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Rönnblom, Lars
Alternative names
Publications (10 of 172) Show all publications
Eriksson, K., Eloranta, M.-L., Kozyrev, S. V., Dahlqvist, J., Nilsson, B., Knight, A. & Rönnblom, L. (2019). A case of systemic lupus erythematosus with C1q deficiency, increased serum interferon-a levels and high serum interferogenic activity [Letter to the editor]. Rheumatology, 58(5), 918-919
Open this publication in new window or tab >>A case of systemic lupus erythematosus with C1q deficiency, increased serum interferon-a levels and high serum interferogenic activity
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2019 (English)In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 58, no 5, p. 918-919Article in journal, Letter (Other academic) Published
Place, publisher, year, edition, pages
Oxford University Press, 2019
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-391433 (URN)10.1093/rheumatology/key419 (DOI)000475751700028 ()30608615 (PubMedID)
Funder
Swedish Research Council, D0283001Swedish Rheumatism AssociationKing Gustaf V Jubilee FundSwedish Society of Medicine
Note

Ann Knight and Lars Rönnblom contributed equally to the study

Available from: 2019-10-03 Created: 2019-10-03 Last updated: 2019-10-03Bibliographically approved
Farias, F. H. G., Dahlqvist, J., Kozyrev, S. V., Leonard, D., Wilbe, M., Abramov, S., . . . Lindblad-Toh, K. (2019). A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts. European Journal of Human Genetics, 27, 432-441
Open this publication in new window or tab >>A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts
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2019 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, p. 432-441Article in journal (Refereed) Published
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.

National Category
Medical Genetics
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-368313 (URN)10.1038/s41431-018-0297-x (DOI)000458626500013 ()30459414 (PubMedID)
Funder
Swedish Research CouncilSwedish Research Council FormasSwedish Rheumatism AssociationKnut and Alice Wallenberg Foundation
Note

These authors contributed equally: Johanna Dahlqvist, Sergey V. Kozyrev, Dag Leonard, Maria Wilbe

Available from: 2018-12-04 Created: 2018-12-04 Last updated: 2019-03-11Bibliographically approved
Idborg, H., Zandian, A., Ossipova, E., Wigren, E., Preger, C., Mobarrez, F., . . . Jakobsson, P.-J. (2019). Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients.. Frontiers in Immunology, 10, Article ID 1029.
Open this publication in new window or tab >>Circulating Levels of Interferon Regulatory Factor-5 Associates With Subgroups of Systemic Lupus Erythematosus Patients.
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1029Article in journal (Refereed) Published
Abstract [en]

Systemic Lupus Erythematosus (SLE) is a heterogeneous autoimmune disease, which currently lacks specific diagnostic biomarkers. The diversity within the patients obstructs clinical trials but may also reflect differences in underlying pathogenesis. Our objective was to obtain protein profiles to identify potential general biomarkers of SLE and to determine molecular subgroups within SLE for patient stratification. Plasma samples from a cross-sectional study of well-characterized SLE patients (n = 379) and matched population controls (n = 316) were analyzed by antibody suspension bead array targeting 281 proteins. To investigate the differences between SLE and controls, Mann-Whitney U-test with Bonferroni correction, generalized linear modeling and receiver operating characteristics (ROC) analysis were performed. K-means clustering was used to identify molecular SLE subgroups. We identified Interferon regulating factor 5 (IRF5), solute carrier family 22 member 2 (SLC22A2) and S100 calcium binding protein A12 (S100A12) as the three proteins with the largest fold change between SLE patients and controls (SLE/Control = 1.4, 1.4, and 1.2 respectively). The lowest p-values comparing SLE patients and controls were obtained for S100A12, Matrix metalloproteinase-1 (MMP1) and SLC22A2 (padjusted = 3 × 10-9, 3 × 10-6, and 5 × 10-6 respectively). In a set of 15 potential biomarkers differentiating SLE patients and controls, two of the proteins were transcription factors, i.e., IRF5 and SAM pointed domain containing ETS transcription factor (SPDEF). IRF5 was up-regulated while SPDEF was found to be down-regulated in SLE patients. Unsupervised clustering of all investigated proteins identified three molecular subgroups among SLE patients, characterized by (1) high levels of rheumatoid factor-IgM, (2) low IRF5, and (3) high IRF5. IRF5 expressing microparticles were analyzed by flow cytometry in a subset of patients to confirm the presence of IRF5 in plasma and detection of extracellular IRF5 was further confirmed by immunoprecipitation-mass spectrometry (IP-MS). Interestingly IRF5, a known genetic risk factor for SLE, was detected extracellularly and suggested by unsupervised clustering analysis to differentiate between SLE subgroups. Our results imply a set of circulating molecules as markers of possible pathogenic importance in SLE. We believe that these findings could be of relevance for understanding the pathogenesis and diversity of SLE, as well as for selection of patients in clinical trials.

