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Rantapää-Dahlqvist, SolbrittORCID iD iconorcid.org/0000-0001-8259-3863
Alternative names
Publications (10 of 392) Show all publications
Lindelöf, L., Rantapää-Dahlqvist, S., Lundtoft, C., Sandling, J. K., Leonard, D., Sayadi, A., . . . Eriksson, O. (2024). A survey of ficolin-3 activity in Systemic lupus erythematosus reveals a link to hematological disease manifestations and autoantibody profile. Journal of Autoimmunity, 143, Article ID 103166.
Open this publication in new window or tab >>A survey of ficolin-3 activity in Systemic lupus erythematosus reveals a link to hematological disease manifestations and autoantibody profile
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2024 (English)In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 143, article id 103166Article in journal (Refereed) Published
Abstract [en]

The complement system plays a central role in the pathogenesis of Systemic Lupus Erythematosus (SLE), but most studies have focused on the classical pathway. Ficolin-3 is the main initiator of the lectin pathway of complement in humans, but its role in systemic autoimmune disease has not been conclusively determined. Here, we combined biochemical and genetic approaches to assess the contribution of ficolin-3 to SLE risk and disease manifestations. Ficolin-3 activity was measured by a functional assay in serum or plasma samples from Swedish SLE patients (n = 786) and controls matched for age and sex (n = 566). Genetic variants in an extended 300 kb genomic region spanning the FCN3 locus were analyzed for their association with ficolin-3 activity and SLE manifestations in a Swedish multicenter cohort (n = 985). Patients with ficolin-3 activity in the highest tertile showed a strong enrichment in an SLE cluster defined by anti-Sm/DNA/nucleosome antibodies (OR 3.0, p < 0.001) and had increased rates of hematological disease (OR 1.4, p = 0.078) and lymphopenia (OR = 1.6, p = 0.039). Genetic variants associated with low ficolin-3 activity mapped to an extended haplotype in high linkage disequilibrium upstream of the FCN3 gene. Patients carrying the lead genetic variant associated with low ficolin-3 activity had a lower frequency of hematological disease (OR 0.67, p = 0.018) and lymphopenia (OR 0.63, p = 0.031) and fewer autoantibodies (p = 0.0019). Loss-of-function variants in the FCN3 gene were not associated with SLE, but four (0.5 %) SLE patients developed acquired ficolin-3 deficiency where ficolin-3 activity in serum was depleted following diagnosis of SLE. Taken together, our results provide genetic and biochemical evidence that implicate the lectin pathway in hematological SLE manifestations. We also identify lectin pathway activation through ficolin-3 as a factor that contributes to the autoantibody response in SLE.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Autoantibodies, Complement system, Ficolin-3, Lectin pathway, Systemic lupus erythematosus
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-220019 (URN)10.1016/j.jaut.2023.103166 (DOI)38219652 (PubMedID)2-s2.0-85182582637 (Scopus ID)
Funder
Göran Gustafsson Foundation for Research in Natural Sciences and MedicineAgnes and Mac Rudberg FoundationSwedish Rheumatism AssociationStiftelsen Konung Gustaf V:s 80-årsfondSwedish Society of MedicineSwedish Research Council, 2018-02551Swedish Research Council, 2018-02399Swedish Research Council, 2021–02252Swedish Research Council, 2018-02535Swedish Research Council, 2022–00783Swedish Heart Lung FoundationSwedish National Infrastructure for Computing (SNIC)Swedish Research Council, 2018-05973Swedish Research Council, 2022–06725Harald Jeanssons stiftelse
Available from: 2024-01-29 Created: 2024-01-29 Last updated: 2024-01-30Bibliographically approved
Öberg Sysojev, A., Saevarsdottir, S., Diaz-Gallo, L.-M., Silberberg, G. N., Alfredsson, L., Klareskog, L., . . . Westerlind, H. (2024). Genome-wide investigation of persistence with methotrexate treatment in early rheumatoid arthritis. Rheumatology, 63(5), 1221-1229
Open this publication in new window or tab >>Genome-wide investigation of persistence with methotrexate treatment in early rheumatoid arthritis
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2024 (English)In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 63, no 5, p. 1221-1229Article in journal (Refereed) Published
Abstract [en]

Objectives: To investigate the influence of genetic factors on persistence to treatment of early rheumatoid arthritis (RA) with methotrexate (MTX) monotherapy.

