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  • 1.
    Abramov, Sergei
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Kazan Fed Univ, Inst Fundamental Med & Biol, Kazan, Russia.
    Kozyrev, Sergey V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Farias, Fabiana H. G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Washington Univ, Genome Inst, Sch Med, St Louis, MO USA.
    Dahlqvist, Johanna
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Leonard, Dag
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wilbe, Maria
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Swedish Univ Agr Sci SLU, Dept Anim Breeding & Genet, Uppsala, Sweden.
    Alexsson, Andrei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pielberg, Gerli
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hansson-Hamlin, H.
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Uppsala, Sweden.
    Andersson, G.
    Swedish Univ Agr Sci SLU, Dept Anim Breeding & Genet, Uppsala, Sweden.
    Tandre, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ronnblom, L.
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Uppsala, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    The risk allele A of rs200395694 associated with SLE in Swedish patients affects on MEF2D gene regulation and alternative splicing2018Ingår i: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 29, nr 12, s. A44-A44Artikel i tidskrift (Övrigt vetenskapligt)
  • 2.
    Ahlgren, Kerstin, M.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Wilbe, Maria
    Sundberg, Katarina
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lindblad-Toh, Kerstin
    Andersson, Göran
    Lobell, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Hansson-Hamlin, Helene
    Kämpe, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Type I Interferon signature in Nova Scotia duck tolling retriever dogs with steroid responsive meningitis-arteritisManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Objective: Dogs of the breed Nova Scotia duck tolling retriever (NSDTR) are prone to develop a disease complex in some aspects resembling human systemic lupus erythematosus (SLE). Peripheral blood mononuclear cells (PBMCs) from human SLE patients have an increased mRNA expression type I interferon (IFN) regulated genes. However, it is unknown whether diseased dogs also display the typical type I IFN signature.

    Methods: To test canine sera for their capacity to induce type I IFN response Mardin-Darby canine kidney (MDCK) cells were cultured with sera from healthy dogs (n=25),  immune-mediated rheumatic disease (IMRD) dogs with anti-nuclear antibodies (ANA+) (n=30) or dogs with steroid responsive meningitis-arteritis (SRMA) (n=25). mRNA expression of the genes MX1, IFIT1 and CXCL10 was measured by quantitative Real Time PCR.

    Results: A highly significant (p=0.0009) increase in mRNA expression of the type I IFN responsive gene MX1 was detected in cells stimulated by sera from dogs with SRMA, but not from IMRD ANA+ dogs. Expression of IFIT1 was twice as high in cells stimulated by sera from dogs with SRMA compared to both healthy dogs and ANA+ dogs. The mean expression of CXCL10 was nearly ten times higher in cells stimulated by sera from SRMA dogs than by ANA+ dogs and four times higher compared to cells stimulated by control dogs.

    Conclusion: Presence of type I IFN in sera from diseased NSDTR dogs was found in this study. This implies that this canine model can be used for identification of pathways of importance for autoimmune disorders in humans and for testing of novel therapeutic approaches. Our results can also be a step on the way towards personalized drugs in these dogs.

  • 3.
    Almlöf, Jonas Carlsson
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nystedt, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Leonard, Dag
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Grosso, Giorgia
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit,Rheumatol, S-17177 Stockholm, Sweden.
    Sjowall, Christopher
    Linkoping Univ, Div Neuro & Inflammat Sci, Dept Clin & Expt Med, Rheumatol, S-58183 Linkoping, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Rheumatol, S-22242 Lund, Sweden.
    Jonsen, Andreas
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Rheumatol, S-22242 Lund, Sweden.
    Gunnarsson, Iva
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit,Rheumatol, S-17177 Stockholm, Sweden.
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit,Rheumatol, S-17177 Stockholm, Sweden.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus2019Ingår i: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 138, nr 2, s. 141-150Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Systemic lupus erythematosus (SLE, OMIM 152700) is a systemic autoimmune disease with a complex etiology. The mode of inheritance of the genetic risk beyond familial SLE cases is currently unknown. Additionally, the contribution of heterozygous variants in genes known to cause monogenic SLE is not fully understood. Whole-genome sequencing of DNA samples from 71 Swedish patients with SLE and their healthy biological parents was performed to investigate the general genetic risk of SLE using known SLE GWAS risk loci identified using the ImmunoChip, variants in genes associated to monogenic SLE, and the mode of inheritance of SLE risk alleles in these families. A random forest model for predicting genetic risk for SLE showed that the SLE risk variants were mainly inherited from one of the parents. In the 71 patients, we detected a significant enrichment of ultra-rare (0.1%) missense and nonsense mutations in 22 genes known to cause monogenic forms of SLE. We identified one previously reported homozygous nonsense mutation in the C1QC (Complement C1q C Chain) gene, which explains the immunodeficiency and severe SLE phenotype of that patient. We also identified seven ultra-rare, coding heterozygous variants in five genes (C1S, DNASE1L3, DNASE1, IFIH1, and RNASEH2A) involved in monogenic SLE. Our findings indicate a complex contribution to the overall genetic risk of SLE by rare variants in genes associated with monogenic forms of SLE. The rare variants were inherited from the other parent than the one who passed on the more common risk variants leading to an increased genetic burden for SLE in the child. Higher frequency SLE risk variants are mostly passed from one of the parents to the offspring affected with SLE. In contrast, the other parent, in seven cases, contributed heterozygous rare variants in genes associated with monogenic forms of SLE, suggesting a larger impact of rare variants in SLE than hitherto reported.

  • 4. Balboni, Imelda
    et al.
    Niewold, Timothy B
    Morgan, Gabrielle
    Limb, Cindy
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Utz, Paul J
    Pachman, Lauren M
    Brief Report: Interferon-α Induction and Detection of Anti-Ro, Anti-La, Anti-Sm, and Anti-RNP Autoantibodies by Autoantigen Microarray Analysis in Juvenile Dermatomyositis2013Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, nr 9, s. 2424-2429Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective:

    To evaluate serum interferon- (IFN) activity in the context of autoantibody profiles in patients with juvenile dermatomyositis (JDM). 

    Methods:

    Sera from 36 patients with JDM were analyzed. Autoantibody profiles were determined by probing microarrays, which were fabricated with approximate to 80 distinct autoantigens, with serum and a Cy3-conjugated secondary antibody. Arrays were scanned and analyzed to determine antigen reactivity. Serum IFN activity was measured using a functional reporter cell assay. Sera were assayed alone or in combination with cellular material released from necrotic U937 cells to stimulate peripheral blood mononuclear cells from healthy donors in vitro, and IFN production in culture was measured by a dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA). 

    Results:

    Reactivity against at least 1 of 41 autoantigens on the microarray, including Ro 52, Ro 60, La, Sm, and RNP, was observed in 75% of the serum samples from patients with JDM. IFN activity was detected in 7 samples by reporter cell assay. The reporter cell assay showed a significant association of reactivity against Ro, La, Sm, and proliferating cell nuclear antigen with serum IFN activity (P = 0.005). Significance Analysis of Microarrays (SAM) identified increased reactivity against Sm, RNP, Ro 52, U1-C, and Mi-2 in these sera. Sixteen samples induced IFN production as measured by DELFIA, and there was a significant association of reactivity against Ro, La, Sm, and RNP with the induction of IFN by serum and necrotic cell material (P = 0.034). SAM identified increased reactivity against Ro 60 in these sera. 

    Conclusion:

    These data support the hypothesis that nucleic acid-associated autoantibodies, including the Ro/La and Sm/RNP complexes, may stimulate the production of active IFN in children with JDM.

