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  • 1. Adoue, Veronique
    et al.
    Schiavi, Alicia
    Light, Nicholas
    Carlsson Almlöf, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ge, Bing
    Kwan, Tony
    Caron, Maxime
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Wang, Chuan
    Chen, Shu-Huang
    Goodall, Alison H
    Cambien, Francois
    Deloukas, Panos
    Ouwehand, Willem H
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Pastinen, Tomi
    Allelic expression mapping across cellular lineages to establish impact of non-coding SNPs2014In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 10, no 10, p. 754-Article in journal (Refereed)
    Abstract [en]

    Most complex disease-associated genetic variants are located in non-coding regions and are therefore thought to be regulatory in nature. Association mapping of differential allelic expression (AE) is a powerful method to identify SNPs with direct cis-regulatory impact (cis-rSNPs). We used AE mapping to identify cis-rSNPs regulating gene expression in 55 and 63 HapMap lymphoblastoid cell lines from a Caucasian and an African population, respectively, 70 fibroblast cell lines, and 188 purified monocyte samples and found 40-60% of these cis-rSNPs to be shared across cell types. We uncover a new class of cis-rSNPs, which disrupt footprint-derived de novo motifs that are predominantly bound by repressive factors and are implicated in disease susceptibility through overlaps with GWAS SNPs. Finally, we provide the proof-of-principle for a new approach for genome-wide functional validation of transcription factor-SNP interactions. By perturbing NFκB action in lymphoblasts, we identified 489 cis-regulated transcripts with altered AE after NFκB perturbation. Altogether, we perform a comprehensive analysis of cis-variation in four cell populations and provide new tools for the identification of functional variants associated to complex diseases.

  • 2. Allum, Fiona
    et al.
    Shao, Xiaojian
    Guénard, Frédéric
    Simon, Marie-Michelle
    Busche, Stephan
    Caron, Maxime
    Lambourne, John
    Lessard, Julie
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Hedman, Åsa K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kwan, Tony
    Ge, Bing
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    McCarthy, Mark I
    Deloukas, Panos
    Richmond, Todd
    Burgess, Daniel
    Spector, Timothy D
    Tchernof, André
    Marceau, Simon
    Lathrop, Mark
    Vohl, Marie-Claude
    Pastinen, Tomi
    Grundberg, Elin
    Characterization of functional methylomes by next-generation capture sequencing identifies novel disease-associated variants2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 7211Article in journal (Refereed)
    Abstract [en]

    Most genome-wide methylation studies (EWAS) of multifactorial disease traits use targeted arrays or enrichment methodologies preferentially covering CpG-dense regions, to characterize sufficiently large samples. To overcome this limitation, we present here a new customizable, cost-effective approach, methylC-capture sequencing (MCC-Seq), for sequencing functional methylomes, while simultaneously providing genetic variation information. To illustrate MCC-Seq, we use whole-genome bisulfite sequencing on adipose tissue (AT) samples and public databases to design AT-specific panels. We establish its efficiency for high-density interrogation of methylome variability by systematic comparisons with other approaches and demonstrate its applicability by identifying novel methylation variation within enhancers strongly correlated to plasma triglyceride and HDL-cholesterol, including at CD36. Our more comprehensive AT panel assesses tissue methylation and genotypes in parallel at ∼4 and ∼3 M sites, respectively. Our study demonstrates that MCC-Seq provides comparable accuracy to alternative approaches but enables more efficient cataloguing of functional and disease-relevant epigenetic and genetic variants for large-scale EWAS.

  • 3. Arkema, E.
    et al.
    Jonsen, A.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Sjowall, C.
    Svenungsson, E.
    Simard, J. F.
    Utility of Swedish Register Data in Classifying Systemic Lupus2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, p. 444-444Article in journal (Other academic)
  • 4. Arkema, Elizabeth V
    et al.
    Jönsen, Andreas
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Svenungsson, Elisabet
    Sjöwall, Christopher
    Simard, Julia F
    Case definitions in Swedish register data to identify systemic lupus erythematosus2016In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 6, no 1, article id e007769Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To develop and investigate the utility of several different case definitions for systemic lupus erythematosus (SLE) using national register data in Sweden.

    METHODS: The reference standard consisted of clinically confirmed SLE cases pooled from four major clinical centres in Sweden (n=929), and a sample of non-SLE comparators randomly selected from the National Population Register (n=24 267). Demographics, comorbidities, prescriptions and autoimmune disease family history were obtained from multiple registers and linked to the reference standard. We first used previously published SLE definitions to create algorithms for SLE. We also used modern data mining techniques (penalised least absolute shrinkage and selection operator logistic regression, elastic net regression and classification trees) to objectively create data-driven case definitions. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for the case definitions identified.

    RESULTS: Defining SLE by using only hospitalisation data resulted in the lowest sensitivity (0.79). When SLE codes from the outpatient register were included, sensitivity and PPV increased (PPV between 0.97 and 0.98, sensitivity between 0.97 and 0.99). Addition of medication information did not greatly improve the algorithm's performance. The application of data mining methods did not yield different case definitions.