Methods: We conducted a genome-wide association study (GWAS) in a sample of 3902 Swedish early RA patients initiating MTX in DMARD-monotherapy as their first ever DMARD. The outcome, short- and long-term persistence to this treatment, was defined as remaining on MTX at one and at three years, respectively, with no additional DMARDs added. As genetic predictors, we investigated individual SNPs, and a polygenic risk score (PRS) based on SNPs associated with RA risk. The SNP-based heritability of persistence was estimated overall and by RA serostatus.

Results: No individual SNP reached genome-wide significance (p < 5e-8), neither for persistence at one nor at three years. The RA PRS was not significantly associated with persistence at one (RR = 0.98 (0.96-1.01)) nor three years (RR = 0.96 (0.93-1.00)). The heritability for persistence was estimated to be 0.45 (0.15-0.75) at one year and 0.14 (0-0.40) at three years. Results in seropositive RA were comparable to those in the analysis of RA overall, while heritability estimates and PRS RRs were attenuated towards the null in seronegative RA.

Conclusions: Despite being the largest GWAS on an MTX treatment outcome to date, no genome-wide significant associations were detected. The modest heritability observed, coupled with the broad spread of suggestively associated loci, indicate that genetic influence is of polygenic nature. Nevertheless, persistence to MTX monotherapy was lower in patients with a greater genetic disposition, per the PRS, towards RA.

Place, publisher, year, edition, pages
Oxford University Press, 2024
Keywords
RA, MTX, persistence, heritability, genetic polymorphism, predictors, biomarkers
National Category
Rheumatology and Autoimmunity Medical Genetics
Identifiers
urn:nbn:se:umu:diva-217876 (URN)10.1093/rheumatology/kead301 (DOI)001019692200001 ()37326842 (PubMedID)2-s2.0-85192112578 (Scopus ID)
Note

Errata: Correction to: Genome-wide investigation of persistence with methotrexate treatment in early rheumatoid arthritis. Rheumatology, 2023; kead540. DOI: 10.1093/rheumatology/kead540

Available from: 2023-12-12 Created: 2023-12-12 Last updated: 2024-05-15Bibliographically approved
Ljung, L., Jönsson, E., Franklin, J., Berglin, E., Lundquist, A. & Rantapää-Dahlqvist, S. (2024). Incidence and predisposing factors of extra-articular manifestations in contemporary rheumatoid arthritis. European journal of internal medicine
Open this publication in new window or tab >>Incidence and predisposing factors of extra-articular manifestations in contemporary rheumatoid arthritis
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2024 (English)In: European journal of internal medicine, ISSN 0953-6205, E-ISSN 1879-0828Article in journal (Refereed) In press
Abstract [en]

Objective: Rheumatoid arthritis [RA) is a chronic inflammatory disease, with potential for extra-articular manifestations (ExRA). The incidence and predisposing factors for ExRA and the mortality were evaluated in an early RA inception cohort.

Methods: Patients (n = 1468; 69 % females, mean age (SD) 57.3(16.3) years) were consecutively included at the date of diagnosis, between 1 January 1996 and 31 December 2016, and assessed prospectively. In December 2016 development of ExRA was evaluated by a patient questionnaire and a review of medical records. Cumulative incidence and incidence rates were compared between 5-year periods and between patients included before and after 1 January 2001. Cox proportional hazard regression models were used to identify predictors for ExRA, and models with ExRA as time-dependent variables to estimate the mortality.

Results: After a mean (SD) follow-up of 9.3(4.9) years, 238 cases (23.3 %) had ExRA and 151 (14.7 %) had ExRA without rheumatoid nodules. Most ExRA developed within 5 years from diagnosis. Rheumatoid nodules (10.5 %) and keratoconjunctivitis sicca (7.1 %) were the most frequent manifestations, followed by pulmonary fibrosis (6.1 %). The ExRA incidence among more recently diagnosed patients was similar as to the incidence among patients diagnosed before 2001. Seropositivity, smoking and early biological treatment were associated with development of ExRA. After 15 years 20 % had experienced ExRA. ExRA was associated with increased mortality, HR 3.029 (95 % CI 2.177–4.213).

Conclusions: Early development of ExRA is frequent, particularly rheumatoid nodules. Predisposing factors were age, RF positivity, smoking and early biological treatment. The patients with ExRA had a 3-fold increase in mortality.