  • 5.
    Berggren, Olof
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Alexsson, Andrei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Alm, Gunnar V.
    Syvanen, Ann-Christine
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Variation of Interferon-Alpha Production in Healthy Individuals and Association with Autoimmune Susceptibility Genes2012Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, nr S10, s. S961-S961Artikel i tidskrift (Övrigt vetenskapligt)
  • 6.
    Berggren, Olof
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Alexsson, Andrei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Morris, David
    King’s College London School of Medicine, Guy’s Hospital, London.
    Tandre, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Weber, Gert
    Free University of Berlin.
    Vyse, Timothy
    King’s College London School of Medicine, Guy’s Hospital, London.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    IFN-α production by plasmacytoid dendritic cell associations with polymorphisms in gene loci related to autoimmune and inflammatory diseases2015Ingår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, nr 12, s. 3571-3581Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The type I interferon (IFN) system is persistently activated in systemic lupus erythematosus (SLE) and many other systemic autoimmune diseases. Studies have shown an association between SLE and several gene variants within the type I IFN system. We investigated whether single nucleotide polymorphisms (SNPs) associated with SLE and other autoimmune diseases affect the IFN-α production in healthy individuals. Plasmacytoid dendritic cells (pDCs), B and NK cells were isolated from peripheral blood of healthy individuals and stimulated with RNA-containing immune complexes (IC), herpes simplex virus (HSV) or the oligonucleotide ODN2216. IFN-α production by pDCs alone or in cocultures with B or NK cells was measured by an immunoassay. All donors were genotyped with the 200K ImmunoChip and a 5bp CGGGG length polymorphism in the IFN regulatory factor 5 gene (IRF5) was genotyped by PCR. We found associations between IFN-α production and 18-86 SNPs (p ≤ 0.001), depending on the combination of the stimulated cell types. However, only three of these associated SNPs were shared between the cell type combinations. Several SNPs showed novel associations to the type I IFN system among all the associated SNPs, while some loci have been described earlier for their association with SLE. Furthermore, we found that the SLE-risk variant of the IRF5 CGGGG-indel was associated with lower IFN-α production. We conclude that the genetic variants affecting the IFN-α production highlight the intricate regulation of the type I IFN system and the importance of understanding the mechanisms behind the dysregulated type I IFN system in SLE.

  • 7.
    Berggren, Olof
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Alexsson, Andrei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Tandre, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Syvanen, A-C
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Effect of single-nucleotide polymorphisms on type I interferon production by plasmacytoid dendritic cells stimulated with SLE-associated immune complexes2014Ingår i: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 43, nr S127, s. 92-92Artikel i tidskrift (Övrigt vetenskapligt)
  • 8.
    Berggren, Olof
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hagberg, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Alexsson, Andrei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Weber, Gert
    Ernst Moritz Arndt Univ Greifswald, Inst Biochem, Dept Mol Struct Biol, Greifswald, Germany..
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Plasmacytoid dendritic cells and RNA-containing immune complexes drive expansion of peripheral B cell subsets with an SLE-like phenotype2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 8, artikel-id e0183946Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 9.
    Berggren, Olof
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hagberg, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Weber, Gert
    Alm, Gunnar V
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    B lymphocytes enhance the interferon-α production by plasmacytoid dendritic cells2012Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, nr 10, s. 3409-3419Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 10.
    Berggren, Olof
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Activated Plasmacytoid Dendritic Cells (PDCS) Alter The Composition of The Blood B Cell Subsets2016Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, s. 179-179Artikel i tidskrift (Övrigt vetenskapligt)
  • 11.
    Berggren, Olof
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    The effect of PTPN22 Gene Variant R620W on the Type I Interferon Production Stimulated by Different TLR7 Agonists: Comment on Article by Wang et al (pages 2403-2414)2016Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 68, nr 4, s. 1045-1045Artikel i tidskrift (Refereegranskat)
  • 12.
    Blomberg, Stina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Eloranta, Maija-Leena
    Cederblad, Brita
    Nordlin, K
    Alm, G.V.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Presence of cutaneous interferon-alpha producing cells in patients with systemic lupus erythematosus2001Ingår i: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 10, nr 7, s. 484-90Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Systemic lupus erythematosus (SLE) patients have increased levels of interferon-alfa (IFN-alpha) in the circulation but a reduced number of functionally intact natural IFN-alpha producing cells (IPC) in peripheral blood. In search for tissue localisation of activated IPC, we investigated skin biopsies from SLE patients for the occurrence of such cells. Eleven SLE patients with inflammatory skin lesions and six healthy controls were biopsied. An immunohistochemical technique (IH) and in situ hybridisation (ISH) were used to detect intracellular IFN-alpha protein and IFN-alpha mRNA, respectively. In all 11 biopsies from SLE lesions, a high number of IPC were detected by IH. In the nonlesional SLE biopsies we could also demonstrate IPC in 10/11 patients. In 6/11 SLE patients, IFN-alpha mRNA containing cells could be detected in the specimens. A low number of IPC were detected in 1/6 healthy controls by IH, but no ISH positive cells were seen. Our results demonstrate that SLE patients have active IPC in both dermal lesions and in noninflammatory skin. A recruitment of IPC from blood to peripheral tissues may explain the low number of circulating natural IPC in SLE patients. Because the type I IFN system is involved in the SLE disease process, these results are of interest for the understanding of the pathogenesis in SLE.

  • 13.
    Bolin, Karin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Zickert, Agneta
    Jönsen, Andreas
    Sjöwall, Christopher
    Svenungsson, Elisabet
    Bengtsson, Anders A
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gunnarsson, Iva
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Association of STAT4 Polymorphism with Severe Renal Insufficiency in Lupus Nephritis2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 12, s. e84450-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lupus nephritis is a cause of significant morbidity in systemic lupus erythematosus (SLE) and its genetic background has not been completely clarified. The aim of this investigation was to analyze single nucleotide polymorphisms (SNPs) for association with lupus nephritis, its severe form proliferative nephritis and renal outcome, in two Swedish cohorts. Cohort I (n = 567 SLE cases, n = 512 controls) was previously genotyped for 5676 SNPs and cohort II (n = 145 SLE cases, n = 619 controls) was genotyped for SNPs in STAT4, IRF5, TNIP1 and BLK.

    Case-control and case-only association analyses for patients with lupus nephritis, proliferative nephritis and severe renal insufficiency were performed. In the case-control analysis of cohort I, four highly linked SNPs in STAT4 were associated with lupus nephritis with genome wide significance with p = 3.7×10−9, OR 2.20 for the best SNP rs11889341. Strong signals of association between IRF5 and an HLA-DR3 SNP marker were also detected in the lupus nephritis case versus healthy control analysis (p <0.0001). An additional six genes showed an association with lupus nephritis with p <0.001 (PMS2, TNIP1, CARD11, ITGAM, BLK and IRAK1). In the case-only meta-analysis of the two cohorts, the STAT4 SNP rs7582694 was associated with severe renal insufficiency with p = 1.6×10−3 and OR 2.22. We conclude that genetic variations in STAT4 predispose to lupus nephritis and a worse outcome with severe renal insufficiency.

  • 14.
    Bremer, Hanna D.
    et al.
    Swedish Univ Agr Sci, Dept Clin Sci, SE-75007 Uppsala, Sweden..
    Landegren, Nils
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Autoimmunitet. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden..
    Sjöberg, Ronald
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, SE-17121 Solna, Sweden..
    Hallgren, Åsa
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, CMM, L8 01, SE-17176 Stockholm, Sweden..
    Renneker, Stefanie
    Euroimmun AG, D-23560 Lubeck, Germany..
    Lattwein, Erik
    Euroimmun AG, D-23560 Lubeck, Germany..
    Leonard, Dag
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nilsson, Peter
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, SE-17121 Solna, Sweden..
    Andersson, Goran
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden..
    Lilliehöök, Inger
    Swedish Univ Agr Sci, Dept Clin Sci, SE-75007 Uppsala, Sweden..
    Lindblad-Toh, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Broad Inst Harvard & MIT, Cambridge, USA..
    Kämpe, Olle
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Autoimmunitet. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, CMM, L8 01, SE-17176 Stockholm, Sweden.; Univ Bergen, Dept Clin Sci, N-5021 Bergen, Norway.;Univ Bergen, KG Jebsen Ctr Autoimmune Disorders, N-5021 Bergen, Norway.;Haukeland Hosp, Dept Med, N-5021 Bergen, Norway..
    Hansson-Hamlin, Helene
    Swedish Univ Agr Sci, Dept Clin Sci, SE-75007 Uppsala, Sweden..
    ILF2 and ILF3 are autoantigens in canine systemic autoimmune disease2018Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikel-id 4852Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Dogs can spontaneously develop complex systemic autoimmune disorders, with similarities to human autoimmune disease. Autoantibodies directed at self-antigens are a key feature of these autoimmune diseases. Here we report the identification of interleukin enhancer-binding factors 2 and 3 (ILF2 and ILF3) as autoantigens in canine immune-mediated rheumatic disease. The ILF2 autoantibodies were discovered in a small, selected canine cohort through the use of human protein arrays; a method not previously described in dogs. Subsequently, ILF3 autoantibodies were also identified in the same cohort. The results were validated with an independent method in a larger cohort of dogs. ILF2 and ILF3 autoantibodies were found exclusively, and at a high frequency, in dogs that showed a speckled pattern of antinuclear antibodies on immunofluorescence. ILF2 and ILF3 autoantibodies were also found at low frequency in human patients with SLE and Sjogren's syndrome. These autoantibodies have the potential to be used as diagnostic biomarkers for canine, and possibly also human, autoimmune disease.