    CONCLUSIONS: The use of SLE International Classification of Diseases (ICD) codes in outpatient clinics increased the accuracy for identifying individuals with SLE using Swedish registry data. This study implies that it is possible to use ICD codes from national registers to create a cohort of individuals with SLE.

  • 5. Balboni, Imelda
    et al.
    Niewold, Timothy B
    Morgan, Gabrielle
    Limb, Cindy
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    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 Dermatomyositis2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no 9, p. 2424-2429Article in journal (Refereed)
    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.

  • 6.
    Bengtsson, A. A.
    et al.
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Rheumatol, Lund, Sweden..
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Systemic lupus erythematosus: still a challenge for physicians2017In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 281, no 1, p. 52-64Article, review/survey (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) has a complex clinical picture, and a number of defects in the immune system have been described in patients with the disease. Most organs can be involved in SLE, and in addition to the typical major organ manifestations (e.g. from kidneys and the central nervous system), early cardiovascular disease is a major determinant of prognosis. Several important findings during the last decade have increased the understanding of the mechanisms behind the disease characteristics and the underlying autoimmune process. Amongst, these are defects in the handling of apoptotic cells, increased expression of type I interferon-regulated genes and activation of autoreactive B cells, with both the type I interferon system and the B lymphocyte stimulator (BLyS) having key roles. In addition, a large number of genes have been identified that contribute to these abnormalities. It has also become clear that certain SLE risk genes are associated with some organ manifestations, such as STAT4 with nephritis and IRF8 with myocardial infarction. Furthermore, environmental factors that can induce SLE or trigger a disease flare have been identified. As a consequence of this increased knowledge, new treatments for SLE have been developed. The most recently approved drug for SLE is belimumab, which blocks BLyS, and several new therapies and therapeutic strategies are in the pipeline for clinical application.

  • 7.
    Bengtsson, Anders A.
    et al.
    Lund Univ, Skdne Univ Hosp, Dept Clin Sci Lund, Rheumatol, S-22185 Lund, Sweden..
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Role of interferons in SLE2017In: Baillière's Best Practice & Research: Clinical Rheumatology, ISSN 1521-6942, E-ISSN 1532-1770, Vol. 31, no 3, p. 415-428Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that affects many different organ systems, with excessive production of type I interferons (IFNs) and auto antibodies against nucleic acids as hallmarks. Activation of the type I IFN system in SLE is due to continuous stimulation of plasmacytoid dendritic cells by endogenous nucleic acids, leading to sustained type I IFN production. This is reflected by an over expression of type I IFN-regulated genes or an IFN signature. Type I IFNs have effects on both the innate and adaptive immune systems, which contribute to both loss of tolerance and the autoimmune disease process. In this review, we discuss the current understanding of IFNs in SLE, focusing on their regulation, the influence of genetic background, and environmental factors and therapies that are under development aiming to inhibit the type I IFN system in SLE.

  • 8. Bengtsson, Anders A
    et al.
    Sturfelt, Gunnar
    Lood, Christian
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    van Vollenhoven, Ronald F
    Axelsson, Bengt
    Sparre, Birgitta
    Tuvesson, Helén
    Wallén Öhman, Marie
    Leanderson, Tomas
    Pharmacokinetics, tolerability, and preliminary efficacy of ABR-215757, a new quinoline-3-carboxamide derivative, in murine and human SLE2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no 5, p. 1579-1588Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To assess the efficacy of ABR-215757, a new immunomodulatory small molecule in a murine SLE model, to evaluate the pharmacokinetics and tolerability in SLE patients at doses predicted to be efficacious and safe, and to determine the maximum tolerated dose (MTD).

    METHODS: The efficacy of ABR-215757 was studied in lupus prone MRLlpr/lpr mice and compared with established SLE treatments. Dose response data of ABR-215757 were together with pharmacokinetic data used to calculate effective and safe clinical doses. The pharmacokinetics and tolerance of ABR-215757 were evaluated in a Phase Ib double-blind, placebo controlled, dose-escalation study where cohorts of SLE patients received daily oral treatment for 12 weeks.

    RESULTS: Disease inhibition in MRLlpr/lpr mice, comparable to that of prednisolone and mycophenolate mofetil, was obtained with ABR-215757. Prominent effects on disease manifestations, serological markers and a steroid sparing effect were seen for ABR-215757. The pharmacokinetic properties in SLE patients were linear and well suitable for once daily oral treatment. The majority of the adverse events (AEs) were mild or moderate and transient. The most frequent AEs were arthralgia and myalgia, reported at the highest (4.5 and 6 mg/day) dose levels. At 4.5 mg and higher some AEs of severe intensity and serious adverse events (SAEs) were reported.

    CONCLUSION: ABR-215757 effectively inhibited disease and had a steroid sparing effect in experimental lupus. Clinical doses up to 3 mg/day, dose levels predicted from pre-clinical studies to be efficacious and safe, were well tolerated in the SLE patients. The MTD was concluded to be 4.5 mg/day.

  • 9. Bentham, James
    et al.
    Morris, David L
    Cunninghame Graham, Deborah S
    Pinder, Christopher L
    Tombleson, Philip
    Behrens, Timothy W
    Martín, Javier
    Fairfax, Benjamin P
    Knight, Julian C
    Chen, Lingyan
    Replogle, Joseph
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Graham, Robert R
    Wither, Joan E
    Rioux, John D
    Alarcón-Riquelme, Marta E
    Vyse, Timothy J
    Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus2015In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, no 12, p. 1457-1464Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.

