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  • 1.
    Abramov, Sergei
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Kazan Fed Univ, Inst Fundamental Med & Biol, Kazan, Russia.
    Kozyrev, Sergey V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Farias, Fabiana 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. Washington Univ, Genome Inst, Sch Med, St Louis, MO USA.
    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, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    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. Swedish Univ Agr Sci SLU, Dept Anim Breeding & Genet, Uppsala, Sweden.
    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.
    Pielberg, Gerli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hansson-Hamlin, H.
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Uppsala, Sweden.
    Andersson, G.
    Swedish Univ Agr Sci SLU, Dept Anim Breeding & Genet, Uppsala, Sweden.
    Tandre, Karolina
    Uppsala 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.
    Ronnblom, L.
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Uppsala, 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.
    The risk allele A of rs200395694 associated with SLE in Swedish patients affects on MEF2D gene regulation and alternative splicing2018In: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 29, no 12, p. A44-A44Article in journal (Other academic)
  • 2.
    Almlöf, Jonas Carlsson
    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.
    Nystedt, Sara
    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.
    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.
    Grosso, Giorgia
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit,Rheumatol, S-17177 Stockholm, Sweden.
    Sjowall, Christopher
    Linkoping Univ, Div Neuro & Inflammat Sci, Dept Clin & Expt Med, Rheumatol, S-58183 Linkoping, Sweden.
    Bengtsson, Anders A.
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Rheumatol, S-22242 Lund, Sweden.
    Jonsen, Andreas
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Rheumatol, S-22242 Lund, Sweden.
    Gunnarsson, Iva
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit,Rheumatol, S-17177 Stockholm, Sweden.
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit,Rheumatol, S-17177 Stockholm, Sweden.
    Rönnblom, Lars
    Uppsala 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, 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.
    Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus2019In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 138, no 2, p. 141-150Article in journal (Refereed)
    Abstract [en]

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

  • 3.
    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)
  • 4.
    Bremer, Hanna D.
    et al.
    Swedish Univ Agr Sci, Dept Clin Sci, SE-75007 Uppsala, Sweden..
    Landegren, Nils
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, Stockholm, Sweden..
    Sjöberg, Ronald
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, SE-17121 Solna, Sweden..
    Hallgren, Åsa
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, CMM, L8 01, SE-17176 Stockholm, Sweden..
    Renneker, Stefanie
    Euroimmun AG, D-23560 Lubeck, Germany..
    Lattwein, Erik
    Euroimmun AG, D-23560 Lubeck, Germany..
    Leonard, Dag
    Uppsala 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.
    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.
    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.
    Nilsson, Peter
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, SE-17121 Solna, Sweden..
    Andersson, Goran
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75007 Uppsala, Sweden..
    Lilliehöök, Inger
    Swedish Univ Agr Sci, Dept Clin Sci, SE-75007 Uppsala, Sweden..
    Lindblad-Toh, Kerstin
    Uppsala 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 Harvard & MIT, Cambridge, USA..
    Kämpe, Olle
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Karolinska Inst, Karolinska Univ Hosp, Dept Med Solna, CMM, L8 01, SE-17176 Stockholm, Sweden.; Univ Bergen, Dept Clin Sci, N-5021 Bergen, Norway.;Univ Bergen, KG Jebsen Ctr Autoimmune Disorders, N-5021 Bergen, Norway.;Haukeland Hosp, Dept Med, N-5021 Bergen, Norway..
    Hansson-Hamlin, Helene
    Swedish Univ Agr Sci, Dept Clin Sci, SE-75007 Uppsala, Sweden..
    ILF2 and ILF3 are autoantigens in canine systemic autoimmune disease2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 4852Article in journal (Refereed)
    Abstract [en]

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

  • 5.
    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.

  • 6.
    Farias, Fabiana H. G.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
    Dahlqvist, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kozyrev, Sergey V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. 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.
    Wilbe, Maria
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences (SLU), Box 7023, SE-750 07, Uppsala, Sweden.
    Abramov, Sergei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, 420008, Russia.
    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.
    Pielberg, Gerli
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hansson-Hamlin, Helene
    Department of Clinical Sciences, Swedish University of Agricultural Sciences (SLU), Box 7054, SE-750 07, Uppsala, Sweden.
    Andersson, Göran
    Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences (SLU), Box 7023, SE-750 07, Uppsala, Sweden.
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bengtsson, Anders A
    Department of Clinical Sciences Lund, Lund University, Skane University Hospital, SE-221 00, Lund, Sweden.
    Sjöwall, Christopher
    Department of Clinical and Experimental Medicine, Rheumatology/Division of Neuro and Inflammation Sciences, Linköping University, SE-581 85, Linköping, Sweden.
    Svenungsson, Elisabet
    Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.
    Gunnarsson, Iva
    Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, SE-901 85, Umeå, Sweden.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. 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, 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.
    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.
    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 Institute, Cambridge, 7 Cambridge Center, Cambridge, MA, 02142, USA.
    A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts2019In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, p. 432-441Article in journal (Refereed)
    Abstract [en]

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

  • 7.
    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)
  • 8.
    Frodlund, M.
    et al.
    Linkoping Univ, Dept Clin & Expt Med, Div Neuro & Inflammat Sci, Linkoping, Sweden.
    Reid, Sarah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wettero, J.
    Linkoping Univ, Dept Clin & Expt Med, Div Neuro & Inflammat Sci, Linkoping, Sweden.
    Dahlstrom, O.
    Linkoping Univ, Swedish Inst Disabil Res, Dept Behav Sci & Learning, Linkoping, Sweden.
    Sjowall, C.
    Linkoping Univ, Dept Clin & Expt Med, Div Neuro & Inflammat Sci, Linkoping, Sweden.
    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.
    The majority of Swedish systemic lupus erythematosus patients are still affected by irreversible organ impairment: factors related to damage accrual in two regional cohorts2019In: Lupus, ISSN 0961-2033, E-ISSN 1477-0962, Vol. 28, no 10, p. 1261-1272, article id UNSP 0961203319860198Article in journal (Refereed)
    Abstract [en]

