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Lloyd, K. A., Wigerblad, G., Sahlstrom, P., Garimella, M. G., Chemin, K., Steen, J., . . . Gronwall, C. (2019). Differential ACPA Binding to Nuclear Antigens Reveals a PAD-Independent Pathway and a Distinct Subset of Acetylation Cross-Reactive Autoantibodies in Rheumatoid Arthritis. Frontiers in Immunology, 9, 1-22, Article ID 3033.
Open this publication in new window or tab >>Differential ACPA Binding to Nuclear Antigens Reveals a PAD-Independent Pathway and a Distinct Subset of Acetylation Cross-Reactive Autoantibodies in Rheumatoid Arthritis
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 9, p. 1-22, article id 3033Article in journal (Refereed) Published
Abstract [en]

Rheumatoid arthritis (RA) associated anti-citrullinated protein autoantibodies (ACPA) target a wide range of modified proteins. Citrullination occurs during physiological processes such as apoptosis, yet little is known about the interaction of ACPA with nuclear antigens or apoptotic cells. Since uncleared apoptotic cells and neutrophil extracellular trap (NET) products have been postulated to be central sources of autoantigen and immunostimulation in autoimmune disease, we sought to characterize the anti-nuclear and anti-neutrophil reactivities of ACFA. Serology showed that a subset of anti-CCP2 seropositive RA patients had high reactivity to full-length citrullinated histones. In contrast, seronegative RA patients displayed elevated IgG reactivity to native histone compared to controls, but no citrulline-specific reactivity. Screening of 10 single B-cell derived monoclonal AGFA from RA patients revealed that four ACPA exhibited strong binding to apoptotic cells and three of these had anti-nuclear (ANA) autoantibody reactivity. Modified histones were confirmed to be the primary targets of this anti-nuclear ACPA subset following immunoprecipitation from apoptotic cell lysates. Monoclonal ACPA were also screened for reactivities against stimulated murine and human neutrophils, and all the nuclear-reactive monoclonal ACPA bound to NETs. Intriguingly, one ACPA mAb displayed a contrasting cytoplasmic perinuclear neutrophil binding and may represent a different NET-reactive ACPA subset. Notably, studies of CRISPR-Cas9 PAD4 KO cells and cells from PAD KO mice showed that the cytoplasmic NET-binding was fully dependent on PAD4, whilst nuclear- and histone-mediated NEI reactivity was largely PAD-independent. Our further analysis revealed that the nuclear binding could be explained by consensus-motif driven ACPA cross-reactivity to acetylated histones. Specific acetylated histone peptides targeted by the monoclonal antibodies were identified and the anti-modified protein autoantibody (AMPA) profile of the ACPA was found to correlate with the functional activity of the antibodies. In conclusion, when investigating monoclonal ACPA, we could group ACPA into distinct subsets based on their nuclear binding-patterns and acetylation-mediated binding to apoptotic cells, neutrophils, and NETs. Differential anti-modified protein reactivities of RA-autoantibody subsets could have an important functional impact and provide insights in RA pathogenesis.

Keywords
anti-citrullinated protein autoantibodies, acetylation, rheumatoid arthritis, anti-CCP, PAD4, apoptosis, neutrophil extracellular traps (NETs), ANA
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-374429 (URN)10.3389/fimmu.2018.03033 (DOI)000454910500001 ()30662440 (PubMedID)
Funder
Swedish Research CouncilSwedish Rheumatism Association
Available from: 2019-01-28 Created: 2019-01-28 Last updated: 2019-01-28Bibliographically approved
Tjärnlund, A., Rönnelid, J., Bottai, M. & Lundberg, I. E. (2019). Response to: ‘Detection of myositis-specific antibodies’ by Vulsteke et al [Letter to the editor]. Annals of the Rheumatic Diseases, 78(1), Article ID UNSP e8.
Open this publication in new window or tab >>Response to: ‘Detection of myositis-specific antibodies’ by Vulsteke et al
2019 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, no 1, article id UNSP e8Article in journal, Letter (Other academic) Published
Keywords
autoantibodies, disease activity, inflammation
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-343353 (URN)10.1136/annrheumdis-2018-212948 (DOI)000455953500008 ()29382639 (PubMedID)
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2019-02-05Bibliographically approved
Tjärnlund, A., Tang, Q., Wick, C., Dastmalchi, M., Mann, H., Studynkova, J. T., . . . Lundberg, I. E. (2018). Abatacept in the treatment of adult dermatomyositis and polymyositis: a randomised, phase IIb treatment delayed-start trial. Annals of the Rheumatic Diseases, 77(1), 55-62
Open this publication in new window or tab >>Abatacept in the treatment of adult dermatomyositis and polymyositis: a randomised, phase IIb treatment delayed-start trial
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2018 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 1, p. 55-62Article in journal (Refereed) Published
Abstract [en]