  • 10.
    Berggren, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Alm, Gunnar V.
    Syvanen, Ann-Christine
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Variation of Interferon-Alpha Production in Healthy Individuals and Association with Autoimmune Susceptibility Genes2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no S10, p. S961-S961Article in journal (Other academic)
  • 11.
    Berggren, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Morris, David
    King’s College London School of Medicine, Guy’s Hospital, London.
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Weber, Gert
    Free University of Berlin.
    Vyse, Timothy
    King’s College London School of Medicine, Guy’s Hospital, London.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    IFN-α production by plasmacytoid dendritic cell associations with polymorphisms in gene loci related to autoimmune and inflammatory diseases2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 12, p. 3571-3581Article in journal (Refereed)
    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.

  • 12.
    Berggren, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Syvanen, A-C
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Effect of single-nucleotide polymorphisms on type I interferon production by plasmacytoid dendritic cells stimulated with SLE-associated immune complexes2014In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 43, no S127, p. 92-92Article in journal (Other academic)
  • 13.
    Berggren, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hagberg, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Weber, Gert
    Ernst Moritz Arndt Univ Greifswald, Inst Biochem, Dept Mol Struct Biol, Greifswald, Germany..
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Plasmacytoid dendritic cells and RNA-containing immune complexes drive expansion of peripheral B cell subsets with an SLE-like phenotype2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 8, article id e0183946Article in journal (Refereed)
    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.

  • 14.
    Berggren, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hagberg, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Weber, Gert
    Alm, Gunnar V
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    B lymphocytes enhance the interferon-α production by plasmacytoid dendritic cells2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no 10, p. 3409-3419Article in journal (Refereed)
    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.

  • 15.
    Berggren, Olof
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    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)2016In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 68, no 4, p. 1045-1045Article in journal (Refereed)
  • 16.
    Bolin, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gunnarsson, I.
    Sjowall, C.
    Eriksson, P.
    Forsblad-d'Elia, H.
    Jonsen, A.
    Theander, E.
    Omdal, R.
    Jonsson, R.
    Sivils, K.
    Wahren-Herlenius, M.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Early B Cell Factor 1 is Associated to Clinical Manifestations in Primary Sjogren's Syndrome and SLE2015In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 81, no 5, p. 416-416Article in journal (Other academic)
  • 17.
    Bolin, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Zickert, Agneta
    Jönsen, Andreas
    Sjöwall, Christopher
    Svenungsson, Elisabet
    Bengtsson, Anders A
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gunnarsson, Iva
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Association of STAT4 Polymorphism with Severe Renal Insufficiency in Lupus Nephritis2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. e84450-Article in journal (Refereed)
    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.

  • 18. Bolstad, Anne Isine
    et al.
    Le Hellard, Stephanie
    Kristjansdottir, Gudlaug
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vasaitis, Lilian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Kvarnström, Marika
    Sjöwall, Christopher
    Johnsen, Svein Joar Auglænd
    Eriksson, Per
    Omdal, Roald
    Brun, Johan G
    Wahren-Herlenius, Marie
    Theander, Elke
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jonsson, Roland
    Association between genetic variants in the tumour necrosis factor/lymphotoxin α/lymphotoxin β locus and primary Sjogren's syndrome in Scandinavian samples2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, no 6, p. 981-988Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    Lymphotoxin β (LTB) has been found to be upregulated in salivary glands of patients with primary Sjögren's syndrome (pSS). An animal model of pSS also showed ablation of the lymphoid organisation and a marked improvement in salivary gland function on blocking the LTB receptor pathway. This study aimed to investigate whether single-nucleotide polymorphisms (SNP) in the lymphotoxin α (LTA)/LTB/tumour necrosis factor (TNF) gene clusters are associated with pSS.

    METHODS:

    527 pSS patients and 532 controls participated in the study, all of Caucasian origin from Sweden and Norway. 14 SNP markers were genotyped and after quality control filtering, 12 SNP were analysed for their association with pSS using single marker and haplotype tests, and corrected by permutation testing.

    RESULTS:

    Nine markers showed significant association with pSS at the p=0.05 level. Markers rs1800629 and rs909253 showed the strongest genotype association (p=1.64E-11 and p=4.42E-08, respectively, after correcting for sex and country of origin). When the analysis was conditioned for the effect of rs1800629, only the association with rs909253 remained nominally significant (p=0.027). In haplotype analyses the strongest effect was observed for the haplotype rs909253G_rs1800629A (p=9.14E-17). The associations were mainly due to anti-Ro/SSA and anti-La/SSB antibody-positive pSS.

    CONCLUSIONS:

    A strong association was found between several SNP in the LTA/LTB/TNFα locus and pSS, some of which led to amino acid changes. These data suggest a role for this locus in the development of pSS. Further studies are needed to examine if the genetic effect described here is independent of the known genetic association between HLA and pSS.