  • 15.
    Båve, Ullvi
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Magnuson, Mattias
    Eloranta, Maija-Leena
    Perers, Anders
    Alm, Gunnar V.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Fc gamma RIIa is expressed on natural IFN-alpha-producing cells (plasmacytoid dendritic cells) and is required for the IFN-alpha production induced by apoptotic cells combined with lupus IgG2003Ingår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 171, nr 6, s. 3296-302Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An ongoing production of IFN-alpha may be of etiopathogenic significance in systemic lupus erythematosus (SLE). It may be due to the natural IFN-producing cells (NIPC), also termed plasmacytoid dendritic cells (PDC), activated by immune complexes that contain nucleic acids derived from apoptotic cells. We here examined the role of FcgammaR in the IFN-alpha production in vitro by PBMC induced by the combination of apoptotic U937 cells and autoantibody-containing IgG from SLE patients (SLE-IgG). The Fc portion of the SLE-IgG was essential to induce IFN-alpha production, because Fab fragments or F(ab')(2) were ineffective. Normal, especially heat-aggregated, IgG inhibited the IFN-alpha production, suggesting a role for FcgammaR on PBMC. Using blocking anti-FcgammaR Abs, the FcgammaRIIa,c (CD32) but not FcgammaRI or FcgammaRIII were shown to be involved in the IFN-alpha induction by apoptotic cells combined with SLE-IgG, but not by HSV or CpG DNA. In contrast, the action of all of these inducers was inhibited by the anti-FcgammaRIIa,b,c mAb AT10 or heat-aggregated IgG. Flow cytometric analysis revealed that approximately 50% of the BDCA-2-positive PBMC, i.e., NIPC/PDC, expressed low but significant levels of FcgammaRII, as did most of the actual IFN-alpha producers activated by HSV. RT-PCR applied to NIPC/PDC purified by FACS demonstrated expression of FcgammaRIIa, but not of FcgammaRIIb or FcgammaRIIc. We conclude that FcgammaRIIa on NIPC/PDC is involved in the activation of IFN-alpha production by interferogenic immune complexes, but may also mediate inhibitory signals. The FcgammaRIIa could therefore have a key function in NIPC/PDC and be a potential therapeutic target in SLE.

  • 16.
    Båve, Ullvi
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lövgren, Tanja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Rönnelid, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Cajander, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Eloranta, Maija-Leena
    Alm, Gunnar V.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Activation of the type I interferon system in primary Sjögren's syndrome: a possible etiopathogenic mechanism2005Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 52, nr 4, s. 1185-1195Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective

    The etiopathogenesis of primary Sjögren's syndrome (SS) is largely unknown. In other autoimmune diseases, type I interferon (IFN) may play a pivotal role by triggering and sustaining the disease process. We therefore aimed to determine whether patients with primary SS had an activated type I IFN system.

    Methods

    Salivary gland biopsy specimens and sera from patients with primary SS were investigated for the occurrence of IFNα-producing cells and measurable IFNα levels, respectively. The ability of primary SS sera together with apoptotic or necrotic cells to induce IFNα production in normal peripheral blood mononuclear cells was examined. The IFNα inducer was characterized, and IFNα-producing cells were identified. Clinical data were correlated with the IFNα-inducing capacity of primary SS sera.

    Results

    Numerous IFNα-producing cells were detected in salivary gland biopsy specimens, despite low serum IFNα levels. Autoantibodies to RNA-binding proteins, combined with material released by necrotic or late apoptotic cells, were potent inducers of IFNα production in plasmacytoid dendritic cells (PDCs). This appeared to be attributable to RNA-containing immune complexes triggering PDCs by means of RNA and interaction with Fcγ receptor IIa. The IFNα-inducing capacity of sera was associated with positive results of a labial salivary gland biopsy (focus score ≥1) and with dermatologic, hematologic, and pulmonary manifestations.

    Conclusion

    Patients with primary SS have an activated type I IFN system. Although virus may initiate the production of IFN, the continued IFNα synthesis is caused by RNA-containing immune complexes that activate PDCs to prolong IFNα production at the tissue level. This IFNα promotes the autoimmune process by a vicious circle–like mechanism, with increased autoantibody production and formation of more endogenous IFNα inducers.

  • 17.
    Carlsson Almlöf, Jonas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Alexsson, Andrei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Imgenberg-Kreuz, Juliana
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin.
    Sylwan, Lina
    Karolinska Inst, Dept Biosci & Nutr, Sci Life Lab SciLifeLab, Solna, Sweden..
    Bäcklin, Christofer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Leonard, Dag
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tandre, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Padyukov, Leonid
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Bengtsson, Christine
    Umea Univ, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden..
    Jonsen, Andreas
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Rheumatol, Lund, Sweden..
    Dahlqvist, Solbritt Rantapaa
    Umea Univ, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden..
    Sjowall, Christopher
    Linkoping Univ, Dept Clin & Expt Med, AIR Rheumatol, Linkoping, Sweden..
    Bengtsson, Anders A.
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Rheumatol, Lund, Sweden..
    Gunnarsson, Iva
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Novel risk genes for systemic lupus erythematosus predicted by random forest classification2017Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, artikel-id 6236Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genome-wide association studies have identified risk loci for SLE, but a large proportion of the genetic contribution to SLE still remains unexplained. To detect novel risk genes, and to predict an individual's SLE risk we designed a random forest classifier using SNP genotype data generated on the "Immunochip" from 1,160 patients with SLE and 2,711 controls. Using gene importance scores defined by the random forest classifier, we identified 15 potential novel risk genes for SLE. Of them 12 are associated with other autoimmune diseases than SLE, whereas three genes (ZNF804A, CDK1, and MANF) have not previously been associated with autoimmunity. Random forest classification also allowed prediction of patients at risk for lupus nephritis with an area under the curve of 0.94. By allele-specific gene expression analysis we detected cis-regulatory SNPs that affect the expression levels of six of the top 40 genes designed by the random forest analysis, indicating a regulatory role for the identified risk variants. The 40 top genes from the prediction were overrepresented for differential expression in B and T cells according to RNA-sequencing of samples from five healthy donors, with more frequent over-expression in B cells compared to T cells.

  • 18.
    Cavalli, Marco
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Pan, Gang
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Nord, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Wallerman, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Arzt, Emelie Wallén
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Karolinska Inst, Dept Biosci & Nutr, Ctr Biosci, Huddinge, Sweden..
    Berggren, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Elvers, Ingegerd
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Toh, Kerstin Lindblad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Wadelius, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Allele-specific transcription factor binding to common and rare variants associated with disease and gene expression2016Ingår i: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 135, nr 5, s. 485-497Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genome-wide association studies (GWAS) have identified a large number of disease-associated SNPs, but in few cases the functional variant and the gene it controls have been identified. To systematically identify candidate regulatory variants, we sequenced ENCODE cell lines and used public ChIP-seq data to look for transcription factors binding preferentially to one allele. We found 9962 candidate regulatory SNPs, of which 16 % were rare and showed evidence of larger functional effect than common ones. Functionally rare variants may explain divergent GWAS results between populations and are candidates for a partial explanation of the missing heritability. The majority of allele-specific variants (96 %) were specific to a cell type. Furthermore, by examining GWAS loci we found >400 allele-specific candidate SNPs, 141 of which were highly relevant in our cell types. Functionally validated SNPs support identification of an SNP in SYNGR1 which may expose to the risk of rheumatoid arthritis and primary biliary cirrhosis, as well as an SNP in the last intron of COG6 exposing to the risk of psoriasis. We propose that by repeating the ChIP-seq experiments of 20 selected transcription factors in three to ten people, the most common polymorphisms can be interrogated for allele-specific binding. Our strategy may help to remove the current bottleneck in functional annotation of the genome.

