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Rönnblom, Lars
Alternative names
Publications (10 of 147) Show all publications
Imgenberg-Kreuz, J., Almlöf, J. C., Leonard, D., Alexsson, A., Nordmark, G., Eloranta, M.-L., . . . Sandling, J. K. (2018). DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus. Annals of the Rheumatic Diseases, 77(5), 736-743
Open this publication in new window or tab >>DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus
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2018 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 5, p. 736-743Article in journal (Refereed) Published
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.

Keywords
gene polymorphism, systemic lupus erythematosus
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-342164 (URN)10.1136/annrheumdis-2017-212379 (DOI)000430492600020 ()29437559 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, KAW 2011.0073Swedish Research Council, 521-2014-2263; 521-2013-2830; 521-2014-3954; 2016-01982; 350-2012-256AstraZenecaSwedish Society for Medical Research (SSMF)Swedish Rheumatism AssociationThe King Gustaf V's Jubilee FoundationSwedish Heart Lung FoundationStockholm County CouncilScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-02-19 Created: 2018-02-19 Last updated: 2018-06-19Bibliographically approved
Chemin, K., Ramsköld, D., Diaz-Gallo, L.-M., Herrath, J., Houtman, M., Tandre, K., . . . Malmström, V. (2018). EOMES-positive CD4+ T cells are increased in PTPN22 (1858T) risk allele carriers.. European Journal of Immunology, 48(4), 655-669
Open this publication in new window or tab >>EOMES-positive CD4+ T cells are increased in PTPN22 (1858T) risk allele carriers.
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2018 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 48, no 4, p. 655-669Article in journal (Refereed) Published
Abstract [en]

The presence of the PTPN22 risk allele (1858T) is associated with several autoimmune diseases including rheumatoid arthritis (RA). Despite a number of studies exploring the function of PTPN22 in T cells, the exact impact of the PTPN22 risk allele on T-cell function in humans is still unclear. In this study, using RNA sequencing, we show that, upon TCR-activation, naïve human CD4+ T cells homozygous for the PTPN22 risk allele overexpress a set of genes including CFLAR and 4-1BB, which are important for cytotoxic T-cell differentiation. Moreover, the protein expression of the T-box transcription factor Eomesodermin (EOMES) was increased in T cells from healthy donors homozygous for the PTPN22 risk allele and correlated with a decreased number of naïve CD4+ T cells. There was no difference in the frequency of other CD4+ T cell subsets (Th1, Th17, Tfh, Treg). Finally, an accumulation of EOMES+CD4+ T cells was observed in synovial fluid of RA patients with a more pronounced production of Perforin-1 in PTPN22 risk allele carriers. Altogether, we propose a novel mechanism of action of PTPN22 risk allele through the generation of cytotoxic CD4+ T cells and identify EOMES+CD4+ T cells as a relevant T-cell subset in RA pathogenesis.

Keywords
4-1BB, CD4+ T cells, Cytotoxic T lymphocytes, Perforin-1, Rheumatoid Arthritis (RA)
National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-343246 (URN)10.1002/eji.201747296 (DOI)000430105600012 ()29388193 (PubMedID)
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-06-13Bibliographically approved
Bremer, H. D., Landegren, N., Sjöberg, R., Hallgren, Å., Renneker, S., Lattwein, E., . . . Hansson-Hamlin, H. (2018). ILF2 and ILF3 are autoantigens in canine systemic autoimmune disease. Scientific Reports, 8, Article ID 4852.
Open this publication in new window or tab >>ILF2 and ILF3 are autoantigens in canine systemic autoimmune disease
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 4852Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-351425 (URN)10.1038/s41598-018-23034-w (DOI)000427688100045 ()29556082 (PubMedID)
Funder
Swedish Research CouncilSwedish Research Council Formas, 2011-1404Novo NordiskRagnar Söderbergs stiftelseSwedish Rheumatism Association
Available from: 2018-06-01 Created: 2018-06-01 Last updated: 2018-06-01Bibliographically approved
Imgenberg-Kreuz, J., Sandling, J. K., Bjork, A., Nordlund, J., Kvarnstrom, M., Eloranta, M.-L., . . . Nordmark, G. (2018). Transcription profiling of peripheral B cells in antibody-positive primary Sjogren's syndrome reveals upregulated expression of CX3CR1 and a type I and type II interferon signature. Scandinavian Journal of Immunology, 87(5), Article ID UNSP e12662.
Open this publication in new window or tab >>Transcription profiling of peripheral B cells in antibody-positive primary Sjogren's syndrome reveals upregulated expression of CX3CR1 and a type I and type II interferon signature
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2018 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 87, no 5, article id UNSP e12662Article in journal (Refereed) Published
Abstract [en]