  • 19.
    Båve, Ullvi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Alm, Gunar V.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The combination of apoptotic U937 cells and lupus IgG is a potent IF inducer2000In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 165, no 6, p. 3519-26Article in journal (Refereed)
    Abstract [en]

    Patients with active systemic lupus erythematosus (SLE) have signs of an ongoing IFN-alpha production, that may be of pathogenic significance in the disease. We previously showed that SLE patients have an IFN-alpha-inducing factor in blood, probably consisting of complexes containing anti-DNA Abs and immunostimulatory DNA. The DNA component could be derived from apoptotic cells, because SLE patients have been reported to have both increased apoptosis and reduced clearance of apoptotic cell material. In the present study, we therefore investigated whether apoptotic cells, together with IgG from SLE patients, could act as an IFN-alpha inducer in normal PBMC in vitro. We found that apoptotic cells of the myeloid leukemia cell line U937 as well as four other cell lines (MonoMac6, H9, Jurkat, U266) could induce IFN-alpha production in PBMC when combined with IgG from SLE patients. The IFN-alpha production by PBMC was much enhanced when PBMC were costimulated by IFN-alpha2b. The ability of IgG from different SLE patients to promote IFN-alpha induction by apoptotic U937 cells was associated with the presence of anti-ribonucleoprotein Abs, but not clearly with occurrence of anti-DNA Abs. These results suggest that apoptotic cells in the presence of autoantibodies can cause production of a clearly immunostimulatory cytokine, which is IFN-alpha. This mechanism for induction of IFN-alpha production could well be operative also in vivo, explain the IFN-alpha production seen in SLE patients, and be important in the pathogenesis of SLE.

  • 20.
    Båve, Ullvi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Magnuson, Mattias
    Eloranta, Maija-Leena
    Perers, Anders
    Alm, Gunnar V.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    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 IgG2003In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 171, no 6, p. 3296-302Article in journal (Refereed)
    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.

  • 21.
    Båve, Ullvi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lövgren, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cajander, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eloranta, Maija-Leena
    Alm, Gunnar V.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Activation of the type I interferon system in primary Sjögren's syndrome: a possible etiopathogenic mechanism2005In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 52, no 4, p. 1185-1195Article in journal (Refereed)
    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.

  • 22.
    Carlsson Almlöf, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Imgenberg-Kreuz, Juliana
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Sylwan, Lina
    Karolinska Inst, Dept Biosci & Nutr, Sci Life Lab SciLifeLab, Solna, Sweden..
    Bäcklin, Christofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, 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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Novel risk genes for systemic lupus erythematosus predicted by random forest classification2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 6236Article in journal (Refereed)
    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.

  • 23.
    Cavalli, Marco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Pan, Gang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Nord, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Arzt, Emelie Wallén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Karolinska Inst, Dept Biosci & Nutr, Ctr Biosci, Huddinge, Sweden..
    Berggren, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Elvers, Ingegerd
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Toh, Kerstin Lindblad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Allele-specific transcription factor binding to common and rare variants associated with disease and gene expression2016In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 135, no 5, p. 485-497Article in journal (Refereed)
    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.

  • 24.
    Chemin, Karine
    et al.
    Karolinska Inst, Rheumatol Unit, Dept Med, Med, Stockholm, Sweden..
    Pollastro, Sabrina
    Dept Clin Immunol & Rheumatol, Amsterdam, Netherlands..
    James, Eddie
    Virginia Mason, Benaroya Res Inst, Seattle, WA USA..
    Ge, Changrong
    Karolinska Inst, Dept Med Biochem & Biophys, Med Inflammat Res, Stockholm, Sweden..
    Albrecht, Inka
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Herrath, Jessica
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Gerstner, Christina
    Karolinska Univ Hosp, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Rizzi, Thais
    Dept Clin Immunol & Rheumatol, Amsterdam, Netherlands..
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Catrina, Anca I.
    Karolinska Inst, Dept Med Solna, Unit Rheumatol, Karolinska Univ Hosp, Stockholm, Sweden..
    Holmdahl, Rikard
    Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Klareskog, L.
    Karolinska Univ Hosp, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    De Vries, Niek
    Univ Amsterdam, Acad Med Ctr, Dept Clin Immunol & Rheumatol, Amsterdam Rheumatol & Immunol Ctr, NL-1105 AZ Amsterdam, Netherlands..
    Malmstrom, Vivianne
    Karolinska Univ Hosp, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    A Novel HLA-DRB1*10:01 Restricted T Cell Epitope from Citrullinated Type II Collagen Relevant for Rheumatoid Arthritis2015In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, no Suppl. 10, article id 1946Article in journal (Other academic)
  • 25.
    Chemin, Karine
    et al.
    Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Pollastro, Sabrina
    Amsterdam Rheumatol & Immunol Ctr, Amsterdam, Netherlands.;Univ Amsterdam, Acad Med Ctr, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands..
    James, Eddie
    Virginia Mason, Benaroya Res Inst, Seattle, WA USA..
    Ge, Changrong
    Karolinska Inst, Stockholm, Sweden..
    Albrecht, Inka
    Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Herrath, Jessica
    Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Gerstner, Christina
    Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Tandre, Karolina
    Rizzi, Thais Sampaio
    Amsterdam Rheumatol & Immunol Ctr, Amsterdam, Netherlands.;Univ Amsterdam, Acad Med Ctr, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands..
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Catrina, Anca
    Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Holmdahl, Rikard
    Karolinska Inst, Stockholm, Sweden..
    Klareskog, Lars
    Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    de Vries, Niek
    Amsterdam Rheumatol & Immunol Ctr, Amsterdam, Netherlands.;Univ Amsterdam, Acad Med Ctr, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands..
    Malmstrom, Vivianne
    Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    A Novel HLA-DRB1*10:01-Restricted T Cell Epitope From Citrullinated Type II Collagen Relevant to Rheumatoid Arthritis2016In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 68, no 5, p. 1124-1135Article in journal (Refereed)
    Abstract [en]