    Background Although the survival of patients with systemic lupus erythematosus (SLE) has improved, irreversible organ damage remains a critical concern. We aimed to characterize damage accrual and its clinical associations and causes of death in Swedish patients. Methods Accumulation of damage was evaluated in 543 consecutively recruited and well-characterized cases during 1998-2017. The Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology damage index (SDI) was used to estimate damage. Results Organ damage (SDI >= 1) was observed in 59%, and extensive damage (SDI >= 3) in 25% of cases. SDI >= 1 was significantly associated with higher age at onset, SLE duration, the number of fulfilled SLICC criteria, neurologic disorder, antiphospholipid antibody syndrome (APS), hypertension, hyperlipidemia, depression and secondary Sjogren's syndrome (SS). In addition, SDI >= 3 was associated with serositis, renal and haematological disorders and interstitial lung disease. A multiple regression model identified not only well-known risk factors like APS, antihypertensives and corticosteroids, but pericarditis, haemolytic anaemia, lymphopenia and myositis as being linked to SDI. Malignancy, infection and cardiovascular disease were the leading causes of death. Conclusions After a mean SLE duration of 17 years, the majority of today's Swedish SLE patients have accrued damage. We confirm previous observations and report some novel findings regarding disease phenotypes and damage accrual.

  • 9.
    Gallo, Lina Marcela Diaz
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Dept Med,Rheumatol Unit, Stockholm, Sweden..
    Lundstrom, Emeli
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Dept Med,Rheumatol Unit, Stockholm, Sweden..
    Oke, Vilija
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Dept Med,Rheumatol Unit, Stockholm, Sweden..
    Elvin, Kerstin
    Karolinska Univ Hosp, Karolinska Inst, Dept Clin Immunol & Transfus Med, Unit Clin Immunol,Dept Med Solna,Rheumatol Unit, Stockholm, Sweden..
    Wu, Yee Ling
    Nationwide Childrens Hosp, Res Inst, Columbus, OH USA.;Ohio State Univ, Columbus, OH 43210 USA..
    Gustafsson, Johanna
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Dept Med,Rheumatol Unit, Stockholm, Sweden..
    Jonsen, Andreas
    Lund Univ, Dept Clin Sci, Rheumatol, Lund, Sweden..
    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.
    Zickert, Agneta
    Karolinska Univ Hosp, Karolinska Inst, Rheumatol Unit, Dept Med, Stockholm, Sweden..
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Bengtsson, Anders A.
    Lund Univ, Dept Clin Sci, Rheumatol, Lund, Sweden..
    Sandling, Johanna K.
    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.
    Gunnarsson, Iva
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Dept Med,Rheumatol Unit, Stockholm, Sweden..
    Yu, Chack-Yung
    Nationwide Childrens Hosp, Res Inst, Ctr Mol & Human Genet, Columbus, OH USA..
    Padyukov, Leonid
    Karolinska Univ Hosp, Karolinska Inst, Rheumatol Unit, Dept Med Solna, Stockholm, Sweden..
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Karolinska Inst, Rheumatol Unit, Dept Med Solna, Stockholm, Sweden..
    SLE Comprises Four Immune-Phenotypes, Which Differ Regarding HLA-DRB1 and Clinical Associations2017In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, no S10, article id 1675Article in journal (Other academic)
  • 10.
    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.

  • 11.
    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.
    Joelsson, Martin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    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.
    Reid, Sarah
    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.
    Mo, John
    AstraZeneca, Resp Inflammat & Autoimmun, IMED Biotech Unit, Gothenburg, Sweden.
    Nilsson, Magnus K.
    AstraZeneca, Resp Inflammat & Autoimmun, IMED Biotech Unit, Gothenburg, Sweden.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bryceson, Yenan T.
    Karolinska Inst, Dept Med, Ctr Hematol & Regenerat Med, Karolinska Univ Hosp Huddinge, Stockholm, Sweden;Univ Bergen, Dept Clin Sci, Broegelmann Res Lab, Bergen, Norway.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The STAT4 SLE risk allele rs7574865[T] is associated with increased IL-12-induced IFN-γ production in T cells from patients with SLE2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 7, p. 1070-1077Article in journal (Refereed)
    Abstract [en]

    Objectives Genetic variants in the transcription factor STAT4 are associated with increased susceptibility to systemic lupus erythematosus (SLE) and a more severe disease phenotype. This study aimed to clarify how the SLE-associated intronic STAT4 risk allele rs7574865[T] affects the function of immune cells in SLE.

    Methods Peripheral blood mononuclear cells (PBMCs) were isolated from 52 genotyped patients with SLE. Phosphorylation of STAT4 (pSTAT4) and STAT1 (pSTAT1) in response to interferon (IFN)-α, IFN-γ or interleukin (IL)-12, total levels of STAT4, STAT1 and T-bet, and frequency of IFN-γ+ cells on IL-12 stimulation were determined by flow cytometry in subsets of immune cells before and after preactivation of cells with phytohaemagglutinin (PHA) and IL-2. Cellular responses and phenotypes were correlated to STAT4 risk allele carriership. Janus kinase inhibitors (JAKi) selective for TYK2 (TYK2i) or JAK2 (JAK2i) were evaluated for inhibition of IL-12 or IFN-γ-induced activation of SLE PBMCs.

    Results In resting PBMCs, the STAT4 risk allele was neither associated with total levels of STAT4 or STAT1, nor cytokine-induced pSTAT4 or pSTAT1. Following PHA/IL-2 activation, CD8+ T cells from STAT4 risk allele carriers displayed increased levels of STAT4 resulting in increased pSTAT4 in response to IL-12 and IFN-α, and an augmented IL-12-induced IFN-γ production in CD8+ and CD4+ T cells. The TYK2i and the JAK2i efficiently blocked IL-12 and IFN-γ-induced activation of PBMCs from STAT4 risk patients, respectively.

    Conclusions T cells from patients with SLE carrying the STAT4 risk allele rs7574865[T] display an augmented response to IL-12 and IFN-α. This subset of patients may benefit from JAKi treatment.

