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Rönnblom, Lars
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Publications (10 of 128) Show all publications
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, 1607-1613 p.Article 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
Li, H., Reksten, T. R., Ice, J. A., Kelly, J. A., Adrianto, I., Rasmussen, A., . . . Sivils, K. L. (2017). Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons. PLoS Genetics, 13(6), Article ID e1006820.
Open this publication in new window or tab >>Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons
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2017 (English)In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 6, e1006820Article in journal (Refereed) Published
Abstract [en]

Sjogren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 x 10(-14)). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (P-meta = 2.59 x 10(-9); odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-330755 (URN)10.1371/journal.pgen.1006820 (DOI)000404512600013 ()28640813 (PubMedID)
Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2017-10-03Bibliographically approved
Smith-Anttila, C. J. A., Bensing, S., Alimohammadi, M., Dalin, F., Oscarson, M., Zhang, M.-D., . . . Kämpe, O. (2017). Identification of endothelin-converting enzyme-2 as an autoantigen in autoimmune polyendocrine syndrome type 1. Autoimmunity, 50(4), 223-231.
Open this publication in new window or tab >>Identification of endothelin-converting enzyme-2 as an autoantigen in autoimmune polyendocrine syndrome type 1
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2017 (English)In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 50, no 4, 223-231 p.Article in journal (Refereed) Published
Abstract [en]

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High titer autoantibodies are a characteristic feature of APS1 and are often associated with particular disease manifestations. Pituitary deficits are reported in up to 7% of all APS1 patients, with immunoreactivity to pituitary tissue frequently reported. We aimed to isolate and identify specific pituitary autoantigens in patients with APS1. Immunoscreening of a pituitary cDNA expression library identified endothelin-converting enzyme (ECE)-2 as a potential candidate autoantigen. Immunoreactivity against ECE-2 was detected in 46% APS1 patient sera, with no immunoreactivity detectable in patients with other autoimmune disorders or healthy controls. Quantitative-PCR showed ECE-2 mRNA to be most abundantly expressed in the pancreas with high levels also in the pituitary and brain. In the pancreas ECE-2 was co-expressed with insulin or somatostatin, but not glucagon and was widely expressed in GH producing cells in the guinea pig pituitary. The correlation between immunoreactivity against ECE-2 and the major recognized clinical phenotypes of APS1 including hypopituitarism was not apparent. Our results identify ECE-2 as a specific autoantigen in APS1 with a restricted neuroendocrine distribution.

Keyword
APS1, endothelin-converting enzyme-2, ECE-2, pituitary autoantibodies, pancreas
National Category
Immunology
Identifiers
urn:nbn:se:uu:diva-333619 (URN)10.1080/08916934.2017.1332183 (DOI)000407564500005 ()28557628 (PubMedID)
Available from: 2017-11-16 Created: 2017-11-16 Last updated: 2017-11-16Bibliographically approved
Wirestam, L., Enocsson, H., Skogh, T., Eloranta, M.-L., Rönnblom, L., Sjöwall, C. & Wetterö, J. (2017). Interferon-α coincides with suppressed levels of pentraxin-3 (PTX3) in systemic lupus erythematosus and regulates leucocyte PTX3 in vitro. Clinical and Experimental Immunology, 189(1), 83-91.
Open this publication in new window or tab >>Interferon-α coincides with suppressed levels of pentraxin-3 (PTX3) in systemic lupus erythematosus and regulates leucocyte PTX3 in vitro
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2017 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 189, no 1, 83-91 p.Article in journal (Refereed) Published
Abstract [en]

Dysfunctional elimination of cell debris, and the role of opsonins such as pentraxins, is of interest regarding systemic lupus erythematosus (SLE) pathogenesis. Interferon (IFN)- is typically elevated during SLE flares, and inhibits hepatocyte production of the pentraxin C-reactive protein' (CRP), partly explaining the poor correlation between CRP levels and SLE disease activity. The extrahepatically produced pentraxin 3' (PTX3) shares waste disposal functions with CRP, but has not been studied extensively in SLE. We analysed serum PTX3 in SLE, and assessed its interference with IFN- in vitro. Serum samples from 243 patients with SLE and 100 blood donors were analysed regarding PTX3. Patient sera were analysed for IFN-, and genotyped for three PTX3 single nucleotide polymorphisms reported previously to associate with PTX3 levels. Stimulated PTX3 release was assessed in the presence or absence of IFN- in blood donor neutrophils and peripheral blood mononuclear cells (PBMC). Serum PTX3 was 44% lower in patients with SLE compared to blood donors (P<00001) and correlated with leucocyte variables. Patients with undetectable IFN- had 29% higher median PTX3 level than patients with detectable IFN- (P=001). PTX3 production by PBMC was inhibited by IFN-, whereas neutrophil degranulation of PTX3 was increased. No differences in PTX3 levels were observed between the SNPs. In conclusion, median serum PTX3 is lower in SLE (especially when IFN- is detectable) compared to blood donors. In addition to its potential consumption during waste disposal, it is plausible that IFN- also attenuates PTX3 by inhibiting synthesis by PBMC and/or exhausting PTX3 storage in neutrophil granules.

