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Tandre, Karolina
Publications (10 of 18) Show all publications
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
Odqvist, L., Jevnikar, Z., Riise, R., Oberg, L., Rhedin, M., Leonard, D., . . . Vaarala, O. (2019). Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus. Annals of the Rheumatic Diseases, 78(10), 1363-1370
Open this publication in new window or tab >>Genetic variations in A20 DUB domain provide a genetic link to citrullination and neutrophil extracellular traps in systemic lupus erythematosus
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2019 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, no 10, p. 1363-1370Article in journal (Refereed) Published
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.

National Category
Rheumatology and Autoimmunity Cell Biology
Identifiers
urn:nbn:se:uu:diva-396653 (URN)10.1136/annrheumdis-2019-215434 (DOI)000487465000024 ()31300459 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2019-11-14 Created: 2019-11-14 Last updated: 2019-11-14Bibliographically 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
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
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
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
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
Abramov, S., Kozyrev, S. V., Farias, F. H. G., Dahlqvist, J., Leonard, D., Wilbe, M., . . . Lindblad-Toh, K. (2018). The risk allele A of rs200395694 associated with SLE in Swedish patients affects on MEF2D gene regulation and alternative splicing. Paper presented at Conference on Changing the Face of Modern Medicine - Stem Cell and Gene Therapy, OCT 16-19, 2018, Lausanne, SWITZERLAND. Human Gene Therapy, 29(12), A44-A44
Open this publication in new window or tab >>The risk allele A of rs200395694 associated with SLE in Swedish patients affects on MEF2D gene regulation and alternative splicing
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2018 (English)In: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 29, no 12, p. A44-A44Article in journal, Meeting abstract (Other academic) Published
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-373072 (URN)000453707700143 ()
Conference
Conference on Changing the Face of Modern Medicine - Stem Cell and Gene Therapy, OCT 16-19, 2018, Lausanne, SWITZERLAND
Available from: 2019-01-11 Created: 2019-01-11 Last updated: 2019-01-11Bibliographically approved
Carlsson Almlöf, J., Alexsson, A., Imgenberg-Kreuz, J., Sylwan, L., Bäcklin, C., Leonard, D., . . . Syvänen, A.-C. (2017). Novel risk genes for systemic lupus erythematosus predicted by random forest classification. Scientific Reports, 7, Article ID 6236.
Open this publication in new window or tab >>Novel risk genes for systemic lupus erythematosus predicted by random forest classification
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 6236Article in journal (Refereed) Published
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.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-333524 (URN)10.1038/s41598-017-06516-1 (DOI)000406260100040 ()28740209 (PubMedID)
Funder
Swedish Research Council, 521-2014-2263, 521-2013-2830
Available from: 2017-11-14 Created: 2017-11-14 Last updated: 2017-11-14Bibliographically approved
Wahlberg, P., Lundmark, A., Nordlund, J., Busche, S., Raine, A., Tandre, K., . . . Syvänen, A.-C. (2016). DNA methylome analysis of acute lymphoblastic leukemia cells reveals stochastic de novo DNA methylation in CpG islands. Epigenomics, 8(10), 1367-1387
Open this publication in new window or tab >>DNA methylome analysis of acute lymphoblastic leukemia cells reveals stochastic de novo DNA methylation in CpG islands
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2016 (English)In: Epigenomics, ISSN 1750-1911, Vol. 8, no 10, p. 1367-1387Article in journal (Refereed) Published
Abstract [en]

Aim: To identify regions of aberrant DNA methylation in acute lymphoblastic leukemia (ALL) cells of different subtypes on a genome-wide scale. Materials & methods: Whole-genome bisulfite sequencing (WGBS) was used to determine the DNA methylation levels in cells from four pediatric ALL patients of different subtypes. The findings were confirmed by 450k DNA methylation arrays in a large patient set. Results: Compared with mature B or T cells WGBS detected on average 82,000 differentially methylated regions per patient. Differentially methylated regions are enriched to CpG poor regions, active enhancers and transcriptional start sites. We also identified approximately 8000 CpG islands with variable intermediate DNA methylation that seems to occur as a result of stochastic de novo methylation. Conclusion: WGBS provides an unbiased view and novel insights into the DNA methylome of ALL cells.

Keywords
acute lymphoblastic leukemia, CpG islands, DNA methylation, epigenome, methylome, whole-genome bisulfite sequencing
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-308929 (URN)10.2217/epi-2016-0052 (DOI)000385653900006 ()27552300 (PubMedID)
Funder
Swedish Foundation for Strategic Research , RBc08-008Swedish Cancer Society, 140581Swedish Childhood Cancer Foundation, PR2014-0100Swedish Research Council, C0524801;259-2012-23Forte, Swedish Research Council for Health, Working Life and WelfareSwedish Research Council FormasVINNOVA
Available from: 2016-12-01 Created: 2016-12-01 Last updated: 2019-10-23Bibliographically approved
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