B cells play a key role in the pathogenesis of primary Sjogren's syndrome (pSS). The aim of this study was to analyse the transcriptome of CD19+ B cells from patients with pSS and healthy controls to decipher the B cell-specific contribution to pSS. RNA from purified CD19+ B cells from 12 anti-SSA antibody-positive untreated female patients with pSS and 20 healthy blood donors was subjected to whole transcriptome sequencing. A false discovery rate corrected significance threshold of <0.05 was applied to define differential gene expression. As validation, gene expression in B cells from 17 patients with pSS and 16 healthy controls was analysed using a targeted gene panel. RNA-sequencing identified 4047 differentially expressed autosomal genes in pSS B cells. Upregulated expression of type I and type II interferon (IFN)-induced genes was observed, establishing an IFN signature in pSS B cells. Among the top upregulated and validated genes were CX3CR1, encoding the fractalkine receptor involved in regulation of B-cell malignancies, CCL5/RANTES and CCR1. Increased expression of several members of the TNF superfamily was also identified; TNFSF4/Ox40L, TNFSF10/TRAIL, TNFSF13B/BAFF, TNFRSF17/BCMA as well as S100A8 and -A9/calprotectin, TLR7, STAT1 and STAT2. Among genes with downregulated expression in pSS B cells were SOCS1 and SOCS3, CD70 and TNFAIP3/A20. We conclude that B cells from patients with anti-SSA antibody-positive pSS display immune activation with upregulated expression of chemokines, chemokine receptors and a prominent type I and type II IFN signature, while suppressors of cytokine signalling are downregulated. This adds insight into the autoimmune process and suggests potential targets for future functional studies.

