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Rönnblom, Lars
Alternative names
Publications (10 of 182) Show all publications
Yavuz, S. & Rönnblom, L. (2020). Biomarkers: to be or not to be [Letter to the editor]. Annals of the Rheumatic Diseases, 79(1), Article ID e8.
Open this publication in new window or tab >>Biomarkers: to be or not to be
2020 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 79, no 1, article id e8Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2020
Keywords
autoimmune diseases, disease activity, systemic lupus erythematosus
National Category
Rheumatology and Autoimmunity
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-366412 (URN)10.1136/annrheumdis-2018-214608 (DOI)000507367800008 ()30415201 (PubMedID)
Available from: 2018-11-20 Created: 2018-11-20 Last updated: 2020-03-24Bibliographically approved
Reid, S., Alexsson, A., Frodlund, M., Morris, D., Sandling, J. K., Bolin, K., . . . Leonard, D. (2020). High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus. Annals of the Rheumatic Diseases, 79(3), 363-369
Open this publication in new window or tab >>High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus
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2020 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 79, no 3, p. 363-369Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: To investigate associations between a high genetic disease risk and disease severity in patients with systemic lupus erythematosus (SLE).

METHODS: Patients with SLE (n=1001, discovery cohort and n=5524, replication cohort) and healthy controls (n=2802 and n=9859) were genotyped using a 200K Immunochip single nucleotide polymorphism array. A genetic risk score (GRS) was assigned to each individual based on 57 SLE risk loci.

RESULTS: SLE was more prevalent in the high, compared with the low, GRS-quartile (OR 12.32 (9.53 to 15.71), p=7.9×10-86 and OR 7.48 (6.73 to 8.32), p=2.2×10-304 for the discovery and the replication cohorts, respectively). In the discovery cohort, patients in the high GRS-quartile had a 6-year earlier mean disease onset (HR 1.47 (1.22 to 1.75), p=4.3×10-5), displayed higher prevalence of damage accrual (OR 1.47 (1.06 to 2.04), p=2.0×10-2), renal disorder (OR 2.22 (1.50 to 3.27), p=5.9×10-5), anti-dsDNA (OR 1.83 (1.19 to 2.81), p=6.1×10-3), end-stage renal disease (ESRD) (OR 5.58 (1.50 to 20.79), p=1.0×10-2), proliferative nephritis (OR 2.42 (1.30 to 4.49), p=5.1×10-3), anti-cardiolipin-IgG (OR 1.89 (1.13 to 3.18), p=1.6×10-2), anti-β2-glycoprotein-I-IgG (OR 2.29 (1.29 to 4.06), p=4.8×10-3) and positive lupus anticoagulant test (OR 2.12 (1.16 to 3.89), p=1.5×10-2) compared with patients in the low GRS-quartile. Survival analysis showed earlier onset of the first organ damage (HR 1.51 (1.04 to 2.25), p=3.7×10-2), first cardiovascular event (HR 1.65 (1.03 to 2.64), p=2.6×10-2), nephritis (HR 2.53 (1.72 to 3.71), p=9.6×10-7), ESRD (HR 6.78 (1.78 to 26.86), p=6.5×10-3) and decreased overall survival (HR 1.83 (1.02 to 3.30), p=4.3×10-2) in high to low quartile comparison.

