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Rönnblom, Lars
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Publications (10 of 156) Show all publications
Thorlacius, G. E., Wahren-Herlenius, M. & Rönnblom, L. (2018). An update on the role of type I interferons in systemic lupus erythematosus and Sjogren's syndrome. Current Opinion in Rheumatology, 30(5), 471-481
Open this publication in new window or tab >>An update on the role of type I interferons in systemic lupus erythematosus and Sjogren's syndrome
2018 (English)In: Current Opinion in Rheumatology, ISSN 1040-8711, E-ISSN 1531-6963, Vol. 30, no 5, p. 471-481Article, review/survey (Refereed) Published
Abstract [en]

Purpose of review Systemic lupus erythematosus (SLE) and primary Sjogren's syndrome (pSS) share several clinical and laboratory features, including an overexpression of type I interferon (IFN) regulated genes. The genetic background to this IFN signature and the role of the type I IFN system in the disease process have been partly clarified. Here, we summarize the latest information concerning the type I IFN system in both diseases. Recent findings A number of gene variants in the type I IFN signalling pathways associate with an increased risk for both SLE and pSS in several ethnicities. The function of some risk gene variants has been elucidated, as well as the importance of epigenetic changes in type I IFN regulated genes. MicroRNA-451 and miR-302d have been shown to target IFN regulatory factor 8 and 9, suggesting that noncoding RNAs can control the IFN system. A prominent type I IFN activation is related to several disease manifestations, and in SLE to a more severe disease phenotype. Phase II studies in SLE suggest beneficial effects of blocking the type I IFN receptor. Summary The activated type I IFN system in SLE and pSS has a strong genetic component, is important in the disease etiopathogenesis and can be targeted.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2018
Keywords
genes, Sjogren's syndrome, systemic lupus erythematosus, therapy, type I interferon
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-363867 (URN)10.1097/BOR.0000000000000524 (DOI)000442248600004 ()29889694 (PubMedID)
Funder
Swedish Research Council
Available from: 2018-11-14 Created: 2018-11-14 Last updated: 2018-11-14
Eriksson, D., Bianchi, M., Landegren, N., Dalin, F., Skov, J., Hultin-Rosenberg, L., . . . Kampe, O. (2018). Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison's disease in Sweden. Scientific Reports, 8, Article ID 8395.
Open this publication in new window or tab >>Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison's disease in Sweden
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 8395Article in journal (Refereed) Published
Abstract [en]

Autoimmune Addison's disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-357556 (URN)10.1038/s41598-018-26842-2 (DOI)000433538800022 ()29849176 (PubMedID)
Funder
Swedish Research CouncilEU, FP7, Seventh Framework Programme, 201167Swedish Research Council FormasKnut and Alice Wallenberg FoundationRagnar Söderbergs stiftelseTorsten Söderbergs stiftelseNovo NordiskMarianne and Marcus Wallenberg FoundationTore Nilsons Stiftelse för medicinsk forskningÅke Wiberg FoundationSwedish Rheumatism AssociationSwedish Society of Medicine
Available from: 2018-08-20 Created: 2018-08-20 Last updated: 2018-08-20Bibliographically approved
Hjorton, K., Hagberg, N., Israelsson, E., Berggren, O., Sandling, J. K., Thorn, K., . . . Rönnblom, L. (2018). Cytokine production by activated plasmacytoid dendritic cells and NK cells is suppressed by an IRAK4 inhibitor. Paper presented at Congress of the European-League-Against-Rheumatism (EULAR), JUN 13-16, 2018, Amsterdam, NETHERLANDS. Annals of the Rheumatic Diseases, 77, 1268-1269
Open this publication in new window or tab >>Cytokine production by activated plasmacytoid dendritic cells and NK cells is suppressed by an IRAK4 inhibitor
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2018 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, p. 1268-1269Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2018
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-368669 (URN)10.1136/annrheumdis-2018-eular.6369 (DOI)000444351003561 ()
Conference
Congress of the European-League-Against-Rheumatism (EULAR), JUN 13-16, 2018, Amsterdam, NETHERLANDS
Available from: 2018-12-10 Created: 2018-12-10 Last updated: 2018-12-10Bibliographically approved
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
Pieper, J., Dubnovitsky, A., Gerstner, C., James, E. A., Rieck, M., Kozhukh, G., . . . Malmström, V. (2018). Memory T cells specific to citrullinated alpha-enolase are enriched in the rheumatic joint. Journal of Autoimmunity, 92, 47-56
Open this publication in new window or tab >>Memory T cells specific to citrullinated alpha-enolase are enriched in the rheumatic joint
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2018 (English)In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 92, p. 47-56Article in journal (Refereed) Published
Abstract [en]