Objectives: To study the effects of abatacept on disease activity and on muscle biopsy features of adult patients with dermatomyositis (DM) or polymyositis (PM).

Methods: Twenty patients with DM (n=9) or PM (n=11) with refractory disease were enrolled in a randomised treatment delayed-start trial to receive either immediate active treatment with intravenous abatacept or a 3 month delayed-start. The primary endpoint was number of responders, defined by the International Myositis Assessment and Clinical Studies Group definition of improvement (DOI), after 6 months of treatment. Secondary endpoints included number of responders in the early treatment arm compared with the delayed treatment arm at 3 months. Repeated muscle biopsies were investigated for cellular markers and cytokines.

Results: 8/19 patients included in the analyses achieved the DOI at 6 months. At 3 months of study, five (50%) patients were responders after active treatment but only one (11%) patient in the delayed treatment arm. Eight adverse events (AEs) were regarded as related to the drug, four mild and four moderate, and three serious AEs, none related to the drug. There was a significant increase in regulatory T cells (Tregs), whereas other markers were unchanged in repeated muscle biopsies.

Conclusions: In this pilot study, treatment of patients with DM and PM with abatacept resulted in lower disease activity in nearly half of the patients. In patients with repeat muscle biopsies, an increased frequency of Foxp3(+) Tregs suggests a positive effect of treatment in muscle tissue.

Place, publisher, year, edition, pages
BMJ PUBLISHING GROUP, 2018
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-338993 (URN)10.1136/annrheumdis-2017-211751 (DOI)000417778700013 ()28993346 (PubMedID)
Funder
Swedish Research Council, GRANTK2014-52X-14045-14-3Swedish Rheumatism AssociationStockholm County CouncilThe Karolinska Institutet's Research Foundation
Available from: 2018-01-17 Created: 2018-01-17 Last updated: 2018-02-27Bibliographically approved
Manivel, V. A., van der Woude, D., Toes, R., Filer, A., Raza, K. & Rönnelid, J. (2018). Antibodies against collagen type II are not a general marker of acute arthritis onset [Letter to the editor]. Annals of the Rheumatic Diseases, 77(6), 954-956
Open this publication in new window or tab >>Antibodies against collagen type II are not a general marker of acute arthritis onset
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2018 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, no 6, p. 954-956Article in journal, Letter (Other academic) Published
Keywords
autoantibodies, disease activity, early rheumatoid arthritis, gout, reactive arthritis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-343356 (URN)10.1136/annrheumdis-2017-211974 (DOI)000433228800036 ()28839108 (PubMedID)
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-12-10Bibliographically approved
Too, C. L., Manivel, V. A., Persinidou, E., Rönnelid, J. & Murad, S. (2018). ANTI-COLLAGEN TYPE II ANTIBODIES ARE ASSOCIATED WITH EARLY INFLAMMATION IN MALAYSIAN RHEUMATOID ARTHRITIS PATIENTS WITH THREE DIFFERENT ETHINICITIES. Paper presented at 38th European Workshop on Rheumatology Research, FEB 22-24, 2018, Geneva, SWITZERLAND. Annals of the Rheumatic Diseases, 77, A32-A33
Open this publication in new window or tab >>ANTI-COLLAGEN TYPE II ANTIBODIES ARE ASSOCIATED WITH EARLY INFLAMMATION IN MALAYSIAN RHEUMATOID ARTHRITIS PATIENTS WITH THREE DIFFERENT ETHINICITIES
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2018 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, p. A32-A33Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
BMJ PUBLISHING GROUP, 2018
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-357184 (URN)000429442700068 ()
Conference
38th European Workshop on Rheumatology Research, FEB 22-24, 2018, Geneva, SWITZERLAND
Available from: 2018-08-14 Created: 2018-08-14 Last updated: 2018-08-14Bibliographically approved
Baecklund, E., Backlin, C., Rönnelid, J., Toes, R., Huizinga, T., Åhlin, E., . . . Smedby, K. E. (2018). Anti-cyclic citrullinated peptide antibodies, other common autoantibodies, and smoking as risk factors for lymphoma in patients with rheumatoid arthritis. Scandinavian Journal of Rheumatology, 47(4), 270-275
Open this publication in new window or tab >>Anti-cyclic citrullinated peptide antibodies, other common autoantibodies, and smoking as risk factors for lymphoma in patients with rheumatoid arthritis
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2018 (English)In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 47, no 4, p. 270-275Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Patients with rheumatoid arthritis (RA) are at increased risk of lymphoma. There is no biomarker to indicate future lymphoma risk in RA and it is not known whether factors associated with an increased risk of RA also confer an increased risk of lymphoma. We investigated whether anti-cyclic citrullinated peptide (CCP) antibodies, other autoantibodies, and smoking, are associated with lymphoma development in RA.