  • 19. de Jong, T. D.
    et al.
    Vosslamber, S.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Mantel, E.
    Gelderman, K. A.
    von Blomberg, M. E.
    Bultink, I. E.
    Voskuyl, A. E.
    Verweij, C. L.
    On the Origin of the Type I Interferon Activity in Rheumatoid Arthritis2013Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, nr S1, s. A79-A79Artikel i tidskrift (Övrigt vetenskapligt)
  • 20. de Jong, T. D.
    et al.
    Vosslamber, Saskia
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Gelderman, Kyra
    von Blomberg, Mary
    Bultink, Irene
    Voskuyl, Alexandre
    Verweij, Cornelis L.
    On the Origin of the Type I Interferon Signature in Rheumatoid Arthritis2012Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, nr S10, s. S770-S771Artikel i tidskrift (Övrigt vetenskapligt)
  • 21.
    Eloranta, Maija-Leena
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Alm, Gunnar V
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Disease Mechanisms in RheumatologyTools and Pathways: Plasmacytoid Dendritic Cells and Their Role in AutoimmuneRheumatic Diseases2013Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, nr 4, s. 853-863Artikel i tidskrift (Refereegranskat)
  • 22.
    Eloranta, Maija-Leena
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Franck-Larsson, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lövgren, Tanja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kalamajski, Sebastian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Rönnblom, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Rubin, Kristofer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Alm, Gunnar V.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Type I interferon system activation and association with disease manifestations in systemic sclerosis2010Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 69, nr 7, s. 1396-1402Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVES: To study the presence of interferogenic autoantibodies in systemic sclerosis (SSc) and their correlation with clinical manifestations, serum levels of interferon alpha (IFNalpha) and chemokines of importance in the disease process. METHODS: Peripheral blood mononuclear cells (PBMCs) or purified plasmacytoid dendritic cells (pDCs) from healthy donors were stimulated with sera from patients with SSc (n=70) or healthy individuals (n=30), together with necrotic or apoptotic cell material. The IFNalpha produced and serum levels of IFNalpha, IFN-inducible protein-10 (IP-10)/chemokine (C-X-C motif) ligand 10, monocyte chemoattractant protein-1 (MCP-1)/(C-C motif) ligand-2 (CCL-2), macrophage inflammatory protein-1alpha (MIP-1alpha)/CCL-3 and RANTES/CCL-5 were measured and correlated with the presence of autoantibodies and clinical manifestations in the patients with SSc. RESULTS: Sera from both diffuse SSc and limited SSc contained interferogenic antibodies, which correlated with the presence of anti-ribonucleoprotein and anti-Sjögren syndrome antigen autoantibodies. The pDCs were responsible for the IFNalpha production which required interaction with FcgammaRII and endocytosis. Increased serum levels of IP-10 were associated with vascular manifestations such as cardiac involvement (p=0.027) and pulmonary arterial hypertension (p=0.036). Increased MCP-1 or IFNalpha serum levels were associated with lung fibrosis (p=0.019 and 0.048, respectively). Digital ulcers including digital loss were associated with increased serum levels of IFNalpha (p=0.029). CONCLUSION: An activated type I IFN system previously seen in several other systemic autoimmune diseases is also present in SSc and may contribute to the vascular pathology and affect the profibrotic process.

  • 23.
    Eloranta, Maija-Leena
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Helmers, Sevim Barbasso
    Ulfgren, Ann-Kristin
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Alm, Gunnar V.
    SLU.
    Lundberg, Ingrid E.
    A possible mechanism for endogenous activation of the type I interferon system in myositis patients with anti-Jo-1 or anti-Ro 52/anti-Ro 60 autoantibodies2007Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 56, nr 9, s. 3112-3124Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: To investigate type I interferon (IFN) system activation and its correlation with autoantibodies and organ manifestations in polymyositis (PM), dermatomyositis (DM), and inclusion body myositis. METHODS: Sera from 30 patients and 16 healthy controls, or purified IgG, were combined with material released from necrotized cells to stimulate IFNalpha production by peripheral blood mononuclear cells (PBMCs) from healthy blood donors. Muscle biopsy specimens from 25 patients and 7 healthy controls were investigated for blood dendritic cell antigen 2 (BDCA-2)-positive plasmacytoid dendritic cells (PDCs) and IFNalpha/beta-inducible myxovirus resistance 1 (MX-1) protein. RESULTS: Sera from 13 patients who were positive for anti-Jo-1 or anti-Ro 52/anti-Ro 60 autoantibodies induced IFNalpha production in PBMCs when combined with necrotic cell material. In addition, IgG prepared from anti-Jo-1-positive PM sera induced IFNalpha with necrotic material, but not when the latter was treated with RNase. BDCA-2 expression in PDCs in muscle tissue was increased in PM patients with anti-Jo-1 autoantibodies, while MX-1 staining in capillaries was increased in DM patients, compared with healthy individuals. IFNalpha-inducing capacity correlated with interstitial lung disease, while MX-1 expression in the capillaries correlated with DM. CONCLUSION: Immune complexes containing anti-Jo-1 or anti-Ro 52/anti-Ro 60 autoantibodies and RNA may act as endogenous IFNalpha inducers that activate IFNalpha production in PDCs. These PDCs could be of importance for inducing myositis, whereas in DM patients without autoantibodies the presence of MX-1 protein in capillaries suggests another cellular IFNalpha source and induction mechanism. Consequently, the type I IFN system may be of importance in both PM and DM, but via different pathways.

  • 24.
    Eloranta, Maija-Leena
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Lövgren, Tanja
    Uppsala universitet.
    Finke, Doreen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Mathsson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Rönnelid, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för klinisk immunologi.
    Kastner, Berthold
    Alm, Gunnar V.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Regulation of the interferon-alpha production induced by RNA-containing immune complexes in plasmacytoid dendritic cells2009Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, nr 8, s. 2418-2427Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Interferon-alpha (IFNalpha) is produced in several autoimmune diseases, including systemic lupus erythematosus (SLE), and may be important in their pathogenesis. We undertook this study to investigate how IFNalpha production induced by RNA-containing immune complexes (ICs) in plasmacytoid dendritic cells (PDCs) is regulated. METHODS: Normal PDCs purified from peripheral blood mononuclear cells (PBMCs) were cocultivated with other cell populations isolated from healthy individuals or SLE patients. IFNalpha production was induced by RNA-containing ICs, which consisted of anti-RNP autoantibodies and U1 small nuclear RNP particles, and the effects of prostaglandin E2 (PGE2), reactive oxygen species (ROS), or the cytokines IFNalpha2b, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-10 (IL-10), or tumor necrosis factor alpha (TNFalpha) were explored. RESULTS: Monocytes inhibited IFNalpha production by PDCs in PBMC cultures, while natural killer (NK) cells were stimulatory. The monocytes had little effect on IFNalpha production by pure PDCs but inhibited its stimulation by NK cells. Monocytes from SLE patients were less inhibitory. Exposure of PBMCs or PDCs to IFNalpha2b/GM-CSF increased their IFNalpha production. RNA-containing ICs caused production of ROS, PGE2, and TNFalpha, especially in monocytes. These mediators and IL-10 suppressed IFNalpha production in PBMC cultures, with ROS and PGE2 also inhibiting IFNalpha production by purified PDCs. Inhibition by all of these agents, except for ROS, was abolished by IFNalpha2b/GM-CSF. The inhibitory effect of monocytes was significantly counteracted by the ROS scavengers serotonin and catalase. CONCLUSION: IFNalpha production induced by RNA-containing ICs in PDCs is regulated by a network of interactions between monocytes, NK cells, and PDCs, involving several pro- and antiinflammatory molecules. This should be considered when designing and applying new therapies.