ACPA-positive rheumatoid arthritis (RA) is associated with distinct HLA-DR alleles and immune responses to many citrullinated self-antigens. Herein we investigated the T cell epitope confined within alpha-enolase(326-340) in the context of HLA-DRB1*04:01 and assessed the corresponding CD4(+) T cells in both the circulation and in the rheumatic joint. Comparative crystallographic analyses were performed for the native and citrullinated alpha-enolase(326-340) peptides in complex with HLA-DRB1*04:01. HLA-tetramers assembled with either the native or citrullinated peptide were used for ex vivo and in vitro assessment of a enolase-specific T cells in peripheral blood, synovial fluid and synovial tissue by flow cytometry. The native and modified peptides take a completely conserved structural conformation within the peptide binding cleft of HLA-DRB1*04:01. The citrulline residue-327 was located N-terminally, protruding towards TCRs. The frequencies of T cells recognizing native eno(326-340) were similar in synovial fluid and peripheral blood, while in contrast, the frequency of T cells recognizing cit-eno(326-340) was significantly elevated in synovial fluid compared to peripheral blood (3.6-fold, p = 0.0150). Additionally, citrulline-specific T cells with a memory phenotype were also significantly increased (1.6-fold, p = 0.0052) in synovial fluid compared to peripheral blood. The native T cell epitope confined within alpha-enolase(326-340) does not appear to lead to complete negative selection of cognate CD4(+) T cells. In RA patient samples, only T cells recognizing the citrullinated version of alpha-enolase(326-340) were found at elevated frequencies implicating that neo-antigen formation is critical for breach of tolerance. (C) 2018 Elsevier Ltd. All rights reserved.

Place, publisher, year, edition, pages
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, 2018
Keywords
Autoimmunity, Citrullination, Crystal structure, HLA class II tetramers
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-364924 (URN)10.1016/j.jaut.2018.04.004 (DOI)000440770500004 ()29853344 (PubMedID)
Funder
Swedish Rheumatism AssociationThe Swedish Medical AssociationKing Gustaf V Jubilee FundSwedish Research CouncilKnut and Alice Wallenberg FoundationEU, FP7, Seventh Framework Programme, HEALTH-F2-2008-223404
Available from: 2018-11-08 Created: 2018-11-08 Last updated: 2018-11-08Bibliographically approved
Leonard, D., Svenungsson, E., Dahlqvist, J., Alexsson, A., Ärlestig, L., Taylor, K. E., . . . Rönnblom, L. (2018). Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis. Paper presented at Congress of the European-League-Against-Rheumatism (EULAR), JUN 13-16, 2018, Amsterdam, NETHERLANDS. Annals of the Rheumatic Diseases, 77, 1063-1069
Open this publication in new window or tab >>Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis
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2018 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, p. 1063-1069Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2018
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-368663 (URN)10.1136/annrheumdis-2017-212614 (DOI)000444351000526 ()
Conference
Congress of the European-League-Against-Rheumatism (EULAR), JUN 13-16, 2018, Amsterdam, NETHERLANDS
Funder
Swedish Research Council, D0283001, A0258801, E0226301, E0395401Knut and Alice Wallenberg Foundation, 2011.0073AstraZenecaSwedish Society of MedicineSwedish Rheumatism AssociationKing Gustaf V Jubilee FundTorsten Söderbergs stiftelseStockholm County CouncilSwedish Heart Lung FoundationErik, Karin och Gösta Selanders FoundationNIH (National Institute of Health), UL1-TR-00004, P60-AR-053308, R01-AR-44804
Available from: 2018-12-10 Created: 2018-12-10 Last updated: 2018-12-10Bibliographically approved
Imgenberg-Kreuz, J., Leonard, D., Carlsson Almlöf, J., Rantapaa-Dahlqvist, S., Bengtsson, A., Jonsen, A., . . . Sandling, J. K. (2018). Shared and unique patterns of DNA methylation in primary Sjogren's syndrome and systemic lupus erythematosus. Scandinavian Journal of Rheumatology, 47, 3-3
Open this publication in new window or tab >>Shared and unique patterns of DNA methylation in primary Sjogren's syndrome and systemic lupus erythematosus
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2018 (English)In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 47, p. 3-3Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2018
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-363887 (URN)000442295400005 ()
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2018-11-12Bibliographically approved
Houtman, M., Shchetynsky, K., Chemin, K., Hensvold, A. H., Ramsköld, D., Tandre, K., . . . Padyukov, L. (2018). T cells are influenced by a long non-coding RNA in the autoimmune associated PTPN2 locus. Journal of Autoimmunity, 90, 28-38
Open this publication in new window or tab >>T cells are influenced by a long non-coding RNA in the autoimmune associated PTPN2 locus
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2018 (English)In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 90, p. 28-38Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD, 2018
Keywords
RA, Genome-wide association, methQTL, eQTL, Long non-coding RNA, T cell
National Category
Rheumatology and Autoimmunity Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-357383 (URN)10.1016/j.jaut.2018.01.003 (DOI)000433645600002 ()29398253 (PubMedID)
Funder
VINNOVASwedish Research CouncilEU, European Research CouncilKing Gustaf V Jubilee Fund
Available from: 2018-08-24 Created: 2018-08-24 Last updated: 2018-08-31Bibliographically approved
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