Keyword
Systemic lupus erythematosus (SLE), biomarkers, interferon-α, leukocytes, pentraxin
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-318787 (URN)10.1111/cei.12957 (DOI)000402977200008 ()28257596 (PubMedID)
Funder
Swedish Research CouncilSwedish Rheumatism AssociationSwedish Society for Medical Research (SSMF)
Available from: 2017-03-28 Created: 2017-03-28 Last updated: 2017-08-22Bibliographically approved
Sepulveda, J. I. R., Kvarnstrom, M., Eriksson, P., Mandl, T., Norheim, K. B., Johnsen, S. J., . . . Wahren-Herlenius, M. (2017). Long-term follow-up in primary Sjogren's syndrome reveals differences in clinical presentation between female and male patients. Biology of Sex Differences, 8, Article ID 25.
Open this publication in new window or tab >>Long-term follow-up in primary Sjogren's syndrome reveals differences in clinical presentation between female and male patients
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2017 (English)In: Biology of Sex Differences, ISSN 2042-6410, Vol. 8, 25Article in journal (Refereed) Published
Abstract [en]

Background: Despite men being less prone to develop autoimmune diseases, male sex has been associated with a more severe disease course in several systemic autoimmune diseases. In the present study, we aimed to investigate differences in the clinical presentation of primary Sjogren's syndrome (pSS) between the sexes and establish whether male sex is associated with a more severe form of long-term pSS. Methods: Our study population included 967 patients with pSS (899 females and 68 males) from Scandinavian clinical centers. The mean follow-up time (years) was 8.8 +/- 7.6 for women and 8.5 +/- 6.2 for men (ns). Clinical data including serological and hematological parameters and glandular and extraglandular manifestations were compared between men and women. Results: Male patient serology was characterized by more frequent positivity for anti-Ro/SSA and anti-La/SSB (p = 0. 02), and ANA (p = 0.02). Further, men with pSS were more frequently diagnosed with interstitial lung disease (p = 0. 008), lymphadenopathy (p = 0.04) and lymphoma (p = 0.007). Conversely, concomitant hypothyroidism was more common among female patients (p = 0.009). Conclusions: We observe enhanced serological responses and higher frequencies of lymphoma-related extraglandular manifestations in men with pSS. Notably, lymphoma itself was also significantly more common in men. These observations may reflect an aggravated immune activation and a more severe pathophysiological state in male patients with pSS and indicate a personalized managing of the disease due to the influence of the sex of patients with pSS.

Place, publisher, year, edition, pages
BioMed Central, 2017
Keyword
Sjogren's syndrome, Autoimmunity, Sex difference, Disease severity, Extraglandular manifestations
National Category
Endocrinology and Diabetes Genetics
Identifiers
urn:nbn:se:uu:diva-334043 (URN)10.1186/s13293-017-0146-6 (DOI)000407219000001 ()
Available from: 2017-11-21 Created: 2017-11-21 Last updated: 2017-11-29Bibliographically 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, 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
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, 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
Bengtsson, A. A. & Rönnblom, L. (2017). Systemic lupus erythematosus: still a challenge for physicians. Journal of Internal Medicine, 281(1), 52-64.
Open this publication in new window or tab >>Systemic lupus erythematosus: still a challenge for physicians
2017 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 281, no 1, 52-64 p.Article, review/survey (Refereed) Published
Abstract [en]

Systemic lupus erythematosus (SLE) has a complex clinical picture, and a number of defects in the immune system have been described in patients with the disease. Most organs can be involved in SLE, and in addition to the typical major organ manifestations (e.g. from kidneys and the central nervous system), early cardiovascular disease is a major determinant of prognosis. Several important findings during the last decade have increased the understanding of the mechanisms behind the disease characteristics and the underlying autoimmune process. Amongst, these are defects in the handling of apoptotic cells, increased expression of type I interferon-regulated genes and activation of autoreactive B cells, with both the type I interferon system and the B lymphocyte stimulator (BLyS) having key roles. In addition, a large number of genes have been identified that contribute to these abnormalities. It has also become clear that certain SLE risk genes are associated with some organ manifestations, such as STAT4 with nephritis and IRF8 with myocardial infarction. Furthermore, environmental factors that can induce SLE or trigger a disease flare have been identified. As a consequence of this increased knowledge, new treatments for SLE have been developed. The most recently approved drug for SLE is belimumab, which blocks BLyS, and several new therapies and therapeutic strategies are in the pipeline for clinical application.