  • 25.
    Eloranta, Maija-Leena
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Cause and consequences of the activated type I interferon system in SLE2016Ingår i: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 94, nr 10, s. 1103-1110Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Patients with systemic lupus erythematosus (SLE) have an increased expression of type I interferon (IFN)-regulated genes (an IFN signature), which is caused by an ongoing production of type I IFNs by plasmacytoid dendritic cells (pDCs). The reasons behind the continuous IFN production in SLE are the presence of self-derived IFN inducers and a lack of negative feed-back signals that downregulate the IFN response. In addition, several cells in the immune system promote the IFN production by pDCs and gene variants in the type I IFN signaling pathway contribute to the IFN signature. The type I IFNs act as an immune adjuvant and stimulate T cells, B cells, and monocytes, which all play an important role in the loss of tolerance and persistent autoimmune reaction in SLE. Consequently, new treatments aiming to inhibit the activated type I IFN system in SLE are now being developed and investigated in clinical trials.

  • 26.
    Eloranta, Maija-Leena
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Dual role of CpG-stimulated B cells in the regulation of dendritic cells: comment on the article by Berggren et al Reply2013Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, nr 8, s. 2216-Artikel i tidskrift (Övrigt vetenskapligt)
  • 27. Enocsson, Helena
    et al.
    Sjöwall, Christopher
    Kastbom, Alf
    Skogh, Thomas
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Wetterö, Jonas
    Serum C-reactive protein (CRP) associates with lupus disease activity in the absence of measurable interferon alpha and a CRP gene variant2014Ingår i: Arthritis & rheumatology, ISSN 2326-5205, Vol. 66, nr 6, s. 1568-1573Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: The type I interferon (IFN) system is important in the pathogenesis of systemic lupus erythematosus (SLE). We previously demonstrated an inhibitory effect of IFNα on interleukin 6 (IL-6) induced C-reactive protein (CRP) in vitro, hypothetically explaining the poor correlation between disease activity and CRP levels in SLE. Herein we investigated disease activity, IL-6 and CRP in relation to a CRP gene polymorphism and IFNα

    Methods: Sera from 155 SLE patients and 100 controls were analyzed for CRP. Patients were genotyped for a CRP single nucleotide polymorphism (rs1205) associated with low CRP levels. Serum IFNα and IL-6 was quantified by immunoassays. Clinical disease activity was assessed by SLE disease activity index 2000 (SLEDAI-2K).

    Results: CRP levels were increased in SLE patients compared to controls, but were not associated with SLEDAI-2K or IL-6 levels. However, exclusion of patients carrying at least one rs1205 minor allele revealed an association between disease activity and CRP levels (p=0.005). We found a strong association between disease activity and CRP levels (p<0.0005) when patients with measurable IFNα as well as the minor allele of rs1205 where excluded from the analysis. Similarly, when patients with raised IFNα and/or the rs1205 polymorphism were excluded, IL-6 associated with CRP levels.

    Conclusions: The present study demonstrates that serum IFNα as well as CRP genotype affects the CRP response in SLE patients. Lack of correlation between serum levels of CRP and disease activity could therefore be explained by activation of the type I IFN system and polymorphisms in the CRP gene.

  • 28. Enocsson, Helena
    et al.
    Sjöwall, Christopher
    Skogh, Thomas
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Wetterö, Jonas
    Interferon-alpha Mediates Suppression of C-Reactive Protein Explanation for Muted C-Reactive Protein Response in Lupus Flares?2009Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, nr 12, s. 3755-3760Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective. C-reactive protein (CRP) is synthesized by hepatocytes in response to interleukin-6 (IL-6) during inflammation. Despite raised IL-6 levels and extensive systemic inflammation, serum CRP levels remain low during most viral infections and disease flares of systemic lupus erythematosus (SLE). Because both viral infections and SLE are characterized by high levels of interferon-alpha (IFN alpha), the aim of this study was to determine whether this cytokine can inhibit the induction of CRP. Methods. The interference of all 12 IFN alpha subtypes with CRP promoter activity induced by IL-6 and IL-1 beta was studied in a CRP promoter- and luciferase reporter-transfected human hepatoma cell line, Hep-G2. CRIP secretion by primary human hepatocytes was analyzed by enzyme-linked immunosorbent assay. Results. CRP promoter activity was inhibited by all single IFN alpha subtypes, as well as by 2 different mixtures of biologically relevant IFN alpha subtypes. The most prominent effect was seen using a leukocyte-produced mixture of IFN alpha (56% inhibition at 1,000 IU/ml). The inhibitory effect of IFN alpha was confirmed in primary human hepatocytes. CRP promoter inhibition was dose dependent and mediated via the type I IFN receptor. Transferrin production and Hep-G2 proliferation/viability were not affected by IFN alpha. Conclusion. The current study demonstrates that IFN alpha is an inhibitor of CRP promoter activity and CRP secretion. This finding concords with previous observations of up-regulated IFN alpha and a muted CRP response during SLE disease flares. Given the fundamental role of both IFN alpha and CRP in the immune response, our results are of importance for understanding the pathogenesis of SLE and may also contribute to understanding the differences in the CRP response between viral and bacterial infections.

  • 29. Espinosa, Alexander
    et al.
    Dardalhon, Valerie
    Brauner, Susanna
    Ambrosi, Aurelie
    Higgs, Rowan
    Quintana, Fransisco J.
    Sjöstrand, Maria
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ní Gabhann, Joan
    Winqvist, Ola
    Sundelin, Birgitta
    Jefferies, Caroline A.
    Rozell, Björn
    Kuchroo, Vijay K.
    Wahren-Herlenius, Marie
    Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway2009Ingår i: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 206, nr 8, s. 1661-1671Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ro52/Trim21 is targeted as an autoantigen in systemic lupus erythematosus and Sjögren's syndrome. Polymorphisms in the Ro52 gene have been linked to these autoimmune conditions, but the molecular mechanism by which Ro52 may promote development of systemic autoimmune diseases has not been explored. To address this issue, we generated Ro52-null mice (Ro52(-/-)), which appear phenotypically normal if left unmanipulated. However, Ro52(-/-) mice develop severe dermatitis extending from the site of tissue injury induced by ear tags. The affected mice further develop several signs of systemic lupus with hypergammaglobulinemia, autoantibodies to DNA, proteinuria, and kidney pathology. Ro52, which was recently identified as an E3 ligase, mediates ubiquitination of several members of the interferon regulatory factor (IRF) family, and the Ro52-deficient mice have an enhanced production of proinflammatory cytokines that are regulated by the IRF transcription factors, including cytokines involved in the Th17 pathway (interleukin [IL] 6, IL-12/IL-23p40, and IL-17). Loss of IL-23/IL-17 by genetic deletion of IL-23/p19 in the Ro52(-/-) mice conferred protection from skin disease and systemic autoimmunity. These data reveal that the lupus-associated Ro52 protein is an important negative regulator of proinflammatory cytokine production, and they provide a mechanism by which a defective Ro52 function can lead to tissue inflammation and systemic autoimmunity through the IL-23-Th17 pathway.