    Objective. Antibodies against citrullinated type II collagen (Cit-CII) are common in the sera and synovial fluid of patients with rheumatoid arthritis (RA); however, the known T cell epitope of CII is not dependent on citrullination. The aim of this study was to identify and functionally characterize the Cit-CII-restricted T cell epitopes that are relevant to RA. Methods. Peripheral blood mononuclear cells (PBMCs) from HLA-DRB1*10:01-positive patients with RA and healthy donors were stimulated in vitro with candidate CII peptides. CD154 up-regulation was measured as a marker of antigen-specific activation, and anti-HLA-DR-blocking experiments confirmed HLA restriction. Cytokine production was measured using a Luminex technique. Direct peptide-binding assays using HLA-DRB1*10:01 and HLA-DRB1*04:01 monomeric proteins were performed. The T cell receptor (TCR) beta-chain of CD154-enriched antigen-specific T cells was analyzed using high-throughput sequencing. Results. A novel Cit-CII peptide was identified based on its ability to activate CD4+ T cells from HLA-DRB1*10:01-positive individuals. When stimulated in vitro, Cit-CII autoreactive T cells produced proinflammatory cytokines. Cit-CII311-325 bound (with low affinity) to HLA-DRB1*10:01 but not to HLA-DRB1*04:01, while the native form was unable to bind either protein. In addition, highly expanded clones were identified in the TCR beta repertoire of Cit-CII311-325-stimulated PBMCs. Conclusion. These results illustrate the ability of the citrullination process to create T cell epitopes from CII, a cartilage-restricted protein that is relevant to RA pathogenesis. The exclusive binding of Cit-CII311-325 to HLA-DRB1*10:01 suggests that recognition of citrullinated epitopes might vary between individuals carrying different RA-associated HLA-DR molecules.

  • 26. Cunninghame Graham, Deborah S
    et al.
    Morris, David L
    Bhangale, Tushar R
    Criswell, Lindsey A
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Behrens, Timothy W
    Graham, Robert R
    Vyse, Timothy J
    Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus2011In: PLoS genetics, ISSN 1553-7404, Vol. 7, no 10, p. e1002341-Article in journal (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a complex trait characterised by the production of a range of auto-antibodies and a diverse set of clinical phenotypes. Currently, ∼8% of the genetic contribution to SLE in Europeans is known, following publication of several moderate-sized genome-wide (GW) association studies, which identified loci with a strong effect (OR>1.3). In order to identify additional genes contributing to SLE susceptibility, we conducted a replication study in a UK dataset (870 cases, 5,551 controls) of 23 variants that showed moderate-risk for lupus in previous studies. Association analysis in the UK dataset and subsequent meta-analysis with the published data identified five SLE susceptibility genes reaching genome-wide levels of significance (P(comb)<5×10(-8)): NCF2 (P(comb) = 2.87×10(-11)), IKZF1 (P(comb) = 2.33×10(-9)), IRF8 (P(comb) = 1.24×10(-8)), IFIH1 (P(comb) = 1.63×10(-8)), and TYK2 (P(comb) = 3.88×10(-8)). Each of the five new loci identified here can be mapped into interferon signalling pathways, which are known to play a key role in the pathogenesis of SLE. These results increase the number of established susceptibility genes for lupus to ∼30 and validate the importance of using large datasets to confirm associations of loci which moderately increase the risk for disease.

  • 27. de Jong, T. D.
    et al.
    Vosslamber, S.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    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 Arthritis2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no S1, p. A79-A79Article in journal (Other academic)
  • 28. de Jong, T. D.
    et al.
    Vosslamber, Saskia
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Gelderman, Kyra
    von Blomberg, Mary
    Bultink, Irene
    Voskuyl, Alexandre
    Verweij, Cornelis L.
    On the Origin of the Type I Interferon Signature in Rheumatoid Arthritis2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no S10, p. S770-S771Article in journal (Other academic)
  • 29. Dyke, Stephanie O M
    et al.
    Cheung, Warren A
    Joly, Yann
    Ammerpohl, Ole
    Lutsik, Pavlo
    Rothstein, Mark A
    Caron, Maxime
    Busche, Stephan
    Bourque, Guillaume
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Flicek, Paul
    Beck, Stephan
    Hirst, Martin
    Stunnenberg, Henk
    Siebert, Reiner
    Walter, Jörn
    Pastinen, Tomi
    Epigenome data release: a participant-centered approach to privacy protection2015In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 16, article id 142Article in journal (Refereed)
    Abstract [en]

    Large-scale epigenome mapping by the NIH Roadmap Epigenomics Project, the ENCODE Consortium and the International Human Epigenome Consortium (IHEC) produces genome-wide DNA methylation data at one base-pair resolution. We examine how such data can be made open-access while balancing appropriate interpretation and genomic privacy. We propose guidelines for data release that both reduce ambiguity in the interpretation of open-access data and limit immediate access to genetic variation data that are made available through controlled access.