  • 12.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Almlöf, Jonas Carlsson
    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.
    Alexsson, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Nordmark, Gunnel
    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.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Umeå, Sweden.
    Bengtsson, Anders A
    Lund University, Skane University Hospital, Lund, Sweden.
    Jönsen, Andreas
    Lund University, Skane University Hospital, Lund, Sweden.
    Padyukov, Leonid
    Karolinska University Hospital, Stockholm, Sweden.
    Gunnarsson, Iva
    Karolinska University Hospital, Stockholm, Sweden.
    Svenungsson, Elisabet
    Karolinska University Hospital, Stockholm, Sweden.
    Sjöwall, Christopher
    Linköping University, Linköping, Sweden.
    Rönnblom, Lars
    Uppsala 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 epidemiology. 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, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 5, p. 736-743Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 13.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Almlöf, Jonas Carlsson
    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.
    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, Rheumatol Unit, Dept Med Solna, Stockholm, Sweden..
    Gunnarsson, Iva
    Karolinska Univ Hosp, Karolinska Inst, Rheumatol Unit, Dept Med Solna, Stockholm, Sweden..
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Karolinska Inst, Rheumatol Unit, Dept Med Solna, Stockholm, Sweden..
    Sjowall, Christopher
    Linkoping Univ, Rheumatol AIR, Dept Clin & Expt Med, Linkoping, Sweden..
    Rönnblom, Lars
    Uppsala 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.
    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.
    Treatment-Associated DNA Methylation Patterns in Systemic Lupus Erythematosus2017In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, no S10, article id 2654Article in journal (Other academic)
  • 14.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Carlsson Almlöf, Jonas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    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.
    Sjöwall, Christopher
    Linkoping Univ, Dept Clin & Expt Med, Div Neuro & Inflammat Sci, Rheumatol, Linkoping, Sweden.
    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.
    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, Rheumatology.
    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. Uppsala Univ, Sect Rheumatol, Uppsala, Sweden;Uppsala Univ, Sci Life Lab, Dept Med Sci, Uppsala, Sweden.
    Shared and Unique Patterns of DNA Methylation in Systemic Lupus Erythematosus and Primary Sjogren's Syndrome2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1686Article in journal (Refereed)
    Abstract [en]

    Objectives: To performa cross-comparative analysis of DNA methylation in patients with systemic lupus erythematosus (SLE), patients with primary Sjogren's syndrome (pSS), and healthy controls addressing the question of epigenetic sharing and aiming to detect disease-specific alterations. Methods: DNA extracted from peripheral blood from 347 cases with SLE, 100 cases with pSS, and 400 healthy controls were analyzed on the Human Methylation 450k array, targeting 485,000 CpG sites across the genome. A linear regression model including age, sex, and blood cell type distribution as covariates was fitted, and association p-values were Bonferroni corrected. A random forest machine learning classifier was designed for prediction of disease status based on DNA methylation data. Results: We established a combined set of 4,945 shared differentially methylated CpG sites (DMCs) in SLE and pSS compared to controls. In pSS, hypomethylation at type I interferon induced genes was mainly driven by patients who were positive for Ro/SSA and/or La/SSB autoantibodies. Analysis of differential methylation between SLE and pSS identified 2,244 DMCs with a majority of sites showing decreased methylation in SLE compared to pSS. The random forest classifier demonstrated good performance in discerning between disease status with an area under the curve (AUC) between 0.83 and 0.96. Conclusions: The majority of differential DNA methylation is shared between SLE and pSS, however, important quantitative differences exist. Our data highlight neutrophil dysregulation as a shared mechanism, emphasizing the role of neutrophils in the pathogenesis of systemic autoimmune diseases. The current study provides evidence for genes and molecular pathways driving common and disease-specific pathogenic mechanisms.

  • 15.
    Imgenberg-Kreuz, Juliana
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    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.
    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.
    Rantapaa-Dahlqvist, S.
    Umea Univ, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden.
    Bengtsson, A.
    Lund Univ, Dept Clin Sci, Rheumatol, Lund, Sweden.
    Jonsen, A.
    Lund Univ, Dept Clin Sci, Rheumatol, Lund, Sweden.
    Padyukov, L.
    Karolinska Inst, Dept Med Solna, Rheumatol Unit, Stockholm, Sweden.
    Gunnarsson, I.
    Karolinska Inst, Dept Med Solna, Rheumatol Unit, Stockholm, Sweden.
    Svenungsson, E.
    Karolinska Inst, Dept Med Solna, Rheumatol Unit, Stockholm, Sweden.
    Sjowall, C.
    Linkoping Univ, Rheumatol Div Neuro & Inflammat Sci, Dept Clin & Expt Med, Linkoping, Sweden.
    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.
    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.
    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, Rheumatology.
    Shared and unique patterns of DNA methylation in primary Sjogren's syndrome and systemic lupus erythematosus2018In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 47, p. 3-3Article in journal (Other academic)
  • 16. Jonsen, Andreas
    et al.
    Bengtsson, Anders A.
    Bengtsson, Christine
    Gunnarsson, Iva
    Gustafsson, Johanna
    Hjalte, Frida
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Pettersson, Susanne
    Dahlqvist, Solbritt Rantapaa
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Sjowall, Christopher
    Carlsson, Katarina Steen
    Svenungsson, Elisabet
    Willim, Minna
    Nived, Ola
    Direct and Indirect Costs For Patients With Systemic Lupus Erythematosus In National Cohorts In Sweden2013In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 65, no Suppl. 10, p. S752-S752Article in journal (Other academic)
  • 17. Jönsen, Andreas
    et al.
    Hjalte, Frida
    Willim, Minna
    Carlsson, Katarina Steen
    Sjöwall, Christopher
    Svenungsson, Elisabet
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Bengtsson, Christine
    Rantapää-Dahlqvist, Solbritt
    Pettersson, Susanne
    Gunnarsson, Iva
    Zickert, Agneta
    Gustafsson, Johanna T
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Petersson, Ingemar F
    Bengtsson, Anders A
    Nived, Ola
    Direct and indirect costs for systemic lupus erythematosus in Sweden. A nationwide health economic study based on five defined cohorts2016In: Seminars in Arthritis & Rheumatism, ISSN 0049-0172, E-ISSN 1532-866X, Vol. 45, no 6, p. 684-690Article, review/survey (Refereed)
    Abstract [en]

    OBJECTIVES: The main objectives of this study were to calculate total costs of illness and cost-driving disease features among patients with systemic lupus erythematosus (SLE) in Sweden.