METHOD: subclasses of anti-CCP antibodies and for 15 antinuclear antibody (ANA)-associated specific autoantibodies. Relative risks were estimated as crude and adjusted odds ratios (adjOR) with 95% confidence intervals (CIs) using logistic regression.

RESULTS: We found no association between anti-CCP IgG ≥ 25 units/mL (adjOR 1.4, 95% CI 0.7-2.7), anti-CCP IgG ≥ 500 units/mL (adjOR 1.4, 95% CI 0.7-3.0), anti-CCP Ig of other isotypes, other autoantibodies (adjOR any vs none 0.6, 95% CI 0.3-1.2), or cigarette smoking (adjOR ever vs never 1.1, 95% CI 0.5-2.2) and lymphoma risk among patients with RA.

CONCLUSION: In this study, neither anti-CCP antibodies (IgG, IgG1–4, IgM, or IgA), nor other common autoantibodies, nor smoking predicted lymphoma risk in RA

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-342980 (URN)10.1080/03009742.2017.1376108 (DOI)000438147400002 ()29336646 (PubMedID)
Funder
Swedish Cancer SocietyThe King Gustaf V's Jubilee Foundation
Available from: 2018-02-24 Created: 2018-02-24 Last updated: 2018-09-14Bibliographically approved
Rönnelid, J. (2018). Autoantibody standardisation in rheumatic diseases. the role of the european consensus finding study group on autoantibodies in rheumatic diseases (ECFSG). Paper presented at Congress of the European-League-Against-Rheumatism (EULAR), JUN 13-16, 2018, Amsterdam, NETHERLANDS. Annals of the Rheumatic Diseases, 77, 29-29
Open this publication in new window or tab >>Autoantibody standardisation in rheumatic diseases. the role of the european consensus finding study group on autoantibodies in rheumatic diseases (ECFSG)
2018 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, p. 29-29Article 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-368385 (URN)10.1136/annrheumdis-2018-eular.7708 (DOI)000444351000108 ()
Conference
Congress of the European-League-Against-Rheumatism (EULAR), JUN 13-16, 2018, Amsterdam, NETHERLANDS
Available from: 2018-12-04 Created: 2018-12-04 Last updated: 2018-12-04Bibliographically approved
Westman, G., Sohrabian, A., Aurelius, E., Ahlm, C., Schliamser, S., Sund, F., . . . Rönnelid, J. (2018). Clinical significance of IgM and IgA class anti-NMDAR antibodies in herpes simplex encephalitis. Journal of Clinical Virology, 103, 75-80
Open this publication in new window or tab >>Clinical significance of IgM and IgA class anti-NMDAR antibodies in herpes simplex encephalitis
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2018 (English)In: Journal of Clinical Virology, ISSN 1386-6532, E-ISSN 1873-5967, Vol. 103, p. 75-80Article in journal (Refereed) Published
Abstract [en]