Keywords
Interferon regulating factor 5 (IRF5), SLE - Systemic Lupus Erythematous, antibody suspension bead arrays, biomarker discovery, hierarchical clustering, plasma proteomics, subgroups, unsupervised clustering
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-385062 (URN)10.3389/fimmu.2019.01029 (DOI)000468162000001 ()31156624 (PubMedID)
Funder
Swedish Research Council, 2017-02577Swedish Research Council, 2018-02399Swedish Research Council, 2018-02535Swedish Research Council, 2018-02000Stockholm County Council, 20160378Stockholm County Council, 20170038Swedish Rheumatism Association, R-748261Swedish Rheumatism Association, R-755861Swedish Rheumatism Association, R-753741Swedish Rheumatism Association, R-850611Swedish Rheumatism Association, R-739631Swedish Society of Medicine
Available from: 2019-06-10 Created: 2019-06-10 Last updated: 2019-06-11Bibliographically approved
Vasaitis, L., Nordmark, G., Theander, E., Backlin, C., Smedby, K. E., Askling, J., . . . Baecklund, E. (2019). Comparison of patients with and without pre-existing lymphoma at diagnosis of primary Sjögren's syndrome. Scandinavian Journal of Rheumatology, 48(3), 207-212
Open this publication in new window or tab >>Comparison of patients with and without pre-existing lymphoma at diagnosis of primary Sjögren's syndrome
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2019 (English)In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 48, no 3, p. 207-212Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: In the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for primary Sjögren's syndrome (pSS), pre-existing lymphoma is not an exclusion criterion for pSS diagnosis, as in earlier criteria. We aimed to explore whether there are differences between pSS patients with and without pre-existing lymphoma at pSS diagnosis.

METHOD: Patients with ICD-7-10 codes for Sjögren's syndrome (SS) and a diagnosis of malignant lymphoma before or after SS diagnosis were identified by linking the Swedish Patient Register 1964-2007 with the Cancer Register 1990-2007 (n = 224). Clinical data were collected from medical records. Lymphoma diagnoses were evaluated by tissue review. Characteristics of pSS patients with and without pre-existing lymphoma were compared.

RESULTS: We identified 107 patients with pSS as the reason for an SS diagnosis code and a verified lymphoma. Of these, 18 (17%) had a pre-existing lymphoma at pSS diagnosis, defined as lymphoma diagnosed before or within 6 months of pSS diagnosis. Male gender (39% vs 10%, p = 0.006), enlarged lymph nodes during the pSS disease (61% vs 27%, p = 0.01), mucosa-associated lymphoid tissue (MALT) lymphoma (50% vs 22%, p = 0.02), and salivary gland lymphoma (61% vs 26%, p = 0.006) were more common in patients with a pre-existing lymphoma at pSS diagnosis. Other pSS characteristics were similar.

CONCLUSION: In a substantial proportion of patients, particularly in men, pSS remains undiagnosed until after lymphoma diagnosis. The study highlights the importance of pSS investigation in patients with lymphoma, especially MALT lymphoma, in the salivary glands.

National Category
Rheumatology and Autoimmunity
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-366237 (URN)10.1080/03009742.2018.1523456 (DOI)000467940900005 ()30422723 (PubMedID)
Funder
Swedish Cancer SocietySwedish Rheumatism AssociationSwedish Society of MedicineThe King Gustaf V's Jubilee Foundation
Available from: 2018-11-18 Created: 2018-11-18 Last updated: 2019-06-18Bibliographically approved
Allum, F., Hedman, A. K., Shaol, X., Cheung, W. A., Vijay, J., Guenard, F., . . . Grundberg, E. (2019). Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements. Nature Communications, 10, Article ID 1209.
Open this publication in new window or tab >>Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements
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2019 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, article id 1209Article in journal (Refereed) Published
Abstract [en]