    METHODS: Five cohorts of well-defined SLE patients, located in different parts of the country were merged. Incident and prevalent cases from 2003 through 2010 were included. The American College of Rheumatology (ACR) classification criteria was used. From the local cohorts, data on demographics, disease activity (SLEDAI 2K), and organ damage (SDI) were collected. Costs for inpatient care, specialist outpatient care and drugs were retrieved from national registries at the National Board of Health and Welfare. Indirect costs were calculated based on sickness leave and disability pensions from the Swedish Social Insurance Agency.

    RESULTS: In total, 1029 SLE patients, 88% females, were included, and approximately 75% were below 65 years at the end of follow-up, and thus in working age. The mean number of annual specialist physician visits varied from six to seven; mean annual inpatient days were 3.1-3.6, and mean annual sick leave was 123-148 days, all per patient. The total annual cost was 208,555 SEK ($33,369 = 22,941€), of which direct cost was 63,672kr ($10,188 = 7004€) and the indirect cost was 144,883 SEK ($23,181 = 15,937€), all per patient. The costs for patients with short disease duration were higher. Higher disease activity as measured by a SLEDAI 2K score > 3 was associated with approximately 50% increase in both indirect and direct costs. Damage in the neuropsychiatric and musculoskeletal domains were also linked to higher direct and indirect costs, while organ damage in the renal and ocular systems increased direct costs.

    CONCLUSION: Based on this study and an estimate of slightly more than 6000 SLE patients in Sweden, the total annual cost for SLE in the country is estimated at $188 million (=129.5 million €). Both direct (30%) and indirect costs (70%) are substantial. Medication accounts for less than 10% of the total cost. The tax paid national systems for health care and social security in Sweden ensure equal access to health care, sick leave reimbursements, and disability pensions nationwide. Our extrapolated annual costs for SLE in Sweden are therefore the best supported estimations thus far, and they clearly underline the importance of improved management, especially to reduce the indirect costs.

  • 18.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cardiovascular Disease and Immune Mechanisms in Systemic Lupus Erythematosus2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Systemic lupus erythematosus (SLE) is an autoimmune, inflammatory disease characterized by autoantibody production and an activated type I interferon system. Cardiovascular disease (CVD) is as a major cause of morbidity and mortality. The aim of this thesis was to identify genetic risk factors for CVD in SLE. The role of T cells in regulation of the interferon-α (IFNα) production by plasmacytoid dendritic cells (pDCs) was also investigated.

       In paper I, a thicker intima, thinner media and increased intima/media ratio was found in young premenopausal women with SLE compared to healthy controls indicating increased cardiovascular risk. As traditional ultrasound assessment of the common carotid intima-media thickness (CCA-IMT) in SLE has given conflicting results separate measurement of the intima and media can be a useful tool to identify SLE patients at increased risk of CVD.

       In paper II, an association was demonstrated in SLE between a STAT4 risk allele and ischemic cerebrovascular disease and presence of anti-phospholipid antibodies (aPL). The association remained after adjustment for traditional CVD risk factors. A possible mechanism for this association is that the risk allele leads to increased production of aPL, which promotes thromboembolism.

       In paper III, a genetic locus in IRF8 was identified to be associated to coronary heart disease (CHD) in SLE. The association remained after adjustment of other CHD risk factors.  Patients with the IRF8 risk variant had increased CCA-IMT, more carotid plaques and reduced frequency of circulating B cells. Weaker binding of nuclear protein to the risk allele was demonstrated, suggesting a regulatory function of the IRF8 risk variant.

       In paper IV, activated T cells were found to strongly enhance the IFNα production by pDC stimulated with RNA-containing immune complexes via GM-CSF and IL-3. Activated SLE T cells enhanced the IFNα production to the same extent as T cells from healthy controls. This finding together with previous observations in SLE of increased levels of GM-CSF and IL-3 suggests that T cells contribute to the activated type I interferon system in SLE.

       In conclusion, this thesis demonstrates that genetic predisposition is important for CVD in SLE and describes a new role for T cells in the pathogenesis of SLE.

  • 19. Leonard, Dag
    et al.
    Eloranta, Maija-Leena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Hagberg, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Berggren, Olof
    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.
    Alm, G.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Activated T cells enhance interferon-alpha production by plasmacytoid dendritic cells stimulated by RNA-containing immune complexes2014In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 43, no S127, p. 88-89Article in journal (Other academic)
  • 20.
    Leonard, Dag
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    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.
    Hagberg, Niklas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Berggren, Olof
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Tandre, Karolina
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Alm, Gunnar
    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.
    Activated SLE-T Cells Enhance the Interferon-Alpha Production By Plasmacytoid Dendritic Cells Stimulated By RNA-IC2014In: Arthritis & Rheumatology, ISSN 2326-5191, Vol. 66, no S10, p. S1173-S1173, article id 2681Article in journal (Other academic)
  • 21.
    Leonard, Dag
    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, Rheumatology.
    Hagberg, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Berggren, Olof
    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.
    Alm, Gunnar
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Activated T cells enhance interferon-alpha production by plasmacytoid dendritic cells stimulated by RNA-containing immune complexesManuscript (preprint) (Other academic)
  • 22.
    Leonard, Dag
    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.
    Svenungsson, E.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    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.
    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.
    Ärlestig, L.
    Umea Univ, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden.
    Taylor, K. E.
    Univ Calif San Francisco, Rosalind Russell Ephraim P Engleman Rheumatol Res, San Francisco, CA 94143 USA.
    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, Rheumatology.
    Bengtsson, C.
    Umea Univ, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden.
    Frodlund, M.
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Jönsen, A.
    Skane Univ Hosp, Dept Rheumatol, Lund, Sweden.
    Eketjäll, S.
    Karolinska Inst, Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, AstraZeneca,ICMC, Huddinge, Sweden.
    Jensen-Urstad, K.
    Karolinska Inst, Dept Clin Physiol, Stockholm, Sweden.
    Gunnarsson, I.
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Sjöwall, C.
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Bengtsson, A. A.
    Skane Univ Hosp, Dept Rheumatol, Lund, Sweden.
    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.
    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.
    Rantapää-Dahlqvist, S.
    Umea Univ, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden.
    Criswell, L. A.
    Univ Calif San Francisco, Rosalind Russell Ephraim P Engleman Rheumatol Res, San Francisco, CA 94143 USA.
    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.
    Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, p. 1063-1069Article in journal (Refereed)
    Abstract [en]

