging the HLA class I alleles A*02/A*68 and B*44 are associated with a decreased response to type I IFN stimulation in B cells and T cells. Notably, both HLA-A*02 and HLA-B*44 confer protection from developing multiple sclerosis (MS), which is a chronic inflammatory neurologic disease. In addition to suggesting a pathogenic role of enhanced type I interferon signalling in B cells and T cells in MS, our data emphasize the fact that genetic associations in the HLA locus can affect functions not directly associated to antigen presentation, which conceptually may be important for other diseases genetically associated to the HLA locus.
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| 19. |
- Nilsson, Magnus, et al.
(författare)
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Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma
- 2022
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Ingår i: Drug Design, Development and Therapy. - : Informa Healthcare. - 1177-8881. ; 16, s. 2901-2917
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Janus kinase 1 (JAK1) is implicated in multiple inflammatory pathways that are critical for the pathogenesis of asthma, including the interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin cytokine signaling pathways, which have previously been targeted to treat allergic asthma. Here, we describe the development of AZD0449 and AZD4604, two novel and highly selective JAK1 inhibitors with promising properties for inhalation.Methods: The effects of AZD0449 and AZD4604 in JAK1 signaling pathways were assessed by measuring phosphorylation of signal transducer and activator of transcription (STAT) proteins and chemokine release using immunoassays of whole blood from healthy human volunteers and rats. Pharmacokinetic studies performed on rats evaluated AZD0449 at a lung deposited dose of 52 mu g/kg and AZD4604 at 30 mu g/kg. The efficacy of AZD0449 and AZD4604 was assessed by evaluating lung inflammation (cell count and cytokine levels) and the late asthmatic response (average enhanced pause [Penh]).Results: Both compounds inhibited JAK1-dependent cytokine signaling pathways in a dose-dependent manner in human and rat leukocytes. After intratracheal administration in rats, both compounds exhibited low systemic exposures and medium-to-long terminal lung half-lives (AZD0449, 34 hours; AZD4604, 5 hours). Both compounds inhibited STAT3 and STAT5 phosphorylation in lung tissue from ovalbumin (OVA)-challenged rats. AZD0449 and AZD4604 also inhibited eosinophilia in the lung and reduced the late asthmatic response, measured as Penh in the OVA rat model.Conclusion: AZD0449 and AZD4604 show potential as inhibitors of signaling pathways involved in asthmatic immune responses, with target engagement demonstrated locally in the lung. These findings support the clinical development of AZD0449 and AZD4604 for the treatment of patients with asthma.
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| 20. |
- Reid, Sarah, et al.
(författare)
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Interaction between the STAT4 rs11889341(T) risk allele and smoking confers increased risk of myocardial infarction and nephritis in patients with systemic lupus erythematosus
- 2021
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 80:9, s. 1183-1189
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate how genetics influence the risk of smoking-related systemic lupus erythematosus (SLE) manifestations. Methods: Patients with SLE (ndiscovery cohort=776, nreplication cohort=836) were genotyped using the 200K Immunochip single nucleotide polymorphisms (SNP) Array (Illumina) and a custom array. Sixty SNPs with SLE association (p<5.0×10-8) were analysed. Signal transducer and activator of transcription 4 (STAT4) activation was assessed in in vitro stimulated peripheral blood mononuclear cells from healthy controls (n=45). Results: In the discovery cohort, smoking was associated with myocardial infarction (MI) (OR 1.96 (95% CI 1.09 to 3.55)), with a greater effect in patients carrying any rs11889341 STAT4 risk allele (OR 2.72 (95% CI 1.24 to 6.00)) or two risk alleles (OR 8.27 (95% CI 1.48 to 46.27)). Smokers carrying the risk allele also displayed an increased risk of nephritis (OR 1.47 (95% CI 1.06 to 2.03)). In the replication cohort, the high risk of MI in smokers carrying the risk allele and the association between the STAT4 risk allele and nephritis in smokers were confirmed (OR 6.19 (95% CI 1.29 to 29.79) and 1.84 (95% CI 1.05 to 3.29), respectively). The interaction between smoking and the STAT4 risk allele resulted in further increase in the risk of MI (OR 2.14 (95% CI 1.01 to 4.62)) and nephritis (OR 1.53 (95% CI 1.08 to 2.17)), with 54% (MI) and 34% (nephritis) of the risk attributable to the interaction. Levels of interleukin-12-induced phosphorylation of STAT4 in CD8+ T cells were higher in smokers than in non-smokers (mean geometric fluorescence intensity 1063 vs 565, p=0.0063). Lastly, the IL12A rs564799 risk allele displayed association with MI in both cohorts (OR 1.53 (95% CI 1.01 to 2.31) and 2.15 (95% CI 1.08 to 4.26), respectively). Conclusions: Smoking in the presence of the STAT4 risk gene variant appears to increase the risk of MI and nephritis in SLE. Our results also highlight the role of the IL12-STAT4 pathway in SLE-cardiovascular morbidity.
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- Segerberg, Filip, et al.
(författare)
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Autoantibodies to Killer Cell Immunoglobulin-Like Receptors in Patients With Systemic Lupus Erythematosus Induce Natural Killer Cell Hyporesponsiveness
- 2019
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Natural killer (NK) cell cytotoxicity toward self-cells is restrained by the inhibitory HLA class I-binding receptors CD94/NKG2A and the killer cell immunoglobulin-like receptors (KIRs). CD94/NKG2A and KIRs are also essential for NK cell education, which is a dynamic functional maturation process where a constitutive binding of inhibitory receptors to cognate HLA class I molecules is required for NK cells to maintain their full cytotoxic capacity. Previously, we described autoantibodies to CD94/NKG2A in patients with systemic lupus erythematosus (SLE). In this study we analyzed sera from 191 patients with SLE, 119 patients with primary Sjogren's syndrome (pSS), 48 patients with systemic sclerosis (SSc), and 100 healthy donors (HD) for autoantibodies to eight different KIRs. Anti-KIR autoantibodies were identified in sera from 23.0% of patients with SLE, 10.9% of patients with pSS, 12.5% of patients with SSc, and 3.0% of HD. IgG from anti-KIR-positive SLE patients reduced the degranulation and cytotoxicity of NK cells toward K562 tumor cells. The presence of anti-KIR-autoantibodies reacting with >3 KIRs was associated with an increased disease activity (p < 0.0001), elevated serum levels of IFN-alpha (p < 0.0001), nephritis (p = 0.001), and the presence of anti-Sm (p = 0.007), and anti-RNP (p = 0.003) autoantibodies in serum. Together these findings suggest that anti-KIR autoantibodies may contribute to the reduced function of NK cells in SLE patients, and that a defective NK cell function may be a risk factor for the development of lupus nephritis.
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