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Berggren, Olof
Publications (10 of 20) Show all publications
Hjorton, K., Hagberg, N., Israelsson, E., Jinton, L., Berggren, O., Sandling, J. K., . . . Rönnblom, L. (2018). Cytokine production by activated plasmacytoid dendritic cells and natural killer cells is suppressed by an IRAK4 inhibitor. Arthritis Research & Therapy, 20, Article ID 238.
Open this publication in new window or tab >>Cytokine production by activated plasmacytoid dendritic cells and natural killer cells is suppressed by an IRAK4 inhibitor
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2018 (English)In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 20, article id 238Article in journal (Refereed) Published
Abstract [en]

Background: In systemic lupus erythematosus (SLE), immune complexes (ICs) containing self-derived nucleic acids trigger the synthesis of proinflammatory cytokines by immune cells. We asked how an interleukin (IL)-1 receptor-associated kinase 4 small molecule inhibitor (IRAK4i) affects RNA-IC-induced cytokine production compared with hydroxychloroquine (HCQ).

Methods: Plasmacytoid dendritic cells (pDCs) and natural killer (NK) cells were isolated from peripheral blood mononuclear cells (PBMCs) of healthy individuals. PBMCs from SLE patients and healthy individuals were depleted of monocytes. Cells were stimulated with RNA-containing IC (RNA-IC) in the presence or absence of IRAK4i I92 or HCQ, and cytokines were measured by immunoassay or flow cytometry. Transcriptome sequencing was performed on RNA-IC-stimulated pDCs from healthy individuals to assess the effect of IRAK4i and HCQ.

Results: In healthy individuals, RNA-IC induced interferon (IFN)-α, tumor necrosis factor (TNF)-α, IL-6, IL-8, IFN-γ, macrophage inflammatory protein (MIP)1-α, and MIP1-β production in pDC and NK cell cocultures. IFN-α production was selective for pDCs, whereas both pDCs and NK cells produced TNF-α. IRAK4i reduced the pDC and NK cell-derived cytokine production by 74–95%. HCQ interfered with cytokine production in pDCs but not in NK cells. In monocyte-depleted PBMCs, IRAK4i blocked cytokine production more efficiently than HCQ. Following RNA-IC activation of pDCs, 975 differentially expressed genes were observed (false discovery rate (FDR) < 0.05), with many connected to cytokine pathways, cell regulation, and apoptosis. IRAK4i altered the expression of a larger number of RNA-IC-induced genes than did HCQ (492 versus 65 genes).

Conclusions: The IRAK4i I92 exhibits a broader inhibitory effect than HCQ on proinflammatory pathways triggered by RNA-IC, suggesting IRAK4 inhibition as a therapeutic option in SLE.

Keywords
HCQ, IRAK4, NK, SLE, pDC
National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-366403 (URN)10.1186/s13075-018-1702-0 (DOI)000448243100001 ()30355354 (PubMedID)
Funder
Swedish Rheumatism AssociationAstraZenecaSwedish Research CouncilSwedish Society of Medicine
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2019-01-08Bibliographically 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
Berggren, O., Hagberg, N., Alexsson, A., Weber, G., Rönnblom, L. & Eloranta, M.-L. (2017). Plasmacytoid dendritic cells and RNA-containing immune complexes drive expansion of peripheral B cell subsets with an SLE-like phenotype. PLoS ONE, 12(8), Article ID e0183946.
Open this publication in new window or tab >>Plasmacytoid dendritic cells and RNA-containing immune complexes drive expansion of peripheral B cell subsets with an SLE-like phenotype
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2017 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 8, article id e0183946Article in journal (Refereed) Published
Abstract [en]