  • 30.
    Farias, Fabiana H. G.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
    Dahlqvist, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kozyrev, Sergey V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Leonard, Dag
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wilbe, Maria
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences (SLU), Box 7023, SE-750 07, Uppsala, Sweden.
    Abramov, Sergei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, 420008, Russia.
    Alexsson, Andrei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pielberg, Gerli
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hansson-Hamlin, Helene
    Department of Clinical Sciences, Swedish University of Agricultural Sciences (SLU), Box 7054, SE-750 07, Uppsala, Sweden.
    Andersson, Göran
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences (SLU), Box 7023, SE-750 07, Uppsala, Sweden.
    Tandre, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bengtsson, Anders A
    Department of Clinical Sciences Lund, Lund University, Skane University Hospital, SE-221 00, Lund, Sweden.
    Sjöwall, Christopher
    Department of Clinical and Experimental Medicine, Rheumatology/Division of Neuro and Inflammation Sciences, Linköping University, SE-581 85, Linköping, Sweden.
    Svenungsson, Elisabet
    Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.
    Gunnarsson, Iva
    Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, SE-901 85, Umeå, Sweden.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lindblad-Toh, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Broad Institute, Cambridge, 7 Cambridge Center, Cambridge, MA, 02142, USA.
    A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts2019Ingår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, s. 432-441Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical presentation and complex etiology involving the interplay between genetic, epigenetic, environmental and hormonal factors. Many common SNPs identified by genome wide-association studies (GWAS) explain only a small part of the disease heritability suggesting the contribution from rare genetic variants, undetectable in GWAS, and complex epistatic interactions. Using targeted re-sequencing of coding and conserved regulatory regions within and around 215 candidate genes selected on the basis of their known role in autoimmunity and genes associated with canine immune-mediated diseases, we identified a rare regulatory variant rs200395694:G > T located in intron 4 of the MEF2D gene encoding the myocyte-specific enhancer factor 2D transcription factor and associated with SLE in Swedish cohorts (504 SLE patients and 839 healthy controls, p = 0.014, CI = 1.1-10). Fisher's exact test revealed an association between the genetic variant and a triad of disease manifestations including Raynaud, anti-U1-ribonucleoprotein (anti-RNP), and anti-Smith (anti-Sm) antibodies (p = 0.00037) among the patients. The DNA-binding activity of the allele was further studied by EMSA, reporter assays, and minigenes. The region has properties of an active cell-specific enhancer, differentially affected by the alleles of rs200395694:G > T. In addition, the risk allele exerts an inhibitory effect on the splicing of the alternative tissue-specific isoform, and thus may modify the target gene set regulated by this isoform. These findings emphasize the potential of dissecting traits of complex diseases and correlating them with rare risk alleles with strong biological effects.

  • 31.
    Farias, Fabiana
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Wilbe, Maria
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Dahlqvist, Johanna
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Leonard, Dag
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Kozyrev, Sergey
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Pielberg, Gerli
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Eloranta, Maija-Leena
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Rönnblom, Lars
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Lindblad-Toh, Kerstin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    High-Throughput Sequencing of 219 Candidate Genes for Identification of SLE-Associated Risk Variants2014Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, Vol. 66, nr S10, s. S1170-S1170, artikel-id 2673Artikel i tidskrift (Övrigt vetenskapligt)
  • 32. Feng, Di
    et al.
    Stone, Rivka C.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Sangster-Guity, Niquiche
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Sigurdsson, Snaevar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Wang, Chuan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Alm, Gunnar
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Barnes, Betsy J.
    Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus2010Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, nr 2, s. 562-573Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Genetic variants of the interferon (IFN) regulatory factor 5 gene (IRF5) are associated with susceptibility to systemic lupus erythematosus (SLE). The contribution of these variants to IRF-5 expression in primary blood cells of SLE patients has not been addressed, nor has the role of type I IFNs. The aim of this study was to determine the association between increased IRF-5 expression and the IRF5 risk haplotype in SLE patients. METHODS: IRF-5 transcript and protein levels in 44 Swedish patients with SLE and 16 healthy controls were measured by quantitative real-time polymerase chain reaction, minigene assay, and flow cytometry. Single-nucleotide polymorphisms rs2004640, rs10954213, and rs10488631 and the CGGGG insertion/deletion were genotyped in these patients. Genotypes of these polymorphisms defined both a common risk haplotype and a common protective haplotype. RESULTS: IRF-5 expression and alternative splicing were significantly up-regulated in SLE patients compared with healthy donors. Enhanced transcript and protein levels were associated with the risk haplotype of IRF5; rs10488631 displayed the only significant independent association that correlated with increased transcription from the noncoding first exon 1C. Minigene experiments demonstrated an important role for rs2004640 and the CGGGG insertion/deletion, along with type I IFNs, in regulating IRF5 expression. CONCLUSION: This study provides the first formal proof that IRF-5 expression and alternative splicing are significantly up-regulated in primary blood cells of patients with SLE. Furthermore, the risk haplotype is associated with enhanced IRF-5 transcript and protein expression in patients with SLE.

  • 33.
    Finke, Doreen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Endogenous type I interferon inducers in autoimmune diseases2009Ingår i: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 42, nr 4, s. 349-352Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Type I interferon (IFN) is produced by the innate immune system in several autoimmune diseases, such as systemic lupus erythematosus (SLE), polymyositis, and systemic sclerosis. In these diseases, immune complex (IC)-containing DNA or RNA may act as endogenous IFN inducers. The abilities of these IC to reach the endosomes in the plasmacytoid dendritic cells (PDC) cause the intracellular toll-like receptor (TLR) to initiate a cascade of transcription factors--a critical step in triggering type I IFN production. A special configuration of the nucleic acid (NA), such as CpG-rich non-methylated DNA or GU-rich RNA, appears crucial. However, other components of the IC, like HMGB1, may also be necessary. Studies regarding the genetic background of autoimmune diseases suggest that variants of genes involved in both IFN production and response are associated with disease susceptibility. This knowledge is important for the development of new therapeutic strategies in autoimmune diseases.

  • 34.
    Folkersen, Lasse
    et al.
    Department of Bioinformatics, Technical University of Denmark, Lyngby, Denmark.; Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Brynedal, Boel
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Diaz-Gallo, Lina Marcela
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Ramsköld, Daniel
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Shchetynsky, Klementy
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Westerlind, Helga
    nstitute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Sundström, Yvonne
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Schepis, Danika
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Hensvold, Aase
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Vivar, Nancy
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Eloranta, Maija-Leena
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Brunak, Søren
    Department of Bioinformatics, Technical University of Denmark, Lyngby, Denmark.
    Malmström, Vivianne
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Catrina, Anca
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Moerch, Ulrik Gw
    Klareskog, Lars
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Padyukov, Leonid
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Berg, Louise
    Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Integration of known DNA, RNA and protein biomarkers provides prediction of anti-TNF response in rheumatoid arthritis: results from the COMBINE study.2016Ingår i: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 22, s. 322-328Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: In rheumatoid arthritis (RA) several recent efforts have sought to discover means of predicting which patients would benefit from treatment. However, results have been discrepant with few successful replications. Our objective was to build a biobank with DNA, RNA and protein measurements to test the claim that the current state-of-the-art precision medicine will benefit RA patients.

    METHODS: We collected 451 blood samples from 61 healthy individuals and 185 RA patients initiating treatment, before treatment initiation and at a 3 month follow-up time. All samples were subjected to high-throughput RNA sequencing, DNA genotyping, extensive proteomics and flow cytometry measurements, as well as comprehensive clinical phenotyping. Literature review identified 2 proteins, 52 single-nucleotide polymorphisms (SNPs) and 72 gene-expression biomarkers that had previously been proposed as predictors of TNF inhibitor response (∆DAS28-CRP).

    RESULTS: From these published TNFi biomarkers we found that 2 protein, 2 SNP and 8 mRNA biomarkers could be replicated in the 59 TNF initiating patients. Combining these replicated biomarkers into a single signature we found that we could explain 51% of the variation in ∆DAS28-CRP. This corresponds to a sensitivity of 0.73 and specificity of 0.78 for the prediction of three month ∆DAS28-CRP better than -1.2.

    CONCLUSIONS: The COMBINE biobank is currently the largest collection of multi-omics data from RA patients with high potential for discovery and replication. Taking advantage of this we surveyed the current state-of-the-art of drug-response stratification in RA, and identified a small set of previously published biomarkers available in peripheral blood which predicts clinical response to TNF blockade in this independent cohort.