Keywords
ACPA, Disease modifying anti-rheumatic drugs, RF, Rheumatoid arthritis
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-224250 (URN)10.1016/j.ejim.2024.04.026 (DOI)2-s2.0-85192184871 (Scopus ID)
Funder
Swedish Research Council, K2013–52X-20307–07–3Swedish Research Council, 2018–02551Stiftelsen Konung Gustaf V:s 80-årsfondSwedish Rheumatism AssociationUmeå University
Available from: 2024-05-15 Created: 2024-05-15 Last updated: 2024-05-15
Lundtoft, C., Knight, A., Meadows, J. R. .., Karlsson, Å., Rantapää-Dahlqvist, S., Berglin, E., . . . Dahlqvist, J. (2024). The HLA region in ANCA-associated vasculitis: characterisation of genetic associations in a Scandinavian patient population. RMD Open, 10(2), Article ID e004039.
Open this publication in new window or tab >>The HLA region in ANCA-associated vasculitis: characterisation of genetic associations in a Scandinavian patient population
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2024 (English)In: RMD Open, E-ISSN 2056-5933, Vol. 10, no 2, article id e004039Article in journal (Refereed) Published
Abstract [en]

Objective: The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are inflammatory disorders with ANCA autoantibodies recognising either proteinase 3 (PR3-AAV) or myeloperoxidase (MPO-AAV). PR3-AAV and MPO-AAV have been associated with distinct loci in the human leucocyte antigen (HLA) region. While the association between MPO-AAV and HLA has been well characterised in East Asian populations where MPO-AAV is more common, studies in populations of European descent are limited. The aim of this study was to thoroughly characterise associations to the HLA region in Scandinavian patients with PR3-AAV as well as MPO-AAV.

Methods: Genotypes of single-nucleotide polymorphisms (SNPs) located in the HLA region were extracted from a targeted exome-sequencing dataset comprising Scandinavian AAV cases and controls. Classical HLA alleles were called using xHLA. After quality control, association analyses were performed of a joint SNP/classical HLA allele dataset for cases with PR3-AAV (n=411) and MPO-AAV (n=162) versus controls (n=1595). Disease-associated genetic variants were analysed for association with organ involvement, age at diagnosis and relapse, respectively.

Results: PR3-AAV was significantly associated with both HLA-DPB1*04:01 and rs1042335 at the HLADPB1 locus, also after stepwise conditional analysis. MPO-AAV was significantly associated with HLADRB1*04:04. Neither carriage of HLA-DPB1*04:01 alleles in PR3-AAV nor of HLA-DRB1*04:04 alleles in MPO-AAV were associated with organ involvement, age at diagnosis or relapse.

Conclusions: The association to the HLA region was distinct in Scandinavian cases with MPO-AAV compared with cases of East Asian descent. In PR3-AAV, the two separate signals of association to the HLD-DPB1 region mediate potentially different functional effects.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2024
National Category
Medical Genetics Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-223645 (URN)10.1136/rmdopen-2023-004039 (DOI)2-s2.0-85190319194 (Scopus ID)
Funder
Swedish Society for Medical Research (SSMF)Swedish Research Council, 2017-00650Swedish Society of MedicineSwedish Rheumatism AssociationStiftelsen Konung Gustaf V:s 80-årsfondKnut and Alice Wallenberg Foundation
Available from: 2024-04-23 Created: 2024-04-23 Last updated: 2024-04-23Bibliographically approved
Hedenstedt, A., Reid, S., Sayadi, A., Eloranta, M.-L., Skoglund, E., Bolin, K., . . . Leonard, D. (2023). B cell polygenic risk scores associate with anti-dsDNA antibodies and nephritis in systemic lupus erythematosus. Lupus Science and Medicine, 10(2), Article ID e000926.
Open this publication in new window or tab >>B cell polygenic risk scores associate with anti-dsDNA antibodies and nephritis in systemic lupus erythematosus
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2023 (English)In: Lupus Science and Medicine, E-ISSN 2053-8790, Vol. 10, no 2, article id e000926Article in journal (Refereed) Published
Abstract [en]

Objective. B cell function and autoantibodies are important in SLE pathogenesis. In this work, we aimed to investigate the impact of cumulative SLE B cell genetics on SLE subphenotype and autoantibody profile.

Methods: Female patients with SLE (n=1248) and healthy controls (n=400) were genotyped using Illumina's Global Screening Array. Two polygenic risk scores (PRSs), one representing B cell genes and the other B cell activation genes, were calculated for each individual using risk loci for SLE in genes assigned to B cell-related pathways according to the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and Reactome Databases.