Background Hyperactive B cells and a continuous interferon (IFN)-alpha production by plasmacytoid dendritic cells (pDCs) play a key role in systemic lupus erythematosus (SLE). We asked whether the interaction between B cells and pDCs stimulated with RNA-containing immune complexes affects peripheral B cell subsets. Methods B cells and pDCs were isolated from blood of healthy individuals and stimulated with immune complexes consisting of SLE-IgG and U1snRNP (RNA-IC). Expression of cell surface molecules as well as IL-6 and IL-10 production were determined by flow cytometry and immunoassays. Gene expression profiles were determined by a NanoString nCounter expression array. Results We found a remarkable increase of double negative CD27-IgD-B cells, from 7% within fresh CD19+B cells to 37% in the RNA-IC-stimulated co-cultures of B cells and pDCs, comparable to the frequency of double negative B cells in SLE patients. Gene expression analysis of the double negative CD27-IgD -and the CD27 + IgD-memory B cells revealed that twenty-one genes were differentially expressed between the two B cell subsets (>= 2-fold, p< 0.001). The, IL21R, IL4R, CCL4, CCL3, CD83 and the IKAROS Family Zinc Finger 2 (IKZ2) showed higher expression in the double negative CD27-IgD-B cells. Conclusion The interactions between B cells and pDCs together with RNA-containing IC led to an expansion of B cells with similar phenotype as seen in SLE, suggesting that the pDC-B cell crosstalk contributes to the autoimmune feed-forward loop in SLE.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2017
National Category
Immunology
Identifiers
urn:nbn:se:uu:diva-335229 (URN)10.1371/journal.pone.0183946 (DOI)000408438600061 ()28846748 (PubMedID)
Available from: 2017-12-05 Created: 2017-12-05 Last updated: 2017-12-05Bibliographically approved
Berggren, O., Rönnblom, L. & Eloranta, M.-L. (2016). Activated Plasmacytoid Dendritic Cells (PDCS) Alter The Composition of The Blood B Cell Subsets. Paper presented at Annual European Congress of Rheumatology (EULAR), JUN 08-11, 2016, London, ENGLAND. Annals of the Rheumatic Diseases, 75, 179-179
Open this publication in new window or tab >>Activated Plasmacytoid Dendritic Cells (PDCS) Alter The Composition of The Blood B Cell Subsets
2016 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, p. 179-179Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
BMJ PUBLISHING GROUP, 2016
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-347373 (URN)10.1136/annrheumdis-2016-eular.3486 (DOI)000401523100472 ()
Conference
Annual European Congress of Rheumatology (EULAR), JUN 08-11, 2016, London, ENGLAND
Available from: 2018-04-09 Created: 2018-04-09 Last updated: 2018-04-09Bibliographically approved
Cavalli, M., Pan, G., Nord, H., Wallerman, O., Arzt, E. W., Berggren, O., . . . Wadelius, C. (2016). Allele-specific transcription factor binding to common and rare variants associated with disease and gene expression. Human Genetics, 135(5), 485-497
Open this publication in new window or tab >>Allele-specific transcription factor binding to common and rare variants associated with disease and gene expression
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2016 (English)In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 135, no 5, p. 485-497Article in journal (Refereed) Published
Abstract [en]