  • 35.
    Funseth, Eva
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Påhlman, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Eloranta, Maija-Leena
    Friman, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ilbäck, Nils-Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Effects of coxsackievirus B3 infection on the acute-phase protein metallothionein and on cytochrome P-4501A1 involved in the detoxification processes of TCDD in the mouse2002Ingår i: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 284, nr 1-3, s. 37-47Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During acute infections, the synthesis of acute-phase proteins and other proteins participating in the host defence are stimulated in the liver and kidney. In previous studies of coxsackievirus B3 (CB3) infection in mice, we found that cadmium (Cd) accumulates in the kidney, whereas 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) accumulates in the liver. To study if CB3 infection affects the synthesis of the Cd-binding protein metallothionein (MT) and the TCDD-binding/detoxifying cytochrome P-450 (CYP-450) isozyme CYP1A1, the basal and TCDD-induced levels of serum MT and liver CYP1A1 isozyme were determined in healthy and CB3-infected A/J mice. Furthermore, because interferons affect CYP450 activity, the serum levels of the interferons alpha (IFN-alpha) and -beta (IFN-beta) were measured in CB3-infected mice and in mice treated with the interferon-inducer polyinosinic/polycytidylic acid (poly I/C). Virus or poly I/C was administered intraperitoneally (i.p.) on day 0 and 500 ng TCDD/kg bodyweight on day 1. On day 4, CB3 infection had induced MT approximately 10-fold, regardless of TCDD treatment (P < 0.01 in infected mice and P < 0.001 in infected, TCDD-treated mice). TCDD alone induced a 10-fold increase in CYP1A1 activity (P < 0.001), whereas infection alone suppressed the normal CYP1A1 activity by 75% (P < 0.001). Infection also suppressed the TCDD-induced CYP1A1 activity by approximately 30% (n.s.). Poly I/C suppressed CYP1A1 by 20-25% (n.s.) at both basal and TCDD-induced levels. Serum IFN-alpha and IFN-beta levels were undetectable in controls, in TCDD-treated and in the poly I/C-treated groups on day 4, probably because the short IFN peak is detectable only hours after injection. Conversely, on day 4 of the infection, IFN-alpha and IFN-beta were consistently raised in the TCDD-treated infected mice, whereas increased IFNs as a result of infection alone could be detected in only one individual. These results suggest that the normal host responses during acute infections down-regulate detoxifying processes in favour of acute-phase protein synthesis. This may explain the observed changed pattern of accumulation, excretion and toxicity of the environmental pollutants cadmium and TCDD during this common virus infection.

  • 36. Gruic, Mirjana
    et al.
    Braga, Tiago
    Lukinius, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylärbiologi.
    Eloranta, Maija-Leena
    Department of Molecular Biosciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Knight, Stefan D.
    Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Pejler, Gunnar
    Åbrink, Magnus
    Serglycin-deficient cytotoxic T lymphocytes display defective secretory granule maturation and granzyme B storage2005Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 280, nr 39, s. 33411-33418Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cytotoxic T lymphocytes eliminate infected and tumor cells mainly by perforin/granzyme-induced apoptosis. Earlier studies suggested that serglycin-proteoglycans form macromolecular complexes with granzymes and perforin in the cytotoxic granule. Serglycin-proteoglycans may also be involved in the delivery of the cytolytic machinery into target cells. We have developed a serglycin-deficient mouse strain, and here we studied the importance of serglycin-proteoglycans for various aspects of cytotoxic T lymphocyte function. 35SO4(2-) radiolabeling of serglycin-deficient cells demonstrated a dramatic reduction of incorporated label as compared with wild type cells, indicating that serglycin is by far the dominating proteoglycan species produced by the cytotoxic T lymphocyte. Moreover, lack of serglycin resulted in impaired ability of cytotoxic T lymphocytes to produce secretory granule of high electron density, although granule of lower electron density were produced both in wild type and serglycin-deficient cells. The serglycin deficiency did not affect the mRNA expression for granzyme A, granzyme B, or perforin. However, the storage of granzyme B, but not granzyme A, Fas ligand, or perforin, was severely defective in serglycin-deficient cells. Serglycin-deficient cells did not display defects in late cytotoxicity toward target cell lines. Taken together, these results point to a key role for serglycin in the storage of granzyme B and for secretory granule maturation but argue against a major role for serglycin in the apoptosis mediated by cytotoxic T lymphocytes.

  • 37.
    Hagberg, Niklas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Berggren, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Leonard, Dag
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Weber, Gert
    Bryceson, Yenan T.
    Alm, Gunnar V.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    IFN-α Production by Plasmacytoid Dendritic Cells Stimulated with RNA-Containing Immune Complexes Is Promoted by NK Cells via MIP-1β and LFA-12011Ingår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 186, nr 9, s. 5085-5094Artikel i tidskrift (Refereegranskat)
    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.

  • 38.
    Hagberg, Niklas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Joelsson, Martin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Leonard, Dag
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Reid, Sarah
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mo, John
    AstraZeneca, Resp Inflammat & Autoimmun, IMED Biotech Unit, Gothenburg, Sweden.
    Nilsson, Magnus K.
    AstraZeneca, Resp Inflammat & Autoimmun, IMED Biotech Unit, Gothenburg, Sweden.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bryceson, Yenan T.
    Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, Karolinska Univ Hosp Huddinge, Stockholm, Sweden;Univ Bergen, Dept Clin Sci, Broegelmann Res Lab, Bergen, Norway.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-γ production in T cells from patients with SLE2018Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, nr 7, s. 1070-1077Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 39.
    Hagberg, Niklas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Theorell, Jakob
    Alm, Gunnar V.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Bryceson, Yenan
    Ronnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Systemic Lupus Erythematosus Immune Complexes Upregulate the Expression of CD319 and CD229 On Plasmacytoid Dendritic Cells2012Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, nr s10, s. S368-S369Artikel i tidskrift (Övrigt vetenskapligt)
  • 40.
    Hagberg, Niklas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Theorell, Jakob
    Alm, Gunnar V.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Bryceson, Yenan
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    SLE immune complexes upregulate the expression of slamf7 (cd319) on plasmacytoid dendritic cells2012Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, s. A3-A3Artikel i tidskrift (Övrigt vetenskapligt)
  • 41.
    Hagberg, Niklas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Theorell, Jakob
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Pascal, Veronique
    Bryceson, Yenan T
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Anti-NKG2A autoantibodies in a patient with systemic lupus erythematosus2013Ingår i: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 52, nr 10, s. 1818-1823Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives

    To 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).

    Methods

    Serum 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.

    Results

    Anti-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.

    Conclusion

    The 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.

  • 42.
    Hagberg, Niklas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Theorell, Jakob
    Hjorton, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Spee, Pieter
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Bryceson, Yenan T.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Functional Anti-CD94/NKG2A and Anti-CD94/NKG2C Autoantibodies in Patients With Systemic Lupus Erythematosus2015Ingår i: ARTHRITIS & RHEUMATOLOGY, ISSN 2326-5191, Vol. 67, nr 4, s. 1000-1011Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 43.
    Hagberg, Niklas
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Theorell, Jakob
    Schlums, Heinrich
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Bryceson, Yenan T.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Systemic Lupus Erythematosus Immune Complexes Increase the Expression of SLAM Family Members CD319 (CRACC) and CD229 (LY-9) on Plasmacytoid Dendritic Cells and CD319 on CD56(dim) NK Cells2013Ingår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 191, nr 6, s. 2989-2998Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Patients with systemic lupus erythematosus (SLE) display an activated type I IFN system due to unceasing IFN-a release from plasmacytoid dendritic cells (pDCs) stimulated by nucleic acid-containing immune complexes (ICs). NK cells strongly promote the IFN-a production by pDCs; therefore, we investigated surface molecules that could be involved in the pDC-NK cell cross-talk. In human PBMCs stimulated with RNA-containing ICs (RNA-ICs), the expression of the signaling lymphocyte activation molecule (SLAM) family receptors CD319 and CD229 on pDCs and CD319 on CD56(dim) NK cells was selectively increased. Upregulation of CD319 and CD229 on RNA-IC-stimulated pDCs was induced by NK cells or cytokines (e. g., GM-CSF, IL-3). IFN-alpha-producing pDCs displayed a higher expression of SLAM molecules compared with IFN-a 2 pDCs. With regard to signaling downstream of SLAM receptors, pDCs expressed SHIP-1, SHP-1, SHP-2, and CSK but lacked SLAM-associated protein (SAP) and Ewing's sarcoma-activated transcript 2 (EAT2), indicating that these receptors may act as inhibitory receptors on pDCs. Furthermore, pDCs from patients with SLE had decreased expression of CD319 on pDCs and CD229 on CD56 dim NK cells, but RNA-IC stimulation increased CD319 and CD229 expression. In conclusion, this study reveals that the expression of the SLAM receptors CD319 and CD229 is regulated on pDCs and NK cells by lupus ICs and that the expression of these receptors is specifically altered in SLE. These results, together with the observed genetic association between the SLAM locus and SLE, suggest a role for CD319 and CD229 in the SLE disease process.