National Category
Immunology in the medical area Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-354096 (URN)10.1111/sji.12662 (DOI)000430398400006 ()29655283 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, 2011.0073Swedish Research Council, 2012-2148Swedish Research Council, 350-2012-256Swedish Research Council, 521-2013-2830Swedish Research Council, 521-2014-2263Swedish Research Council, 2016-01982Knut and Alice Wallenberg FoundationSwedish Research Council
Available from: 2018-06-19 Created: 2018-06-19 Last updated: 2018-06-19Bibliographically approved
Olsson, L. M., Johansson, A. C., Gullstrand, B., Jonsen, A., Saevarsdottir, S., Rönnblom, L., . . . Holmdahl, R. (2017). A single nucleotide polymorphism in the NCF1 gene leading to reduced oxidative burst is associated with systemic lupus erythematosus. Annals of the Rheumatic Diseases, 76(9), 1607-1613
Open this publication in new window or tab >>A single nucleotide polymorphism in the NCF1 gene leading to reduced oxidative burst is associated with systemic lupus erythematosus
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2017 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 76, no 9, p. 1607-1613Article in journal (Refereed) Published
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.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-333949 (URN)10.1136/annrheumdis-2017-211287 (DOI)000407833100033 ()28606963 (PubMedID)
Available from: 2017-12-13 Created: 2017-12-13 Last updated: 2017-12-13Bibliographically approved
Ramirez, J., Kvarnstrom, M., Brauner, S., Baldini, C., Eriksson, P., Mandl, T., . . . Wahren-Herlenius, M. (2017). Difference in Clinical Presentation between Female and Male Patients with Primary Sjogren's Syndrome at Diagnosis and in Long-Term Follow-up. Arthritis & Rheumatology, 69(S10), Article ID 1479.
Open this publication in new window or tab >>Difference in Clinical Presentation between Female and Male Patients with Primary Sjogren's Syndrome at Diagnosis and in Long-Term Follow-up
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2017 (English)In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, no S10, article id 1479Article in journal, Meeting abstract (Other academic) Published
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-346797 (URN)000411824103003 ()
Available from: 2018-03-22 Created: 2018-03-22 Last updated: 2018-03-22Bibliographically approved
Thorlacius, G. E., Hedlund, M., Ivanchenko, M., Ottosson, V., Ossoinak, A., Lagnefeldt, L., . . . Wahren-Herlenius, M. (2017). Expression Patterns of Interferon Induced Genes in Newborns Exposed to Ro/SSA Autoantibodies in Utero. Arthritis & Rheumatology, 69(10), Article ID 2817.
Open this publication in new window or tab >>Expression Patterns of Interferon Induced Genes in Newborns Exposed to Ro/SSA Autoantibodies in Utero
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2017 (English)In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, no 10, article id 2817Article in journal, Meeting abstract (Other academic) Published
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-346802 (URN)000411824106321 ()
Available from: 2018-03-22 Created: 2018-03-22 Last updated: 2018-03-22Bibliographically approved
Norheim, K., Alexsson, A., Imgenberg-Kreuz, J., Brun, J. G., Jonsson, R., Ng, W.-F., . . . Omdal, R. (2017). Genetic Determinants of Fatigue in Primary Sjogren's Syndrome: a Genome Wide Association Study. Arthritis & Rheumatology, 69(S10), Article ID 182.
Open this publication in new window or tab >>Genetic Determinants of Fatigue in Primary Sjogren's Syndrome: a Genome Wide Association Study
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2017 (English)In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, no S10, article id 182Article in journal, Meeting abstract (Other academic) Published
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-346796 (URN)000411824100182 ()
Available from: 2018-03-22 Created: 2018-03-22 Last updated: 2018-03-22Bibliographically approved
Reid, S., Alexsson, A., Frodlund, M., Sandling, J. K., Svenungsson, E., Jonsen, A., . . . Leonard, D. (2017). High Genetic Risk Score Is Associated with Increased Organ Damage in SLE. Arthritis & Rheumatology, 69(S10), Article ID 1638.
Open this publication in new window or tab >>High Genetic Risk Score Is Associated with Increased Organ Damage in SLE
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2017 (English)In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 69, no S10, article id 1638Article in journal, Meeting abstract (Other academic) Published
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-346798 (URN)000411824103162 ()
Available from: 2018-03-22 Created: 2018-03-22 Last updated: 2018-03-22Bibliographically approved
Galindo-Feria, A. S., Albrecht, I., Notarnicola, A., Dastmalchi, M., Dubnovitsky, A., Sandalova, T., . . . Lundberg, I. (2017). Identification of a novel pro-inflammatory T cell epitope from his-tRNA-synthetase associated with interstitial lung disease in anti-Jo-1 positive patients. Paper presented at 44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN. Scandinavian Journal of Immunology, 86(4), 317-317
Open this publication in new window or tab >>Identification of a novel pro-inflammatory T cell epitope from his-tRNA-synthetase associated with interstitial lung disease in anti-Jo-1 positive patients
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2017 (English)In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 317-317Article in journal, Meeting abstract (Other academic) Published
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-346965 (URN)000411865200169 ()
Conference
44th Annual Meeting of the Scandinavian-Society-for-Immunology (SSI), OCT 17-20, 2017, Stockholm, SWEDEN
Available from: 2018-03-23 Created: 2018-03-23 Last updated: 2018-03-23Bibliographically approved
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