Genome-wide association studies (GWAS) have identified a large number of disease-associated SNPs, but in few cases the functional variant and the gene it controls have been identified. To systematically identify candidate regulatory variants, we sequenced ENCODE cell lines and used public ChIP-seq data to look for transcription factors binding preferentially to one allele. We found 9962 candidate regulatory SNPs, of which 16 % were rare and showed evidence of larger functional effect than common ones. Functionally rare variants may explain divergent GWAS results between populations and are candidates for a partial explanation of the missing heritability. The majority of allele-specific variants (96 %) were specific to a cell type. Furthermore, by examining GWAS loci we found >400 allele-specific candidate SNPs, 141 of which were highly relevant in our cell types. Functionally validated SNPs support identification of an SNP in SYNGR1 which may expose to the risk of rheumatoid arthritis and primary biliary cirrhosis, as well as an SNP in the last intron of COG6 exposing to the risk of psoriasis. We propose that by repeating the ChIP-seq experiments of 20 selected transcription factors in three to ten people, the most common polymorphisms can be interrogated for allele-specific binding. Our strategy may help to remove the current bottleneck in functional annotation of the genome.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-297809 (URN)10.1007/s00439-016-1654-x (DOI)000374459200004 ()26993500 (PubMedID)
Funder
Swedish National Infrastructure for Computing (SNIC), b2010003Swedish National Infrastructure for Computing (SNIC), b2011107Swedish Research Council, 541-2013-8161Swedish Diabetes AssociationKnut and Alice Wallenberg Foundation
Available from: 2016-06-28 Created: 2016-06-28 Last updated: 2018-01-10Bibliographically approved
Hjorton, K., Hagberg, N., Berggren, O., Mo, J., Sandling, J. K., Eloranta, M.-L. & Rönnblom, L. (2016). The Effect of Hydroxychloroquine and IRAK4 Inhibition on The IFN-A and TNF-A Production Induced by Sle Related Immune Complexes. Paper presented at Annual European Congress of Rheumatology (EULAR), JUN 08-11, 2016, London, ENGLAND. Annals of the Rheumatic Diseases, 75, 277-277
Open this publication in new window or tab >>The Effect of Hydroxychloroquine and IRAK4 Inhibition on The IFN-A and TNF-A Production Induced by Sle Related Immune Complexes
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2016 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 75, p. 277-277Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
BMJ PUBLISHING GROUP, 2016
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-347374 (URN)10.1136/annrheumdis-2016-eular.4663 (DOI)000401523101229 ()
Conference
Annual European Congress of Rheumatology (EULAR), JUN 08-11, 2016, London, ENGLAND
Available from: 2018-04-09 Created: 2018-04-09 Last updated: 2018-04-09Bibliographically approved
Berggren, O., Rönnblom, L. & Eloranta, M.-L. (2016). The effect of PTPN22 Gene Variant R620W on the Type I Interferon Production Stimulated by Different TLR7 Agonists: Comment on Article by Wang et al (pages 2403-2414) [Letter to the editor]. Arthritis & Rheumatology, 68(4), 1045-1045
Open this publication in new window or tab >>The effect of PTPN22 Gene Variant R620W on the Type I Interferon Production Stimulated by Different TLR7 Agonists: Comment on Article by Wang et al (pages 2403-2414)
2016 (English)In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 68, no 4, p. 1045-1045Article in journal, Letter (Refereed) Published
National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-272691 (URN)10.1002/art.39571 (DOI)000373130300033 ()26748951 (PubMedID)
Available from: 2016-01-15 Created: 2016-01-15 Last updated: 2017-11-30Bibliographically approved
Berggren, O., Alexsson, A., Morris, D., Tandre, K., Weber, G., Vyse, T., . . . Eloranta, M.-L. (2015). IFN-α production by plasmacytoid dendritic cell associations with polymorphisms in gene loci related to autoimmune and inflammatory diseases. Human Molecular Genetics, 24(12), 3571-3581
Open this publication in new window or tab >>IFN-α production by plasmacytoid dendritic cell associations with polymorphisms in gene loci related to autoimmune and inflammatory diseases
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2015 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 12, p. 3571-3581Article in journal (Refereed) Published
Abstract [en]

The type I interferon (IFN) system is persistently activated in systemic lupus erythematosus (SLE) and many other systemic autoimmune diseases. Studies have shown an association between SLE and several gene variants within the type I IFN system. We investigated whether single nucleotide polymorphisms (SNPs) associated with SLE and other autoimmune diseases affect the IFN-α production in healthy individuals. Plasmacytoid dendritic cells (pDCs), B and NK cells were isolated from peripheral blood of healthy individuals and stimulated with RNA-containing immune complexes (IC), herpes simplex virus (HSV) or the oligonucleotide ODN2216. IFN-α production by pDCs alone or in cocultures with B or NK cells was measured by an immunoassay. All donors were genotyped with the 200K ImmunoChip and a 5bp CGGGG length polymorphism in the IFN regulatory factor 5 gene (IRF5) was genotyped by PCR. We found associations between IFN-α production and 18-86 SNPs (p ≤ 0.001), depending on the combination of the stimulated cell types. However, only three of these associated SNPs were shared between the cell type combinations. Several SNPs showed novel associations to the type I IFN system among all the associated SNPs, while some loci have been described earlier for their association with SLE. Furthermore, we found that the SLE-risk variant of the IRF5 CGGGG-indel was associated with lower IFN-α production. We conclude that the genetic variants affecting the IFN-α production highlight the intricate regulation of the type I IFN system and the importance of understanding the mechanisms behind the dysregulated type I IFN system in SLE.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-246523 (URN)10.1093/hmg/ddv095 (DOI)000355674400023 ()
Available from: 2015-03-09 Created: 2015-03-09 Last updated: 2017-12-04Bibliographically approved
Berggren, O. (2015). Regulation of Type I Interferon Production in Plasmacytoid Dendritic Cells: Effect of Genetic Factors and Interactions with NK Cells and B Cells. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Regulation of Type I Interferon Production in Plasmacytoid Dendritic Cells: Effect of Genetic Factors and Interactions with NK Cells and B Cells
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The type I interferon (IFN) system plays a central role in the etiopathogenesis of many autoimmune diseases, e.g. systemic lupus erythematosus (SLE). Activation of the type I IFN system in SLE is promoted by endogenous nucleic acid-containing immune complexes (ICs) which stimulate plasmacytoid dendritic cells (pDCs). This thesis focuses on the regulation of IFN-α production in pDCs, by interactions with B cells and natural killer (NK) cells, and by genetic factors.