  • 44.
    Hedlund, Malin
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Expt Rheumatol Unit, Stockholm, Sweden..
    Thorlacius, Gudny Ella
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Expt Rheumatol Unit, Stockholm, Sweden..
    Ivanchenko, Margarita
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Expt Rheumatol Unit, Stockholm, Sweden..
    Kyriakidis, Nikolaos
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Expt Rheumatol Unit, Stockholm, Sweden..
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Espinosa, Alexander
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Expt Rheumatol Unit, Stockholm, Sweden..
    Sonesson, Sven-Erik
    Karolinska Inst, Karolinska Univ Hosp, Dept Womens & Childrens Hlth, Paediat Cardiol Unit, Stockholm, Sweden..
    Wahren-Herlenius, Marie
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Expt Rheumatol Unit, Stockholm, Sweden..
    Type I IFN System Activation In Newborns Exposed To Anti-Ro/Ssa Autoantibodies In Utero2017Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, s. A7-A7Artikel i tidskrift (Övrigt vetenskapligt)
  • 45.
    Hjorton, Karin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Hagberg, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Berggren, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Mo, J.
    AstraZeneca R&D, Mölndal, Sweden.
    Sandling, Johanna K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    The Effect of Hydroxychloroquine and IRAK4 Inhibition on The IFN-A and TNF-A Production Induced by Sle Related Immune Complexes2016Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, s. 277-277Artikel i tidskrift (Övrigt vetenskapligt)
  • 46.
    Hjorton, Karin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hagberg, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Israelsson, Elisabeth
    AstraZeneca, IMED Biotech Unit, Resp Inflammat & Autoimmun, Gothenburg, Sweden.
    Jinton, Lisa
    AstraZeneca, IMED Biotech Unit, Resp Inflammat & Autoimmun, Gothenburg, Sweden.
    Berggren, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Thörn, Kristofer
    AstraZeneca, IMED Biotech Unit, Resp Inflammat & Autoimmun, Gothenburg, Sweden.
    Mo, John
    AstraZeneca, IMED Biotech Unit, Resp Inflammat & Autoimmun, Gothenburg, Sweden.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. SciLifeLaboratory.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Cytokine production by activated plasmacytoid dendritic cells and natural killer cells is suppressed by an IRAK4 inhibitor2018Ingår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 20, artikel-id 238Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 47.
    Houtman, Miranda
    et al.
    Karolinska Univ Hosp Solna, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Shchetynsky, Klementy
    Karolinska Univ Hosp Solna, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Chemin, Karine
    Karolinska Univ Hosp Solna, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Hensvold, Aase Haj
    Karolinska Univ Hosp Solna, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Ramsköld, Daniel
    Karolinska Univ Hosp Solna, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Tandre, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Uebe, Steffen
    Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany.
    Catrina, Anca Irinel
    Karolinska Univ Hosp Solna, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Malmström, Vivianne
    Karolinska Univ Hosp Solna, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Padyukov, Leonid
    Karolinska Univ Hosp Solna, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    T cells are influenced by a long non-coding RNA in the autoimmune associated PTPN2 locus2018Ingår i: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 90, s. 28-38Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Non-coding SNPs in the protein tyrosine phosphatase non-receptor type 2 (PTPN2) locus have been linked with several autoimmune diseases, including rheumatoid arthritis, type I diabetes, and inflammatory bowel disease. However, the functional consequences of these SNPs are poorly characterized. Herein, we show in blood cells that SNPs in the PTPN2 locus are highly correlated with DNA methylation levels at four CpG sites downstream of PTPN2 and expression levels of the long non-coding RNA (IncRNA) LINC01882 downstream of these CpG sites. We observed that LINC01882 is mainly expressed in T cells and that anti-CD3/CD28 activated naive CD4(+) T cells downregulate the expression of LINC01882. RNA sequencing analysis of LINC01882 knockdown in Jurkat T cells, using a combination of antisense oligo-nucleotides and RNA interference, revealed the upregulation of the transcription factor ZEB1 and kinase MAP2K4, both involved in IL-2 regulation. Overall, our data suggests the involvement of LINC01882 in T cell activation and hints towards an auxiliary role of these non-coding SNPs in autoimmunity associated with the PTPN2 locus. 

  • 48.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Almlöf, Jonas Carlsson
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Leonard, Dag
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Alexsson, Andrei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Umeå, Sweden.
    Bengtsson, Anders A
    Lund University, Skane University Hospital, Lund, Sweden.
    Jönsen, Andreas
    Lund University, Skane University Hospital, Lund, Sweden.
    Padyukov, Leonid
    Karolinska University Hospital, Stockholm, Sweden.
    Gunnarsson, Iva
    Karolinska University Hospital, Stockholm, Sweden.
    Svenungsson, Elisabet
    Karolinska University Hospital, Stockholm, Sweden.
    Sjöwall, Christopher
    Linköping University, Linköping, Sweden.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus2018Ingår i: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, nr 5, s. 736-743Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: Systemic lupus erythematosus (SLE) is a chronic autoimmune condition with heterogeneous presentation and complex aetiology where DNA methylation changes are emerging as a contributing factor. In order to discover novel epigenetic associations and investigate their relationship to genetic risk for SLE, we analysed DNA methylation profiles in a large collection of patients with SLE and healthy individuals.

    Methods: DNA extracted from blood from 548 patients with SLE and 587 healthy controls were analysed on the Illumina HumanMethylation 450 k BeadChip, which targets 485 000 CpG sites across the genome. Single nucleotide polymorphism (SNP) genotype data for 196 524 SNPs on the Illumina ImmunoChip from the same individuals were utilised for methylation quantitative trait loci (cis-meQTLs) analyses.

    Results: We identified and replicated differentially methylated CpGs (DMCs) in SLE at 7245 CpG sites in the genome. The largest methylation differences were observed at type I interferon-regulated genes which exhibited decreased methylation in SLE. We mapped cis-meQTLs and identified genetic regulation of methylation levels at 466 of the DMCs in SLE. The meQTLs for DMCs in SLE were enriched for genetic association to SLE, and included seven SLE genome-wide association study (GWAS) loci: PTPRC (CD45), MHC-class III, UHRF1BP1, IRF5, IRF7, IKZF3 and UBE2L3. In addition, we observed association between genotype and variance of methylation at 20 DMCs in SLE, including at the HLA-DQB2 locus.

    Conclusions: Our results suggest that several of the genetic risk variants for SLE may exert their influence on the phenotype through alteration of DNA methylation levels at regulatory regions of target genes.

  • 49.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Almlöf, Jonas Carlsson
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Leonard, Dag
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Padyukov, Leonid
    Karolinska Univ Hosp, Karolinska Inst, Rheumatol Unit, Dept Med Solna, Stockholm, Sweden..
    Gunnarsson, Iva
    Karolinska Univ Hosp, Karolinska Inst, Rheumatol Unit, Dept Med Solna, Stockholm, Sweden..
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Karolinska Inst, Rheumatol Unit, Dept Med Solna, Stockholm, Sweden..
    Sjowall, Christopher
    Linkoping Univ, Rheumatol AIR, Dept Clin & Expt Med, Linkoping, Sweden..
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Syvänen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi.
    Treatment-Associated DNA Methylation Patterns in Systemic Lupus Erythematosus2017Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, nr S10, artikel-id 2654Artikel i tidskrift (Övrigt vetenskapligt)
  • 50.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Almlöf, Jonas Carlsson
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nordlund, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Signer, Linnea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Norheim, Katrine B.
    Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway..
    Omdal, Roald
    Stavanger Univ Hosp, Dept Internal Med, Clin Immunol Unit, Stavanger, Norway..
    Eloranta, Majia-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Syvanen, Ann-Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nordmark, Gunnel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hypomethylation in Enhancer and Promoter Regions of Interferon Regulated Genes in Multiple Tissues Is Associated with Primary Sjogren's Syndrome2015Ingår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, nr Suppl. 10, artikel-id 2100Artikel i tidskrift (Övrigt vetenskapligt)
12 1 - 50 av 100
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