Results: Double-stranded DNA (dsDNA) antibodies were more prevalent among patients with a high compared with a low SLE B cell PRS (OR 1.47 (1.07 to 2.01), p=0.018), and effect sizes were augmented in patients with human leucocyte antigen (HLA) risk haplotypes HLA-DRB1∗03:01 and HLA-DRB1∗15:01 (DRB1∗03/15-/-(OR 0.99 (0.56 to 1.77), p=0.98; DRB1∗03/15 +/-or-/+ (OR 1.64 (1.06 to 2.54), p=0.028; and DRB1∗03/15 +/+ (OR 4.47 (1.21 to 16.47), p=0.024). Further, a high compared with a low B cell PRS was associated with low complement levels in DRB1∗03/15 +/+ patients (OR 3.92 (1.22 to 12.64), p=0.022). The prevalence of lupus nephritis (LN) was higher in patients with a B cell activation PRS above the third quartile compared with patients below (OR 1.32 (1.00 to 1.74), p=0.048).

Conclusions: High genetic burden related to B cell function is associated with dsDNA antibody development and LN. Assessing B cell PRSs may be important in order to determine immunological pathways influencing SLE and to predict clinical phenotype.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2023
Keywords
Autoantibodies, B cells, Lupus Erythematosus, Systemic, Lupus Nephritis, Polymorphism, Genetic
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-216175 (URN)10.1136/lupus-2023-000926 (DOI)001083299300001 ()37844960 (PubMedID)2-s2.0-85175240098 (Scopus ID)
Funder
Swedish Society for Medical Research (SSMF), S20-0127Swedish Society of MedicineSwedish Rheumatism AssociationStiftelsen Konung Gustaf V:s 80-årsfondRegion Uppsala
Available from: 2023-11-10 Created: 2023-11-10 Last updated: 2023-11-10Bibliographically approved
Oddsson, A., Sulem, P., Sveinbjornsson, G., Arnadottir, G. A., Steinthorsdottir, V., Halldorsson, G. H., . . . Gudbjartsson, D. F. (2023). Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality. Nature Communications, 14(1), Article ID 3453.
Open this publication in new window or tab >>Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality
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2023 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 14, no 1, article id 3453Article in journal (Refereed) Published
Abstract [en]

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-211785 (URN)10.1038/s41467-023-38951-2 (DOI)001003866300016 ()37301908 (PubMedID)2-s2.0-85161942886 (Scopus ID)
Funder
The Research Council of Norway, 223273, 273291, 324252, 274611EU, Horizon 2020, 847776
Note

Correction: Oddsson, A., Sulem, P., Sveinbjornsson, G. et al. Publisher Correction: Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality. Nat Commun 14, 3923 (2023). DOI: 10.1038/s41467-023-39492-4

Available from: 2023-07-12 Created: 2023-07-12 Last updated: 2023-09-05Bibliographically approved
Lindquist, S., Wang, Y., Andersson, E.-L., Tsuji Grebe, S., Alenius, G.-M., Rantapää-Dahlqvist, S., . . . Hernell, O. (2023). Effects of bile salt-stimulated lipase on blood cells and associations with disease activity in human inflammatory joint disorders. PLOS ONE, 18(8), Article ID e0289980.
Open this publication in new window or tab >>Effects of bile salt-stimulated lipase on blood cells and associations with disease activity in human inflammatory joint disorders
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2023 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 18, no 8, article id e0289980Article in journal (Refereed) Published
Abstract [en]

The bile salt-stimulated lipase (BSSL) was originally recognized as a lipolytic enzyme expressed by the exocrine pancreas and in some species, notably humans, the lactating mammary gland, being secreted into the duodenum and with the mother’s milk, respectively. However, BSSL is also present in the blood and has been assigned additional functions, even beyond the gastrointestinal tract. Conventional BSSL knockout mice are protected from developing disease in animal models of arthritis, and antibodies directed towards BSSL prevent or mitigate disease in similar models. The aim of this study was to investigate the role of BSSL as a newly discovered player in inflammation and specifically in inflammatory joint disorders. As part of mechanism of action, we here show that BSSL is secreted by neutrophils, interacts with monocytes and stimulates their migration in vitro. An anti-BSSL antibody that blocks the human BSSL-monocyte interaction was shown to simultaneously prevent the signaling pathway by which BSSL induce cell migration. Moreover, in this cohort study we show that BSSL levels are significantly higher in blood samples from patients with rheumatoid arthritis and psoriatic arthritis compared to healthy controls. The BSSL levels in patients’ blood also correlated with disease activity scores and established inflammatory markers. Hence, although the mode of action is not yet fully clarified, we conclude that BSSL could be considered a proinflammatory component in the innate immune system and thus a possible novel target for treatment of chronic inflammation.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2023
National Category
Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-214042 (URN)10.1371/journal.pone.0289980 (DOI)001051705700041 ()37566600 (PubMedID)2-s2.0-85167768925 (Scopus ID)
Funder
Region Västerbotten
Available from: 2023-09-06 Created: 2023-09-06 Last updated: 2023-09-06Bibliographically approved
Boman, A., Kokkonen, H., Berglin, E., Alenius, G.-M. & Rantapää-Dahlqvist, S. (2023). Hormonal and reproductive factors in relation to cardiovascular events in women with early rheumatoid arthritis. Journal of Clinical Medicine, 12(1), Article ID 208.
Open this publication in new window or tab >>Hormonal and reproductive factors in relation to cardiovascular events in women with early rheumatoid arthritis
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2023 (English)In: Journal of Clinical Medicine, E-ISSN 2077-0383, Vol. 12, no 1, article id 208Article in journal (Refereed) Published
Abstract [en]