In Study I, RNA-IC-stimulated CD56dim NK cells were found to be activated via FcγRIIIa and enhanced the IFN-α production by pDCs. The enhancing effect of the NK cells was mediated via both soluble factors, such as the cytokine MIP-1β, and in a cell-cell contact mediated manner via the adhesion molecule LFA-1. In Study II, B cells enhanced the IFN-α production by pDCs via cell-cell contact or soluble factors, depending on the stimuli. The cell-cell contact-mediated enhancement, when the cells were stimulated with RNA-IC, was abolished by blocking the cell adhesion molecule CD31. B cells stimulated with the oligonucleotide ODN2216 enhanced the IFN-α production via soluble factors. In Study III, gene variants related to autoimmune or inflammatory diseases were analyzed for the association to the IFN-α production by pDCs, alone or in coculture with NK or B cells. Depending on cell combination, 18-86 SNPs (p < 0.001) were associated with the IFN-α production. Several of the SNPs showed novel associations to the type I IFN system, while some loci have been described earlier for their association with SLE, e.g. IL10 and PXK. In Study IV, several B cell populations were affected by cocultivation with pDCs and stimulation with RNA-IC. The frequency of CD24hiCD38hi B cells of regulatory character was increased in the pDC-B cell cocultures. However, RNA-IC-stimulation only induced modest levels of IL-10. A remarkably increased frequency of double negative CD27-IgD- B cells was found in the RNA-IC-stimulated cocultures of pDCs and B cells.

In conclusion, the findings in the present thesis reveal novel mechanisms behind the regulation of the type I IFN system which could be important targets in autoimmune diseases with constantly activated pDCs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. p. 59
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1083
Keywords
Systemic lupus erythemtosus, IFN-alpha, autoimmunity, immune complex, single nuclear polymorphisms
National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-246526 (URN)978-91-554-9203-8 (ISBN)
Public defence
2015-05-08, Fåhraeussalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-04-14 Created: 2015-03-09 Last updated: 2015-04-17
Leonard, D., Eloranta, M.-L., Hagberg, N., Berggren, O., Tandre, K., Alm, G. & Rönnblom, L. (2014). Activated SLE-T Cells Enhance the Interferon-Alpha Production By Plasmacytoid Dendritic Cells Stimulated By RNA-IC. Paper presented at American College of Rheumatology (ACR/ARHP) Annual Meeting, 14-19 November 2014, Boston, USA. Arthritis & Rheumatology, 66(S10), S1173-S1173, Article ID 2681.
Open this publication in new window or tab >>Activated SLE-T Cells Enhance the Interferon-Alpha Production By Plasmacytoid Dendritic Cells Stimulated By RNA-IC
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2014 (English)In: Arthritis & Rheumatology, ISSN 2326-5191, Vol. 66, no S10, p. S1173-S1173, article id 2681Article in journal, Meeting abstract (Other academic) Published
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-246744 (URN)000344384905358 ()
Conference
American College of Rheumatology (ACR/ARHP) Annual Meeting, 14-19 November 2014, Boston, USA
Available from: 2015-03-10 Created: 2015-03-10 Last updated: 2015-03-10Bibliographically approved
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