    Objectives Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk of cardiovascular disease (CVD). We investigated whether single nucleotide polymorphisms (SNPs) at autoimmunity risk loci were associated with CVD in SLE and RA. Methods Patients with SLE (n=1045) were genotyped using the 200K Immunochip SNP array (Illumina). The allele frequency was compared between patients with and without different manifestations of CVD. Results were replicated in a second SLE cohort (n=1043) and in an RA cohort (n=824). We analysed publicly available genetic data from general population, performed electrophoretic mobility shift assays and measured cytokine levels and occurrence of antiphospholipid antibodies (aPLs). Results We identified two new putative risk loci associated with increased risk for CVD in two SLE populations, which remained after adjustment for traditional CVD risk factors. An IL19 risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5×10−5) and RA (OR 2.8 (1.4 to 5.6), P=3.8×10−3), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5×10−7), but not in population controls. The IL19 risk allele affected protein binding, and SLE patients with the risk allele had increased levels of plasma-IL10 (P=0.004) and aPL (P=0.01). An SRP54-AS1 risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5×10−5) but not in RA. The SRP54-AS1 risk allele is an expression quantitative trait locus for four genes. Conclusions The IL19 risk allele was associated with stroke/MI in SLE and RA, but not in the general population, indicating that shared immune pathways may be involved in the CVD pathogenesis in inflammatory rheumatic diseases.

  • 23.
    Leonard, Dag
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Svenungsson, E.
    Sandling, J. K.
    Berggren, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Jonsen, A.
    Bengtsson, C.
    Wang, C.
    Jensen-Urstad, K.
    Granstam, Sven-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Bengtsson, A. A.
    Gustafsson, J. T.
    Gunnarsson, I.
    Rantapaa-Dahlqvist, S.
    Nordmark, Gunnel
    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.
    Syvanen, A-C
    Ronnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Coronary Heart Disease in Systemic Lupus Erythematosus is Associated with Interferon Regulatory Factor 8 Gene Variants2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no S3, p. 270-270Article in journal (Other academic)
  • 24.
    Leonard, Dag
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Svenungsson, Elisabet
    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.
    Berggren, Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Jönsen, Andreas
    Bengtsson, Christine
    Wang, Chuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jensen-Urstad, Kerstin
    Granstam, Sven-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Bengtsson, Anders A
    Gustafsson, Johanna T
    Gunnarsson, Iva
    Rantapää-Dahlqvist, Solbritt
    Nordmark, Gunnel
    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.
    Syvänen, Ann-Christine
    Uppsala University, Science for Life Laboratory, SciLifeLab. 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.
    Coronary heart disease in systemic lupus erythematosus is associated with interferon regulatory factor-8 gene variants2013In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 6, no 3, p. 255-263Article in journal (Refereed)
    Abstract [en]

    Background- Patients with systemic lupus erythematosus have increased morbidity and mortality in coronary heart disease (CHD). We asked whether there was a genetic influence on CHD in systemic lupus erythematosus. Methods and Results- The association between single-nucleotide polymorphisms (SNPs) and CHD in 2 populations of patients with systemic lupus erythematosus was assessed. Patients were genotyped on a custom 12k Illumina Array. The allele frequencies were compared between patients with (n=66) and without (n=509) CHD. We found 61 SNPs with an association (P<0.01) to CHD, with the strongest association for 3 SNPs located in the interferon regulatory factor-8 (IRF8) gene. Comparison of the allele frequencies of these 61 SNPs in patients with (n=27) and without (n=212) CHD in the second study population revealed that 2 SNPs, rs925994 and rs10514610 in IRF8 (linkage disequilibrium, r(2)=0.84), were associated with CHD in both study populations. Meta-analysis of the SNP rs925994 gave an odds ratio of 3.6 (2.1-6.3), P value 1.9×10(-6). The identified IRF8 allele remained as a risk factor for CHD after adjustment for traditional CHD risk factors. The IRF8 risk allele was associated with the presence of carotid plaques (P<0.001) and increased intima-media thickness (P=0.01). By electrophoretic mobility shift assays, we show weaker binding of protein to the risk allele of the highly linked SNP rs11117415, and by flow cytometry, a reduced frequency of circulating B cells was detected in patients with the IRF8 risk allele. Conclusions- There is a considerable genetic component for CHD in systemic lupus erythematosus, with IRF8 as a strong susceptibility locus.

  • 25. Lundström, Emeli
    et al.
    Gustafsson, Johanna T
    Jönsen, Andreas
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Zickert, Agneta
    Elvin, Kerstin
    Sturfelt, Gunnar
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Bengtsson, Anders A
    Sundin, Ulf
    Källberg, Henrik
    Sandling, Johanna K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Klareskog, Lars
    Gunnarsson, Iva
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Padyukov, Leonid
    Svenungsson, Elisabet
    HLA-DRB1*04/*13 alleles are associated with vascular disease and antiphospholipid antibodies in systemic lupus erythematosus2013In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 72, no 6, p. 1018-1025Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVES:

    Vascular disease is common in systemic lupus erythematosus (SLE) and patients with antiphospholipid antibodies (aPL) are at high risk to develop arterial and venous thrombosis. Since HLA class II genotypes have been linked to the presence of pro-thrombotic aPL, we investigated the relationship between HLA-DRB1 alleles, aPL and vascular events in SLE patients.