  • 30.
    Elfaitouri, Amal
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Herrmann, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Bölin-Wiener, Agnes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Wang, Yilin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Gottfries, Carl-Gerhard
    Zachrisson, Olof
    Pipkorn, Ruediger
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Epitopes of Microbial and Human Heat Shock Protein 60 and Their Recognition in Myalgic Encephalomyelitis2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, p. 55-Article in journal (Refereed)
    Abstract [en]

    Myalgic encephalomyelitis (ME, also called Chronic Fatigue Syndrome), a common disease with chronic fatigability, cognitive dysfunction and myalgia of unknown etiology, often starts with an infection. The chaperonin human heat shock protein 60 (HSP60) occurs in mitochondria and in bacteria, is highly conserved, antigenic and a major autoantigen. The anti-HSP60 humoral (IgG and IgM) immune response was studied in 69 ME patients and 76 blood donors (BD) (the Training set) with recombinant human and E coli HSP60, and 136 30-mer overlapping and targeted peptides from HSP60 of humans, Chlamydia, Mycoplasma and 26 other species in a multiplex suspension array. Peptides from HSP60 helix I had a chaperonin-like activity, but these and other HSP60 peptides also bound IgG and IgM with an ME preference, theoretically indicating a competition between HSP60 function and antibody binding. A HSP60-based panel of 25 antigens was selected. When evaluated with 61 other ME and 399 non-ME samples (331 BD, 20 Multiple Sclerosis and 48 Systemic Lupus Erythematosus patients), a peptide from Chlamydia pneumoniae HSP60 detected IgM in 15 of 61 (24%) of ME, and in 1 of 399 non-ME at a high cutoff (p<0.0001). IgM to specific cross-reactive epitopes of human and microbial HSP60 occurs in a subset of ME, compatible with infection-induced autoimmunity.

  • 31.
    Eloranta, Maija-Leena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Alm, Gunnar V
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Disease Mechanisms in RheumatologyTools and Pathways: Plasmacytoid Dendritic Cells and Their Role in AutoimmuneRheumatic Diseases2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no 4, p. 853-863Article in journal (Refereed)
  • 32.
    Eloranta, Maija-Leena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Franck-Larsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lövgren, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kalamajski, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rönnblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Alm, Gunnar V.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Type I interferon system activation and association with disease manifestations in systemic sclerosis2010In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 69, no 7, p. 1396-1402Article in journal (Refereed)
    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.

  • 33.
    Eloranta, Maija-Leena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Helmers, Sevim Barbasso
    Ulfgren, Ann-Kristin
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    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 autoantibodies2007In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 56, no 9, p. 3112-3124Article in journal (Refereed)
    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.

  • 34.
    Eloranta, Maija-Leena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lövgren, Tanja
    Uppsala University.
    Finke, Doreen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mathsson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Kastner, Berthold
    Alm, Gunnar V.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Regulation of the interferon-alpha production induced by RNA-containing immune complexes in plasmacytoid dendritic cells2009In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, no 8, p. 2418-2427Article in journal (Refereed)
    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.

  • 35.
    Eloranta, Maija-Leena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Cause and consequences of the activated type I interferon system in SLE2016In: Journal of Molecular Medicine, ISSN 0946-2716, E-ISSN 1432-1440, Vol. 94, no 10, p. 1103-1110Article in journal (Refereed)
    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.

  • 36.
    Eloranta, Maija-Leena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Dual role of CpG-stimulated B cells in the regulation of dendritic cells: comment on the article by Berggren et al Reply2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no 8, p. 2216-Article in journal (Other academic)
  • 37. Enocsson, Helena
    et al.
    Sjöwall, Christopher
    Kastbom, Alf
    Skogh, Thomas
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Wetterö, Jonas
    Serum C-reactive protein (CRP) associates with lupus disease activity in the absence of measurable interferon alpha and a CRP gene variant2014In: Arthritis & rheumatology, ISSN 2326-5205, Vol. 66, no 6, p. 1568-1573Article in journal (Refereed)
    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.

  • 38. Enocsson, Helena
    et al.
    Sjöwall, Christopher
    Skogh, Thomas
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wetterö, Jonas
    Interferon-alpha Mediates Suppression of C-Reactive Protein Explanation for Muted C-Reactive Protein Response in Lupus Flares?2009In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 60, no 12, p. 3755-3760Article in journal (Refereed)
    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.