National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-300369 (URN)10.1111/joim.12529 (DOI)000393950000005 ()27307107 (PubMedID)
Funder
Swedish Research CouncilSwedish Rheumatism AssociationKnut and Alice Wallenberg FoundationAstraZenecaScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2016-08-08 Created: 2016-08-08 Last updated: 2017-04-28Bibliographically approved
Langefeld, C. D., Ainsworth, H. C., Graham, D. S. C., Kelly, J. A., Comeau, M. E., Marion, M. C., . . . Vyse, T. J. (2017). Transancestral mapping and genetic load in systemic lupus erythematosus. Nature Communications, 8, Article ID 16021.
Open this publication in new window or tab >>Transancestral mapping and genetic load in systemic lupus erythematosus
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2017 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, 16021Article in journal (Refereed) Published
Abstract [en]

Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-331233 (URN)10.1038/ncomms16021 (DOI)000405680100001 ()28714469 (PubMedID)
Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2017-11-29Bibliographically approved
Chemin, K., Pollastro, S., James, E., Ge, C., Albrecht, I., Herrath, J., . . . Malmstrom, V. (2016). A Novel HLA-DRB1*10:01-Restricted T Cell Epitope From Citrullinated Type II Collagen Relevant to Rheumatoid Arthritis. Arthritis & Rheumatology, 68(5), 1124-1135.
Open this publication in new window or tab >>A Novel HLA-DRB1*10:01-Restricted T Cell Epitope From Citrullinated Type II Collagen Relevant to Rheumatoid Arthritis
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2016 (English)In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 68, no 5, 1124-1135 p.Article in journal (Refereed) Published
Abstract [en]

Objective. Antibodies against citrullinated type II collagen (Cit-CII) are common in the sera and synovial fluid of patients with rheumatoid arthritis (RA); however, the known T cell epitope of CII is not dependent on citrullination. The aim of this study was to identify and functionally characterize the Cit-CII-restricted T cell epitopes that are relevant to RA. Methods. Peripheral blood mononuclear cells (PBMCs) from HLA-DRB1*10:01-positive patients with RA and healthy donors were stimulated in vitro with candidate CII peptides. CD154 up-regulation was measured as a marker of antigen-specific activation, and anti-HLA-DR-blocking experiments confirmed HLA restriction. Cytokine production was measured using a Luminex technique. Direct peptide-binding assays using HLA-DRB1*10:01 and HLA-DRB1*04:01 monomeric proteins were performed. The T cell receptor (TCR) beta-chain of CD154-enriched antigen-specific T cells was analyzed using high-throughput sequencing. Results. A novel Cit-CII peptide was identified based on its ability to activate CD4+ T cells from HLA-DRB1*10:01-positive individuals. When stimulated in vitro, Cit-CII autoreactive T cells produced proinflammatory cytokines. Cit-CII311-325 bound (with low affinity) to HLA-DRB1*10:01 but not to HLA-DRB1*04:01, while the native form was unable to bind either protein. In addition, highly expanded clones were identified in the TCR beta repertoire of Cit-CII311-325-stimulated PBMCs. Conclusion. These results illustrate the ability of the citrullination process to create T cell epitopes from CII, a cartilage-restricted protein that is relevant to RA pathogenesis. The exclusive binding of Cit-CII311-325 to HLA-DRB1*10:01 suggests that recognition of citrullinated epitopes might vary between individuals carrying different RA-associated HLA-DR molecules.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-297800 (URN)10.1002/art.39553 (DOI)000375551600011 ()26713667 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationEU, European Research Council, LSHB CT-2006-018661EU, FP7, Seventh Framework Programme, HEALTH-F2-2008-223404Swedish Research CouncilSwedish Foundation for Strategic Research EU, European Research Council, 260167
Available from: 2016-06-28 Created: 2016-06-28 Last updated: 2017-11-28Bibliographically approved
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