Sparse profiling of CpG methylation in blood by microarrays has identified epigenetic links to common diseases. Here we apply methylC-capture sequencing (MCC-Seq) in a clinical population of similar to 200 adipose tissue and matched blood samples (N-total similar to 400), providing high- resolution methylation profiling (>1.3 M CpGs) at regulatory elements. We link methylation to cardiometabolic risk through associations to circulating plasma lipid levels and identify lipid-associated CpGs with unique localization patterns in regulatory elements. We show distinct features of tissue-specific versus tissue-independent lipid-linked regulatory regions by contrasting with parallel assessments in similar to 800 independent adipose tissue and blood samples from the general population. We follow-up on adipose-specific regulatory regions under (1) genetic and (2) epigenetic (environmental) regulation via integrational studies. Overall, the comprehensive sequencing of regulatory element methylomes reveals a rich landscape of functional variants linked genetically as well as epigenetically to plasma lipid traits.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-380447 (URN)10.1038/s41467-019-09184-z (DOI)000461161500005 ()30872577 (PubMedID)
Funder
Swedish Research CouncilEU, FP7, Seventh Framework Programme
Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2019-03-28Bibliographically approved
Morin, A., Madore, A.-M., Kwan, T., Ban, M., Partanen, J., Rönnblom, L., . . . Laprise, C. (2019). Exploring rare and low-frequency variants in the Saguenay-Lac-Saint-Jean population identified genes associated with asthma and allergy traits. European Journal of Human Genetics, 27(1), 90-101
Open this publication in new window or tab >>Exploring rare and low-frequency variants in the Saguenay-Lac-Saint-Jean population identified genes associated with asthma and allergy traits
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2019 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 27, no 1, p. 90-101Article in journal (Refereed) Published
Abstract [en]

The Saguenay-Lac-Saint-Jean (SLSJ) region is located in northeastern Quebec and is known for its unique demographic history and founder effect. As founder populations are enriched with population-specific variants, we characterized the variants distribution in SLSJ and compared it with four European populations (Finnish, Sweden, United Kingdom and France), of which the Finnish population is another founder population. Targeted sequencing of the coding and non-coding immune regulatory regions of the SLSJ asthma familial cohort and the four European populations were performed. Rare and low-frequency coding and non-coding regulatory variants identified in the SLSJ population were then investigated for variant-and gene-level associations with asthma and allergy-related traits (eosinophil percentage, immunoglobulin (Ig) E levels and lung function). Our data showed that (1) rare or deleterious variants were not enriched in the two founder populations as compared with the three non-founder European populations; (2) a larger proportion of founder population-specific variants occurred with higher frequencies; and (3) low-frequency variants appeared to be more deleterious. Furthermore, a rare variant, rs1386931, located in the 3'-UTR of CXCR6 and intron of FYCO1 was found to be associated with eosinophil percentage. Gene-based analyses identified NRP2, MRPL44 and SERPINE2 to be associated with various asthma and allergy-related traits. Our study demonstrated the usefulness of using a founder population to identify new genes associated with asthma and allergy-related traits; thus better understand the genes and pathways implicated in pathophysiology.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-373365 (URN)10.1038/s41431-018-0266-4 (DOI)000454111500012 ()30206357 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-01-15Bibliographically approved
Lindahl, H., Guerreiro-Cacais, A. O., Bedri, S. K., Linnerbauer, M., Linden, M., Abdelmagid, N., . . . Olsson, T. (2019). IL-22 Binding Protein Promotes the Disease Process in Multiple Sclerosis. Journal of Immunology, 203(4), 888-898
Open this publication in new window or tab >>IL-22 Binding Protein Promotes the Disease Process in Multiple Sclerosis
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2019 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 203, no 4, p. 888-898Article in journal (Refereed) Published
Abstract [en]

Genome-wide association studies have mapped the specific sequence variants that predispose for multiple sclerosis (MS). The pathogenic mechanisms that underlie these associations could be leveraged to develop safer and more effective MS treatments but are still poorly understood. In this article, we study the genetic risk variant rs17066096 and the candidate gene that encodes IL-22 binding protein (IL-22BP), an antagonist molecule of the cytokine IL-22. We show that monocytes from carriers of the risk genotype of rs17066096 express more IL-22BP in vitro and cerebrospinal fluid levels of IL-22BP correlate with MS lesion load on magnetic resonance imaging. We confirm the pathogenicity of IL-22BP in both rat and mouse models of MS and go on to suggest a pathogenic mechanism involving lack of IL-22-mediated inhibition of T cell-derived IFN-gamma expression. Our results demonstrate a pathogenic role of IL-22BP in three species with a potential mechanism of action involving T cell polarization, suggesting a therapeutic potential of IL-22 in the context of MS.