  • 39.
    Eriksson, D.
    et al.
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.;Metab & Diabet Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden..
    Bianchi, Matteo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden..
    Nordin, Jessika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dalin, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden..
    Mathioudaki, Argyri
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, G. N.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Hultin-Rosenberg, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahlqvist, Johanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zetterqvist, H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlsson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallgren, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden..
    Farias, F. H. G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Murén, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ahlgren, Kerstin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lobell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, G.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahlqvist, S. R.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Soderkvist, P.
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hulting, A. -L
    Wahlberg, J.
    Linkoping Univ, Dept Endocrinol, Dept Med & Hlth Sci, Dept Clin & Expt Med, Linkoping, Sweden..
    Ekwall, O.
    Univ Gothenburg, Sahlgrenska Acad, Dept Pediat, Inst Clin Sci, Gothenburg, Sweden.;Univ Gothenburg, Dept Rheumatol & Inflammat Res, Inst Med, Sahlgrenska Acad, Gothenburg, Sweden..
    Dahlqvist, P.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Meadows, Jennifer R. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bensing, S.
    Metab & Diabet Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.;Metab & Diabet Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden..
    Pielberg, Gerli R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease2016In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 286, no 6, p. 595-608Article in journal (Refereed)
    Abstract [en]

    BackgroundAutoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology. MethodsTo understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls. ResultsWe identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 x 10(-15), MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex. ConclusionWhilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.

  • 40.
    Eriksson, Karin G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Zickert, Agneta
    Sandling, Johanna K.
    Jonsen, Andreas
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Behrens, Timothy W.
    Graham, Robert R.
    Ortmann, Ward
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Gunnarsson, Iva
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Association of STAT4, IRF5 and BLK polymorphisms with severity and outcome in lupus nephritis2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, p. A55-A55Article in journal (Other academic)
  • 41.
    Farias, Fabiana
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wilbe, Maria
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Dahlqvist, Johanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Leonard, Dag
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Kozyrev, Sergey
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pielberg, Gerli
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Eloranta, Maija-Leena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Lindblad-Toh, Kerstin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    High-Throughput Sequencing of 219 Candidate Genes for Identification of SLE-Associated Risk Variants2014In: Arthritis & Rheumatology, ISSN 2326-5191, Vol. 66, no S10, p. S1170-S1170, article id 2673Article in journal (Other academic)
  • 42. Feng, Di
    et al.
    Stone, Rivka C.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sangster-Guity, Niquiche
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sigurdsson, Snaevar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wang, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Alm, Gunnar
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    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 erythematosus2010In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 62, no 2, p. 562-573Article in journal (Refereed)
    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.

  • 43.
    Finke, Doreen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Endogenous type I interferon inducers in autoimmune diseases2009In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 42, no 4, p. 349-352Article, review/survey (Refereed)
    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.

  • 44.
    Forsman, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Uzameckis, Dmitrijs
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Åleskog, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Bindra, Amarinder
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Pipkorn, Rüdiger
    Lejniece, Sandra
    Kozireva, Svetlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Murovska, Modra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Single-tube nested quantitative PCR: a rational and sensitive technique for detection of retroviral DNA. Application to RERV-H/HRV-5 and confirmation of its rabbit origin2003In: Journal of Virological Methods, ISSN 0166-0934, E-ISSN 1879-0984, Vol. 111, no 1, p. 1-11Article in journal (Refereed)
    Abstract [en]

    It was reported earlier that a few patients suffering from non-Hodgkin's lymphoma had low amounts of DNA from the so-called fifth human exogenous retrovirus, HRV-5. A sensitive and rational method for large-scale screening for HRV-5 DNA was therefore developed. It is a single-tube nested quantitative PCR (stnQPCR), which uses two functionally isolated primer pairs and one probe target distinct from related endogenous retroviral sequences, yet encompassing known HRV-5 variation, allowing optimal use of sequence conservation. DNA from lymphoma, myeloma, and follicular dendritic cell lines was tested for HRV-5 positivity, as was DNA from whole blood of blood donors, non-Hodgkin's lymphoma and systemic lupus erythematosus patients, as well as DNA from lymph node biopsies of rheumatoid arthritis patients with lymphoma. One blood donor, one systemic lupus erythematosus patient, two previously known positive non-Hodgkin's lymphoma patients, and one rheumatoid arthritis lymphoma patient, came out positive. They had 24, 2, 148, 480 and 30 proviral copies per microg of DNA from PBMC or lymphoma tissue, respectively. During the completion of this work it was reported that HRV-5 is a rabbit endogenous retrovirus (RERV-H), and that HRV-5 positivity was due to presence of rabbit DNA. DNA from six RERV-H/HRV-5 positive samples was therefore retested. Three also contained rabbit mitochondrial DNA. A search for HRV-5 antibodies using synthetic peptides was negative in sera from three RERV-H/HRV-5 positive individuals, as well as in 144 other sera, according with a noninfectious origin of the RERV-H/HRV-5 DNA in human samples. A search for possible sources of rabbit DNA contamination was negative. Methods for prevention of PCR contamination were strictly adhered to. Three samples from RERV-H/HRV-5 positive individuals positive at the Uppsala laboratory were retested at one or two other laboratories, and all three were positive. Two other samples, which were positive in the Riga laboratory, were tested also in London and also found positive. One non-Hodgkin's lymphoma patient was RERV-H/HRV-5 positive in four consecutive samples, showing that positivity was a property of that patient. It is concluded that the stnQPCR developed to detect and quantify minute amounts of RERV-H/HRV-5 DNA is a principle which can be applied widely and HRV-5 is a RERV-H. Its presence in a few human blood samples could not be explained.