    METHODS:

    665 SLE patients of Caucasian origin and 1403 controls were included. Previous manifestations of ischaemic heart disease, ischaemic cerebrovascular disease (ICVD) and venous thromboembolism (together referred to as any vascular events (AVE)) were tabulated. aPL were measured with ELISA. Two-digit HLA-DRB1 typing was performed by sequence-specific primer-PCR.

    RESULTS:

    HLA-DRB1*04 was more frequent among SLE patients with ICVD compared to unaffected patients. This association remained after adjustment for known traditional cardiovascular risk factors. HLA-DRB1*13 was associated with AVE. All measured specificities of aPL—cardiolipin IgG and IgM, β2-glycoprotein-1 IgG, prothrombin (PT) IgG and a positive lupus anticoagulant test were associated with HLA-DRB1*04—while HLA-DRB1*13 was associated with IgG antibodies (β2-glycoprotein-1, cardiolipin and PT). In patients with the combined risk alleles, HLA-DRB1*04/*13, there was a significant additive interaction for the outcomes AVE and ICVD.

    CONCLUSIONS:

    The HLA-DRB1*04 and HLA-DRB1*13 alleles are associated with vascular events and an aPL positive immune-phenotype in SLE. Results demonstrate that a subset of SLE patients is genetically disposed to vascular vulnerability.

  • 26.
    Odqvist, Lina
    et al.
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    Jevnikar, Zala
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    Riise, Rebecca
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    Oberg, Lisa
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    Rhedin, Magdalena
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    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.
    Yrlid, Linda
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    Jackson, Sonya
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    Mattsson, Johan
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    Nanda, Sambit
    Univ Dundee, MRC Prot Phosphorylat & Ubiquitylat Unit, Dundee, Scotland.
    Cohen, Philip
    Univ Dundee, MRC Prot Phosphorylat & Ubiquitylat Unit, Dundee, Scotland.
    Knebel, Axel
    Univ Dundee, MRC Prot Phosphorylat & Ubiquitylat Unit, Dundee, Scotland.
    Arthur, Simon
    Univ Dundee, Sch Life Sci, Div Immunol & Cell Signaling, Dundee, Scotland.
    Thorn, Kristofer
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    Svenungsson, Elisabet
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.
    Jonsen, Andreas
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Rheumatol, Lund, Sweden.
    Gunnarsson, Iva
    Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, 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.
    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.
    Kastbom, Alf
    Linkoping Univ, Dept Rheumatol, Linkoping, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Med Fak, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden.
    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.
    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.
    Bengtsson, Anders
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Rheumatol, Lund, Sweden.
    Johansson, Patrik
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Discovery Sci, Molndal, Sweden.
    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, Rheumatology.
    Sjowall, Christopher
    Linkoping Univ, Dept Rheumatol, Linkoping, Sweden;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.
    Collins, Barry
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden.
    Vaarala, Outi
    AstraZeneca R&D Gothenburg, BioPharmaceut R&D, Res & Early Dev, Resp Inflammat & Autoimmune, Molndal, Sweden;MedImmune LLC, Resp Inflammat & Autoimmun Dept, Gaithersburg, MD 20878 USA.
    Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus2019In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, no 10, p. 1363-1370Article in journal (Refereed)
    Abstract [en]

    Objectives

    Genetic variations in TNFAIP3 (A20) deubiquitinase (DUB) domain increase the risk of systemic lupus erythematosus (SLE) and rheumatoid arthritis. A20 is a negative regulator of NF-kappa B but the role of its DUB domain and related genetic variants remain unclear. We aimed to study the functional effects of A20 DUB-domain alterations in immune cells and understand its link to SLE pathogenesis.

    Methods

    CRISPR/Cas9 was used to generate human U937 monocytes with A20 DUB-inactivating C103A knock-in (KI) mutation. Whole genome RNA-sequencing was used to identify differentially expressed genes between WT and C103A KI cells. Functional studies were performed in A20 C103A U937 cells and in immune cells from A20 C103A mice and genotyped healthy individuals with A20 DUB polymorphism rs2230926. Neutrophil extracellular trap (NET) formation was addressed ex vivo in neutrophils from A20 C103A mice and SLE-patients with rs2230926.

    Results

    Genetic disruption of A20 DUB domain in human and murine myeloid cells did not give rise to enhanced NF-kappa B signalling. Instead, cells with C103A mutation or rs2230926 polymorphism presented an upregulated expression of PADI4, an enzyme regulating protein citrullination and NET formation, two key mechanisms in autoimmune pathology. A20 C103A cells exhibited enhanced protein citrullination and extracellular trap formation, which could be suppressed by selective PAD4 inhibition. Moreover, SLE-patients with rs2230926 showed increased NETs and increased frequency of autoantibodies to citrullinated epitopes.

    Conclusions

    We propose that genetic alterations disrupting the A20 DUB domain mediate increased susceptibility to SLE through the upregulation of PADI4 with resultant protein citrullination and extracellular trap formation.