Place, publisher, year, edition, pages
AMER ASSOC IMMUNOLOGISTS, 2019
National Category
Immunology in the medical area Immunology
Identifiers
urn:nbn:se:uu:diva-393331 (URN)10.4049/jimmunol.1900400 (DOI)000478980700015 ()31292217 (PubMedID)
Funder
Swedish Research Council, D0283001Knut and Alice Wallenberg Foundation, 2011.0073AstraZeneca
Available from: 2019-09-27 Created: 2019-09-27 Last updated: 2019-09-27Bibliographically approved
Hagberg, N. & Rönnblom, L. (2019). Interferon-α enhances the IL-12-induced STAT4 activation selectively in carriers of the STAT4 SLE risk allele rs7574865[T] [Letter to the editor]. Annals of the Rheumatic Diseases, 78(3), 429-431
Open this publication in new window or tab >>Interferon-α enhances the IL-12-induced STAT4 activation selectively in carriers of the STAT4 SLE risk allele rs7574865[T]
2019 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, no 3, p. 429-431Article in journal, Letter (Refereed) Published
Keywords
T cells, gene polymorphism, systemic lupus erythematosus
National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-366407 (URN)10.1136/annrheumdis-2018-213836 (DOI)000471061000023 ()30269051 (PubMedID)
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2019-06-28Bibliographically approved
Imgenberg-Kreuz, J., Carlsson Almlöf, J., Leonard, D., Sjöwall, C., Syvänen, A.-C., Rönnblom, L., . . . Nordmark, G. (2019). Shared and Unique Patterns of DNA Methylation in Systemic Lupus Erythematosus and Primary Sjogren's Syndrome. Frontiers in Immunology, 10, Article ID 1686.
Open this publication in new window or tab >>Shared and Unique Patterns of DNA Methylation in Systemic Lupus Erythematosus and Primary Sjogren's Syndrome
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 1686Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2019
Keywords
systemic lupus erythematosus, primary Sjogren's syndrome, DNA methylation, EWAS, epigenetics, autoimmunity, type I interferon, random forest
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-391357 (URN)10.3389/fimmu.2019.01686 (DOI)000477805800001 ()31428085 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, KAW 2011.0073Swedish Research Council, VR-MH Dnr 521-2014-2263Swedish Research Council, Dnr 2018-02399Swedish Research Council, Dnr 2016-01982Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2019-09-24 Created: 2019-09-24 Last updated: 2019-09-24Bibliographically approved
Crow, M. K. & Rönnblom, L. (2019). Type I interferons in host defence and inflammatory diseases. Lupus Science and Medicine, 6(1), Article ID e000336.
Open this publication in new window or tab >>Type I interferons in host defence and inflammatory diseases
2019 (English)In: Lupus Science and Medicine, ISSN 2053-8790, E-ISSN 1625-9823, Vol. 6, no 1, article id e000336Article, review/survey (Refereed) Published
Abstract [en]

Type I interferons (IFN) can have dual and opposing roles in immunity, with effects that are beneficial or detrimental to the individual depending on whether IFN pathway activation is transient or sustained. Determinants of IFN production and its functional consequences include the nature of the microbial or nucleic acid stimulus, the type of nucleic acid sensor involved in inducing IFN, the predominant subtype of type I IFN produced and the immune ecology of the tissue at the time of IFN expression. When dysregulated, the type I IFN system drives many autoimmune and non-autoimmune inflammatory diseases, including SLE and the tissue inflammation associated with chronic infection. The type I IFN system may also contribute to outcomes for patients affected by solid cancers or myocardial infarction. Significantly more research is needed to discern the mechanisms of induction and response to type I IFNs across these diseases, and patient endophenotyping may help determine whether the cytokine is acting as 'friend' or 'foe', within a particular patient, and at the time of treatment. This review summarises key concepts and discussions from the second International Summit on Interferons in Inflammatory Diseases, during which expert clinicians and scientists evaluated the evidence for the role of type I IFNs in autoimmune and other inflammatory diseases.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-390013 (URN)10.1136/lupus-2019-000336 (DOI)000471929000016 ()31205729 (PubMedID)
Funder
AstraZeneca
Available from: 2019-08-02 Created: 2019-08-02 Last updated: 2019-08-02Bibliographically approved
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