Hormonal and reproductive factors affect the risk for cardiovascular events (CVE) in the general population. Although the risk of CVE is increased in rheumatoid arthritis (RA), the knowledge about the impact of hormonal factors for CVE in RA is sparse. Female postmenopausal patients ≤80 years with early RA were consecutively included in this observational study (n = 803) between 1 January 1996 until 31 December 2017. Questionnaires regarding hormonal factors were distributed from the index date. Data regarding CVE were obtained from the Swedish National Health Register and Cause of Death Register. Associations between CVE and hormonal factors were analyzed using Cox proportional hazard regression. Of the postmenopausal women, 64 women had a CVE after RA onset. The time period from menopause to RA onset was significantly longer for CVE cases with higher proportion of postmenopausal women. In Cox proportional hazard regression models, years from last childbirth and multiparity were associated with higher CVE risk. Adjustments for traditional risk factors did not affect the results except for hypertension. RA onset after menopause and a longer duration from menopause until onset increased the CVE risk. Multiparity was associated with higher CVE risk whilst oral contraceptives decreased the risk. These results can contribute to identification of high-risk patients for CVE beyond traditional risk factors.

Place, publisher, year, edition, pages
MDPI, 2023
Keywords
cardiovascular disease, cardiovascular events, early rheumatoid arthritis, hormonal factors, reproductive factors, risk factors
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-213602 (URN)10.3390/jcm12010208 (DOI)000909098800001 ()36615009 (PubMedID)2-s2.0-85145986901 (Scopus ID)
Funder
Swedish Research Council, 2018-02551Stiftelsen Konung Gustaf V:s 80-årsfondSwedish Rheumatism AssociationUmeå University
Available from: 2023-08-29 Created: 2023-08-29 Last updated: 2023-08-29Bibliographically approved
Michailidou, D., Johansson, L., Kuley, R., Wang, T., Hermanson, P., Rantapää-Dahlqvist, S. & Lood, C. (2023). Immune complex-mediated neutrophil activation in patients with polymyalgia rheumatica. Rheumatology, 62(8), 2880-2886
Open this publication in new window or tab >>Immune complex-mediated neutrophil activation in patients with polymyalgia rheumatica
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2023 (English)In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 62, no 8, p. 2880-2886Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Neutrophils are important in host defence. However, neutrophils are also linked to inflammation and organ damage. The purpose of this study was to assess whether markers of neutrophil activation are increased in PMR.

METHODS: Levels of immune complexes (IC), calprotectin and neutrophil extracellular traps (NETs) were measured in plasma of healthy individuals (n = 30) and patients with PMR (n = 60), at flare and upon treatment with glucocorticoids using ELISA. Plasma-mediated neutrophil activation was assessed in presence of an FcγRIIA inhibitory antibody (IV.3).

RESULTS: Plasma levels of calprotectin and NETs were elevated in PMR (P < 0.001). Mechanistically, neutrophil activation was driven by ICs, present in plasma, able to up-regulate neutrophil activation markers CD66b and CD11b (P < 0.0001) in an FcγRIIA-dependent manner (P < 0.01). Of note, circulating levels of IC correlated with plasma induced CD66b and CD11b (r = 0.51, P = 0.004, and r = 0.46, P = 0.01, respectively) and decreased after glucocorticoid therapy. In contrast to NETs, calprotectin significantly decreased after glucocorticoid therapy (P < 0.001) and was higher in PMR without overlapping GCA compared with patients with overlapping disease (P = 0.014). Interestingly, musculoskeletal involvement was associated with elevated levels of calprotectin before initiation of glucocorticoid therapy (P = 0.036).