  • 27.
    Olsson, Lina M.
    et al.
    Karolinska Inst, Div Med Inflammat Res, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Johansson, Asa C.
    Lund Univ, Div Hematol & Transfus Med, Dept Lab Med, Fac Med, Lund, Sweden.;Lund Univ, Div Clin Immunol & Transfus Med, Dept Lab Med, Fac Med, Lund, Sweden..
    Gullstrand, Birgitta
    Lund Univ, Dept Clin Sci Lund, Rheumatol, Fac Med, Lund, Sweden..
    Jonsen, Andreas
    Lund Univ, Dept Clin Sci Lund, Rheumatol, Fac Med, Lund, Sweden..
    Saevarsdottir, Saedis
    Karolinska Inst, Karolinska Univ Hosp, Rheumatol Unit, Dept Med Solna, 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.
    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.
    Wettero, Jonas
    Linkoping Univ, Dept Clin & Expt Med, Rheumatol Div Neuro & Inflammat Sci, Linkoping, Sweden..
    Sjowall, Christopher
    Linkoping Univ, Dept Clin & Expt Med, Rheumatol Div Neuro & Inflammat Sci, Linkoping, Sweden..
    Svenungsson, Elisabet
    Karolinska Inst, Karolinska Univ Hosp, Rheumatol Unit, Dept Med Solna, Stockholm, Sweden..
    Gunnarsson, Iva
    Karolinska Inst, Karolinska Univ Hosp, Rheumatol Unit, Dept Med Solna, Stockholm, Sweden..
    Bengtsson, Anders A.
    Lund Univ, Dept Clin Sci Lund, Rheumatol, Fac Med, Lund, Sweden..
    Holmdahl, Rikard
    Karolinska Inst, Div Med Inflammat Res, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    A single nucleotide polymorphism in the NCF1 gene leading to reduced oxidative burst is associated with systemic lupus erythematosus2017In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, no 9, p. 1607-1613Article in journal (Refereed)
    Abstract [en]

    Objectives

    Ncf1 polymorphisms leading to low production of reactive oxygen species (ROS) are strongly associated with autoimmune diseases in animal models. The human NCF1 gene is very complex with both functional and non-functional gene copies and genotyping requires assays specific for functional NCF1 genes. We aimed at investigating association and function of the missense single nucleotide polymorphism (SNP), rs201802880 (here denoted NCF1-339) in NCF1 with systemic lupus erythematosus (SLE).

    Methods

    We genotyped the NCF1-339 SNP in 973 Swedish patients with SLE and 1301 controls, using nested PCR and pyrosequencing. ROS production and gene expression of type 1 interferon-regulated genes were measured in isolated cells from subjects with different NCF1-339 genotypes.

    Results

    We found an increased frequency of the NCF1-339 T allele in patients with SLE, 11% compared with 4% in controls, OR 3.0, 95% CI 2.4 to 3.9, p=7.0x10(-20) The NCF1-339 T allele reduced extracellular ROS production in neutrophils (p=0.004) and led to an increase expression of type 1 interferon-regulated genes. In addition, the NCF1-339 T allele was associated with a younger age at diagnosis of SLE; mean age 30.3 compared with 35.9, p=2.0x1(-6).

    Conclusions

    These results clearly demonstrate that a genetically controlled reduced production of ROS increases the risk of developing SLE and confirm the hypothesis that ROS regulate chronic autoimmune inflammatory diseases.

  • 28.
    Reid, Sarah
    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.
    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.
    Frodlund, Martina
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    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, Rheumatology.
    Svenungsson, Elisabet
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Jonsen, Andreas
    Lund Univ, Dept Clin Sci, Rheumatol, Lund, Sweden..
    Bengtsson, Christine
    Umea Univ, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden..
    Gunnarsson, Iva
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
    Bengtsson, Anders A.
    Lund Univ, Dept Clin Sci, Rheumatol, Lund, Sweden..
    Rantapaa-Dahlqvist, Solbritt
    Umea Univ, Dept Publ Hlth & Clin Med Rheumatol, Umea, Sweden..
    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.
    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.
    Sjowall, Christopher
    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.
    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.
    High Genetic Risk Score Is Associated with Increased Organ Damage in SLE2017In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, no S10, article id 1638Article in journal (Other academic)
  • 29.
    Rönnblom, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Interferon pathway in SLE: one key to unlocking the mystery of the disease2019In: Lupus Science and Medicine, ISSN 2053-8790, E-ISSN 1625-9823, Vol. 6, no 1, article id e000270Article, review/survey (Refereed)
    Abstract [en]

    SLE is characterised by an activation of the interferon (IFN) system, which leads to an increased expression of IFN-regulated genes. The reasons behind the IFN signature in SLE are (1) the existence of endogenous IFN inducers, (2) activation of several IFN-producing cell types, (3) production of many different IFNs, (4) a genetic setup promoting IFN production and (5) deficient negative feedback mechanisms. The consequences for the immune system is a continuous stimulation to an immune response, and for the patient a number of different organ manifestations leading to typical symptoms for SLE. In the current review, we will present the existing knowledge of the IFN system and pathway activation in SLE. We will also discuss how this information can contribute to our understanding of both the aetiopathogenesis and some organ manifestations of the disease. We will put forward some issues that are unresolved and should be clarified in order to make a proper stratification of patients with SLE, which seems important when selecting a therapy aiming to downregulate the IFN system.

  • 30.
    Segerberg, Filip
    et al.
    Karolinska Inst, Ctr Haematol & Regenerat Med, Dept Med, Stockholm, Sweden.
    Lundtoft, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Reid, Sarah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hjorton, Karin
    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.
    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.
    Carlsten, Mattias
    Karolinska Inst, Ctr Haematol & Regenerat Med, Dept Med, Stockholm, Sweden.
    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. Uppsala Univ, Dept Med Sci, Rheumatol & Sci Life Labs, Uppsala, Sweden.
    Autoantibodies to Killer Cell Immunoglobulin-Like Receptors in Patients With Systemic Lupus Erythematosus Induce Natural Killer Cell Hyporesponsiveness2019In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 2164Article in journal (Refereed)
    Abstract [en]

    Natural killer (NK) cell cytotoxicity toward self-cells is restrained by the inhibitory HLA class I-binding receptors CD94/NKG2A and the killer cell immunoglobulin-like receptors (KIRs). CD94/NKG2A and KIRs are also essential for NK cell education, which is a dynamic functional maturation process where a constitutive binding of inhibitory receptors to cognate HLA class I molecules is required for NK cells to maintain their full cytotoxic capacity. Previously, we described autoantibodies to CD94/NKG2A in patients with systemic lupus erythematosus (SLE). In this study we analyzed sera from 191 patients with SLE, 119 patients with primary Sjogren's syndrome (pSS), 48 patients with systemic sclerosis (SSc), and 100 healthy donors (HD) for autoantibodies to eight different KIRs. Anti-KIR autoantibodies were identified in sera from 23.0% of patients with SLE, 10.9% of patients with pSS, 12.5% of patients with SSc, and 3.0% of HD. IgG from anti-KIR-positive SLE patients reduced the degranulation and cytotoxicity of NK cells toward K562 tumor cells. The presence of anti-KIR-autoantibodies reacting with >3 KIRs was associated with an increased disease activity (p < 0.0001), elevated serum levels of IFN-alpha (p < 0.0001), nephritis (p = 0.001), and the presence of anti-Sm (p = 0.007), and anti-RNP (p = 0.003) autoantibodies in serum. Together these findings suggest that anti-KIR autoantibodies may contribute to the reduced function of NK cells in SLE patients, and that a defective NK cell function may be a risk factor for the development of lupus nephritis.