CONCLUSIONS: A high GRS is associated with increased risk of organ damage, renal dysfunction and all-cause mortality. Our results indicate that genetic profiling may be useful for predicting outcomes in patients with SLE.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2020
Keywords
antiphospholipid syndrome, cardiovascular disease, gene polymorphism, lupus nephritis, systemic lupus erythematosus
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-400460 (URN)10.1136/annrheumdis-2019-216227 (DOI)000519264600019 ()31826855 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Society of MedicineKing Gustaf V Jubilee FundSwedish Heart Lung FoundationErik, Karin och Gösta Selanders Foundation
Available from: 2019-12-20 Created: 2019-12-20 Last updated: 2020-04-07Bibliographically approved
Carlsson, H., Hjorton, K., Abujrais, S., Rönnblom, L., Åkerfeldt, T. & Kultima, K. (2020). Measurement of hydroxychloroquine in blood from SLE patients using LC-HRMS: Evaluation of whole blood, plasma and serum as sample matrices.
Open this publication in new window or tab >>Measurement of hydroxychloroquine in blood from SLE patients using LC-HRMS: Evaluation of whole blood, plasma and serum as sample matrices
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2020 (English)Manuscript (preprint) (Other academic)
National Category
Biomedical Laboratory Science/Technology Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-409045 (URN)
Available from: 2020-04-20 Created: 2020-04-20 Last updated: 2020-04-22
Linge, P., Arve, S., Olsson, L. M., Leonard, D., Sjöwall, C., Frodlund, M., . . . Bengtsson, A. (2020). NCF1-339 polymorphism is associated with altered formation of neutrophil extracellular traps, high serum interferon activity and antiphospholipid syndrome in systemic lupus erythematosus. Annals of the Rheumatic Diseases, 79(2), 254-261
Open this publication in new window or tab >>NCF1-339 polymorphism is associated with altered formation of neutrophil extracellular traps, high serum interferon activity and antiphospholipid syndrome in systemic lupus erythematosus
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2020 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 79, no 2, p. 254-261Article in journal (Refereed) Published
Abstract [en]

Objectives: A single nucleotide polymorphism in the NCF1 gene (NCF1-339, rs201802880), encoding NADPH oxidase type II subunit NCF1/p47(phox), reducing production of reactive oxygen species (ROS) is strongly associated with the development of systemic lupus erythematosus (SLE). This study aimed at characterising NCF1-339 effects on neutrophil extracellular trap (NET) formation, type I interferon activity and antibody profile in patients with SLE.

Methods: Neutrophil NET-release pathways (n=31), serum interferon (n=141) and finally antibody profiles (n=305) were investigated in SLE subjects from Lund, genotyped for NCF1-339. Then, 1087 SLE subjects from the rheumatology departments of four Swedish SLE centres, genotyped for NCF1-339, were clinically characterised to validate these findings.

Results: Compared with patients with normal-ROS NCF1-339 genotypes, neutrophils from patients with SLE with low-ROS NCF1-339 genotypes displayed impaired NET formation (p<0.01) and increased dependence on mitochondrial ROS (p<0.05). Low-ROS patients also had increased frequency of high serum interferon activity (80% vs 21.4%, p<0.05) and positivity for anti-beta 2 glycoprotein I (p<0.01) and anticardiolipin antibodies (p<0.05) but were not associated with other antibodies. We confirmed an over-representation of having any antiphospholipid antibody, OR 1.40 (95% CI 1.01 to 1.95), anti-beta 2 glycoprotein I, OR 1.82 (95% CI 1.02 to 3.24) and the antiphospholipid syndrome (APS), OR 1.74 (95% CI 1.19 to 2.55) in all four cohorts (n=1087).

Conclusions: The NCF1-339 SNP mediated decreased NADPH oxidase function, is associated with high interferon activity and impaired formation of NETs in SLE, allowing dependence on mitochondrial ROS. Unexpectedly, we revealed a striking connection between the ROS deficient NCF1-339 genotypes and the presence of phospholipid antibodies and APS.

Place, publisher, year, edition, pages
BMJ PUBLISHING GROUP, 2020
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-407971 (URN)10.1136/annrheumdis-2019-215820 (DOI)000518219100025 ()31704719 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Heart Lung FoundationSwedish Rheumatism AssociationSwedish Foundation for Strategic Research Swedish Society of Medicine, SLS-713911Stockholm County Council
Available from: 2020-04-02 Created: 2020-04-02 Last updated: 2020-04-02Bibliographically approved
Galindo-Feria, A. S., Albrecht, I., Fernandes-Cerqueira, C., Notarnicola, A., James, E. A., Herrath, J., . . . Lundberg, I. E. (2020). Proinflammatory Histidyl-Transfer RNA Synthetase-Specific CD4+T Cells in the Blood and Lungs of Patients With Idiopathic Inflammatory Myopathies. Arthritis & Rheumatology, 72(1), 179-191
Open this publication in new window or tab >>Proinflammatory Histidyl-Transfer RNA Synthetase-Specific CD4+T Cells in the Blood and Lungs of Patients With Idiopathic Inflammatory Myopathies
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2020 (English)In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 72, no 1, p. 179-191Article in journal (Refereed) Published
Abstract [en]