  • 45. Gateva, Vesela
    et al.
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Hom, Geoff
    Taylor, Kimberly E.
    Chung, Sharon A.
    Sun, Xin
    Ortmann, Ward
    Kosoy, Roman
    Ferreira, Ricardo C.
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gunnarsson, Iva
    Svenungsson, Elisabet
    Padyukov, Leonid
    Sturfelt, Gunnar
    Jönsen, Andreas
    Bengtsson, Anders A.
    Rantapää-Dahlqvist, Solbritt
    Baechler, Emily C.
    Brown, Elizabeth E.
    Alarcón, Graciela S.
    Edberg, Jeffrey C.
    Ramsey-Goldman, Rosalind
    McGwin, Gerald
    Reveille, John D.
    Vilá, Luis M.
    Kimberly, Robert P.
    Manzi, Susan
    Petri, Michelle A.
    Lee, Annette
    Gregersen, Peter K.
    Seldin, Michael F.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Criswell, Lindsey A.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Behrens, Timothy W.
    Graham, Robert R.
    A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus2009In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 41, no 11, p. 1228-1233Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies have recently identified at least 15 susceptibility loci for systemic lupus erythematosus (SLE). To confirm additional risk loci, we selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P < 0.05) in a genome-wide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This replication effort identified five new SLE susceptibility loci (P < 5 x 10(-8)): TNIP1 (odds ratio (OR) = 1.27), PRDM1 (OR = 1.20), JAZF1 (OR = 1.20), UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19). We identified 21 additional candidate loci with P< or = 1 x 10(-5). A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 x 10(-3)) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3. These results expand the number of confirmed and candidate SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis.

  • 46.
    Hagberg, Niklas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Berggren, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Weber, Gert
    Bryceson, Yenan T.
    Alm, Gunnar V.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    IFN-α Production by Plasmacytoid Dendritic Cells Stimulated with RNA-Containing Immune Complexes Is Promoted by NK Cells via MIP-1β and LFA-12011In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 186, no 9, p. 5085-5094Article in journal (Refereed)
    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.

  • 47.
    Hagberg, Niklas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Systemic lupus erythematosus: a disease with a dysregulated type I interferon system2015In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 82, no 3, p. 199-207Article, review/survey (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease characterized by the loss of tolerance to nuclear antigens, immune complex formation and inflammation in multiple organs. The disease is very heterogeneous and most clinicians consider SLE as a group of diseases with similar features where the pathogenesis is driven by a combination of genetic and environmental factors. One of the most prominent features, shared by the majority of SLE patients, is a continuous activation of the type I interferon (IFN) system, which manifests as increased serum levels of IFNα and/or an increased expression of type I IFN induced genes, a so called type I IFN-signature. The mechanisms behind this IFN-signature have partly been clarified during recent years, although the exact function of the IFN regulated genes in the disease process is unclear. In this review we will describe the type I IFN system and its regulation and summarize the numerous findings implicating an important ethiopathogenic role of a dysregulated type I IFN system in SLE. Furthermore, strategies to therapeutically target the type I IFN system that are currently evaluated preclinically and in clinical trials will be mentioned.

  • 48.
    Hagberg, Niklas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    The Interferon System in Lupus Erythematosus2016In: Systemic Lupus Erythematosus: Basic, Applied and Clinical Aspects / [ed] George C. Tsokos, Academic Press, 2016, p. 153-158Chapter in book (Refereed)
    Abstract [en]

    The interferons (IFNs) are a large group of proteins classified into three types (I-III) that induce viral resistance in cells and also act as immune adjuvants and stimulate the adaptive immune system. Increased levels of mainly type I IFN are seen in patients with systemic lupus erythematosus (SLE), which is due to the presence of self-derived inducers of type I IFN production acting on plasmacytoid dendritic cells. Such inducers consist of autoantigens containing nucleic acid that stimulate endosomal Toll-like receptors, which trigger the ongoing IFN synthesis that leads to an increased transcription of type I IFN-regulated genes in target cells (an interferon signature). The type I IFN production contributes to the autoimmune process and several therapies aiming to inhibit the production, or action, of type I IFN have been developed. Preliminary results indicate that this therapeutic strategy may be successful in a subset of patients with SLE.

  • 49.
    Hagberg, Niklas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Theorell, Jakob
    Alm, Gunnar V.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Bryceson, Yenan
    Ronnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Systemic Lupus Erythematosus Immune Complexes Upregulate the Expression of CD319 and CD229 On Plasmacytoid Dendritic Cells2012In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no s10, p. S368-S369Article in journal (Other academic)
  • 50.
    Hagberg, Niklas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Theorell, Jakob
    Alm, Gunnar V.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bryceson, Yenan
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    SLE immune complexes upregulate the expression of slamf7 (cd319) on plasmacytoid dendritic cells2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, p. A3-A3Article in journal (Other academic)
123 1 - 50 of 129
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