  • 31. Svenungsson, Elisabet
    et al.
    Gustafsson, Johanna
    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.
    Sandling, Johanna
    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.
    Jönsen, Andreas
    Bengtsson, Anders A
    Sturfelt, Gunnar
    Rantapää-Dahlqvist, Solbritt
    Elvin, Kerstin
    Sundin, Ulf
    Garnier, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Simard, Julia F
    Sigurdsson, Snaevar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Padyukov, Leonid
    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.
    A STAT4 risk allele is associated with ischaemic cerebrovascular events and anti-phospholipid antibodies in systemic lupus erythematosus2010In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 69, no 5, p. 834-840Article in journal (Refereed)
    Abstract [en]

    Objective

    To investigate whether the risk allele for systemic lupus erythematosus (SLE) in the signal transducer and activator of transcription factor 4 (STAT4) gene, defined by the single nucleotide polymorphism (SNP) rs10181656(G), is associated with vascular events and/or presence of prothrombotic anti-phospholipid antibodies (aPL) in patients with SLE.

    Methods

    Two independent groups of unrelated patients with SLE of Swedish ethnicity (n=424 and 154) were genotyped, and occurrence of previous manifestations of ischaemic heart disease (IHD), ischaemic cerebrovascular disease (ICVD) and venous thromboembolic events (VTE) was tabulated. aPL values were measured by ELISA. Matched controls (n=492 and 194) were genotyped.

    Results

    The STAT4 risk allele was more frequent in patients with SLE with previous arterial events (combined OR (ORc)=1.5, 95% CI 1.1 to 2.0) compared to patients without such events. The association was mainly attributable to an accumulation of the risk allele among patients with ICVD (ORc=2.3, CI 1.6 to 3.3). There was no association with IHD or VTE. The presence of two or more aPLs was associated with the risk allele (ORc=1.6, 95% CI 1.2 to 2.0). In multivariable-adjusted logistic regression analyses treatment for hypertension, at least one STAT4 risk allele, older age, IgG anti-cardiolipin antibodies and longer SLE duration remained independently associated with previous ICVD (p≤0.02 for all).

    Conclusion

    Patients with SLE with the STAT4 risk allele had a strikingly increased risk of ICVD, comparable in magnitude to that of hypertension. The results imply that a genetic predisposition is an important and previously unrecognised risk factor for ICVD in SLE, and that aPLs may be one underlying mechanism.

  • 32. Svenungsson, Elisabet
    et al.
    Lundström, Emeli
    Gustafsson, Johanna
    Jonsen, Andreas
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Zickert, Agneta
    Elvin, Kerstin
    Sturfelt, Gunnar
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bengtsson, Anders
    Klareskog, Lars
    Gunnarsson, Iva
    Ronnblom, Lars
    Padyukov, Leonid
    Ischemic vascular disease and antiphospholipid antibodies are associated with HLA-DRB1 *04/*13 alleles in systemic lupus erythematosus2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, p. A57-A58Article in journal (Other academic)
  • 33. Vikerfors, Anna
    et al.
    Johansson, Anna-Britta
    Gustafsson, Johanna T
    Jönsen, Andreas
    Leonard, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Zickert, Agneta
    Nordmark, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Sturfelt, Gunnar
    Bengtsson, Anders
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Gunnarsson, Iva
    Elvin, Kerstin
    Svenungsson, Elisabet
    Clinical manifestations and anti-phospholipid antibodies in 712 patients with systemic lupus erythematosus: evaluation of two diagnostic assays2013In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 34, no 5, p. 345-353Article in journal (Refereed)
    Abstract [en]

    Objectives

    To evaluate the agreement and performance of two tests for aPLs with regard to association with manifestations of the APS in patients with SLE.

    Methods

    We investigated 712 SLE patients and 280 population controls. Cardiolipin and β2 glycoprotein-I antibodies were measured with routine ELISA and a new automated method. Three positivity cut-offs (99%, 90% of controls and recommended cut-off by manufacturers) were used. Associations with previous thrombotic events, thrombocytopenia and, in a subgroup of patients, obstetric morbidity (n = 296) were evaluated. Results were compared with the LA test, performed in 380 patients.

    Results

    Inter-test agreement was moderate (demonstrated by κ-values 0.16–0.71). Performance of the two tests was similar: at the 99th percentile cut-off, sensitivity for any thrombotic event ranged from 3.7% to 24.8%, while specificity was 84.7–97.7%. Regardless of assay, IgG isotypes were associated with venous thrombosis and ischaemic cerebrovascular disease, whereas aPLs of IgM isotype were weakly associated with ischaemic heart disease. Associations were greatly affected by aPL level. LA performed better than the specific aPL tests. LA was associated with any thrombotic event, odds ratio 5.4 (95% CI 3.1, 9.4), while the specific aPL tests ranged from non-significant to an odds ratio of 1.9 (95% CI 1.03, 3.4) using criteria cut-off. LA was also convincingly associated with other APS manifestations.

    Conclusion

    In relation to thrombotic manifestations, there was moderate agreement but no clear advantages when comparing a routine aPL ELISA with an automated method. APL isotype and titre as well as LA positivity are important for risk assessment in SLE patients.

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