CONCLUSIONS: Neutrophil activation, including NET formation, is increased in PMR, through IC-mediated engagement of FcγRIIA. Clinically, neutrophil activation is associated with musculoskeletal involvement, with calprotectin, but not NETs, being a biomarker of treatment response in PMR patients. In all, IC-mediated neutrophil activation is a central process in PMR pathogenesis identifying potential novel therapeutic targets (FcγRIIA), as well as soluble markers for disease monitoring (calprotectin).

Place, publisher, year, edition, pages
Oxford University Press, 2023
Keywords
calprotectin, immune complexes, neutrophil extracellular traps, neutrophils, PMR
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-212736 (URN)10.1093/rheumatology/keac722 (DOI)000908331800001 ()36562570 (PubMedID)2-s2.0-85162077877 (Scopus ID)
Available from: 2023-08-14 Created: 2023-08-14 Last updated: 2023-08-14Bibliographically approved
Li, T., Ge, C., Krämer, A., Sareila, O., Leu Agelii, M., Johansson, L., . . . Holmdahl, R. (2023). Pathogenic antibody response to glucose-6-phosphate isomerase targets a modified epitope uniquely exposed on joint cartilage. Annals of the Rheumatic Diseases, 82(6), 799-808
Open this publication in new window or tab >>Pathogenic antibody response to glucose-6-phosphate isomerase targets a modified epitope uniquely exposed on joint cartilage
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2023 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 82, no 6, p. 799-808Article in journal (Refereed) Published
Abstract [en]

Objectives: To identify the arthritogenic B cell epitopes of glucose-6-phosphate isomerase (GPI) and their association with rheumatoid arthritis (RA).

Methods: IgG response towards a library of GPI peptides in patients with early RA, pre-symptomatic individuals and population controls, as well as in mice, were tested by bead-based multiplex immunoassays and ELISA. Monoclonal IgG were generated, and the binding specificity and affinity were determined by ELISA, gel size exclusion chromatography, surface plasma resonance and X-ray crystallography. Arthritogenicity was investigated by passive transfer experiments. Antigen-specific B cells were identified by peptide tetramer staining.

Results: Peptide GPI293-307 was the dominant B cell epitope in K/BxN and GPI-immunised mice. We could detect B cells and low levels of IgM antibodies binding the GPI293-307 epitopes, and high affinity anti-GPI293-307 IgG antibodies already 7 days after GPI immunisation, immediately before arthritis onset. Transfer of anti-GPI293-307 IgG antibodies induced arthritis in mice. Moreover, anti-GPI293-307 IgG antibodies were more frequent in individuals prior to RA onset (19%) than in controls (7.5%). GPI293-307-specific antibodies were associated with radiographic joint damage. Crystal structures of the Fab-peptide complex revealed that this epitope is not exposed in native GPI but requires conformational change of the protein in inflamed joint for effective recognition by anti-GPI293-307 antibodies.

Conclusions: We have identified the major pathogenic B cell epitope of the RA-associated autoantigen GPI, at position 293-307, exposed only on structurally modified GPI on the cartilage surface. B cells to this neo-epitope escape tolerance and could potentially play a role in the pathogenesis of RA.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2023
Keywords
arthritis, experimental, arthritis, rheumatoid, autoantibodies, autoimmunity, inflammation
National Category
Immunology in the medical area Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-206885 (URN)10.1136/ard-2022-223633 (DOI)000951597300001 ()36858822 (PubMedID)2-s2.0-85152199960 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2019.0059Swedish Research Council, 2019-01209Swedish Research Council, 2019- 01140Swedish Rheumatism Association, 931878Swedish Rheumatism Association, 757331
Available from: 2023-04-20 Created: 2023-04-20 Last updated: 2023-07-13Bibliographically approved
Projects
Aetio-patogenetic factors of importance for development of rheumatoid arthritis, disease severity and co-morbidity, in particular cardio-vascular disease [2009-03388_VR]; Umeå UniversityAetio-patogenetic factors of importance for development of rheumatoid arthritis, disease severity and co-morbidity, in particular cardio-vascular disease [2012-04096_VR]; Umeå UniversityAetio-pathogenic factors of importance for development of rheumatoid arthritis and of disease progression. Analyses of prospective material from biobanks of northern Sweden. [2018-02551_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8259-3863

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