Objective Autoantibodies targeting histidyl-transfer RNA synthetase (HisRS; anti-Jo-1) are common in the idiopathic inflammatory myopathies (IIMs) and antisynthetase syndrome. This study was undertaken to investigate immunity against HisRS in the blood and lungs of patients with IIM/antisynthetase syndrome. Methods Bronchoalveolar lavage (BAL) fluid, BAL fluid cells, and peripheral blood mononuclear cells (PBMCs) from patients with IIM/antisynthetase syndrome (n = 24) were stimulated with full-length HisRS protein or a HisRS-derived peptide (HisRS(11-23)). BAL fluid and PBMCs from patients with sarcoidosis (n = 7) and healthy subjects (n = 12) were included as controls. The CD4+ T cell response was determined according to levels of CD40L up-regulation and cytokine expression using flow cytometry. Anti-Jo-1 autoantibody responses in the serum and BAL fluid were assessed by enzyme-linked immunosorbent assay. Lung biopsy samples from patients with IIM/antisynthetase syndrome (n = 14) were investigated by immunohistochemistry. Results In BAL fluid, CD4+ T cells from 3 of 4 patients with IIM/antisynthetase syndrome responded to stimulation with HisRS protein, as measured by the median fold change in CD40L expresssion in stimulated cells compared to unstimulated cells (median fold change 3.6, interquartile range [IQR] 2.7-14.7), and 2 of 3 patients with IIM/antisynthetase syndrome had the highest responses to HisRS(11-23) (median fold change 88, IQR 27-149)(.) In PBMCs, CD4+ T cells from 14 of 18 patients with IIM/antisynthetase syndrome responded to HisRS protein (median fold change 7.38, IQR 2.69-31.86; P < 0.001), whereas a HisRS(11-23) response was present in 11 of 14 patients with IIM/antisynthetase syndrome (median fold change 3.4, IQR 1.87-10.9; P < 0.001). In the control group, there was a HisRS(11-23) response in 3 of 7 patients with sarcoidosis (median fold change 2.09, IQR 1.45-3.29) and in 5 of 12 healthy controls (median fold change 2, IQR 1.89-2.42). CD4+ T cells from patients with IIM/antisynthetase syndrome displayed a pronounced Th1 phenotype in the BAL fluid when compared to the PBMCs (P < 0.001), producing high amounts of interferon-gamma and interleukin-2 following stimulation. Anti-Jo-1 autoantibodies were detected in BAL fluid and germinal center (GC)-like structures were seen in the lung biopsy samples from patients with IIM/antisynthetase syndrome. Conclusion The results of this study demonstrate a pronounced presence of HisRS-reactive CD4+ T cells in PBMCs and BAL fluid cells from patients with IIM/antisynthetase syndrome as compared to patients with sarcoidosis and healthy controls. These findings, combined with the presence of anti-Jo-1 autoantibodies in BAL fluid and GC-like structures in the lungs, suggest that immune activation against HisRS might take place within the lungs of patients with IIM/antisynthetase syndrome.

Place, publisher, year, edition, pages
WILEY, 2020
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-408230 (URN)10.1002/art.41075 (DOI)000498469400001 ()31403245 (PubMedID)
Funder
Swedish Heart Lung FoundationSwedish Research Council, K2014-52X-14045-14-3
Available from: 2020-04-06 Created: 2020-04-06 Last updated: 2020-04-06Bibliographically approved
Hjorton, K., Hagberg, N., Pucholt, P., Eloranta, M.-L. & Rönnblom, L. (2020). The regulation and pharmacological modulation of immune complex induced type III IFN production by plasmacytoid dendritic cells. arthritis research and therapy
Open this publication in new window or tab >>The regulation and pharmacological modulation of immune complex induced type III IFN production by plasmacytoid dendritic cells
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2020 (English)In: arthritis research and therapy, ISSN 1478-6354Article in journal (Refereed) Accepted
National Category
Immunology in the medical area Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-409026 (URN)
Available from: 2020-04-20 Created: 2020-04-20 Last updated: 2020-04-22
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: 2020-03-17Bibliographically 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 Clinical Laboratory Medicine
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: 2020-01-08Bibliographically approved
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