Background: Herpes simplex encephalitis (HSE) is a devastating disease, often leaving patients with severe disabilities. It has been shown that IgG anti-N-methyl-o-aspartate receptor (NMDAR) antibodies appear in approximately 25% of HSE patients and could be associated with impaired recovery of cognitive performance.

Objectives: To characterize the prevalence of IgM and IgA anti-NMDAR antibodies in HSE patients, in relation to subsequent development of IgG anti-NMDAR and correlation to cognitive performance.

Study design: A total of 48 subjects were included from a previously described cohort of patients with HSE verified by HSV-1 PCR. Cerebrospinal fluid (CSF) and serum samples drawn close to onset of disease, after 14-21 days of iv aciclovir treatment and after 90 days of follow-up, were analyzed for the presence of IgM and IgA anti-NMDAR, and related to IgG anti-NMDAR. Antibody levels were correlated to the recovery of cognitive performance, as estimated by the Mattis Dementia Rating Scale (MDRS), for a total of 24 months.

Results: In total, 27 of 48 (56%) study subjects were anti-NMDAR positive, defined as the presence of IgG (12/ 48, 25%), IgM (14/48, 29%) or IgA (13/48, 27%) antibodies in CSF and/or serum. IgM or IgA anti-NMDAR did not predict subsequent IgG autoimmunization and did not correlate to cognitive outcome. IgG anti-NMDAR serostatus, but not antibody titers, correlated to impaired recovery of cognitive performance.

Conclusions: A majority of HSE patients develop IgG, IgM or IgA anti-NMDAR antibodies. However, the predictive value and clinical relevance of non-IgG isotypes remains to be shown in this setting.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2018
Keywords
Herpes simplex encephalitis, HSV-1, N-methyl-D-aspartate receptor antibodies, NMDAR, IgA, IgM
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-356622 (URN)10.1016/j.jcv.2018.04.007 (DOI)000432698300014 ()29698873 (PubMedID)
Funder
Fredrik och Ingrid Thurings Stiftelse
Available from: 2018-08-02 Created: 2018-08-02 Last updated: 2018-08-02Bibliographically approved
Frodlund, M., Vikerfors, A., Grosso, G., Skogh, T., Wetterö, J., Elvin, K., . . . Sjöwall, C. (2018). Immunoglobulin A anti-phospholipid antibodies in Swedish cases of systemic lupus erythematosus: associations with disease phenotypes, vascular events and damage accrual. Clinical and Experimental Immunology, 194(1), 27-38
Open this publication in new window or tab >>Immunoglobulin A anti-phospholipid antibodies in Swedish cases of systemic lupus erythematosus: associations with disease phenotypes, vascular events and damage accrual
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2018 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 194, no 1, p. 27-38Article in journal (Refereed) Published
Abstract [en]

Immunoglobulin (Ig) G- and IgM-class anti-cardiolipin antibodies (aCL) and lupus anti-coagulant (LA) are included in the 1997 update of the American College of Rheumatology (ACR-97) systemic lupus erythematosus (SLE) criteria. Despite limited evidence, IgA-aCL and IgA anti-(2)-glycoprotein-I (anti-(2)GPI) were included in the 2012 Systemic Lupus International Collaborating Clinics criteria. The present study aimed to evaluate IgG-/IgA-/IgM-aCL and anti-(2)GPI occurrence in relation to disease phenotype, smoking habits, pharmacotherapy, anti-phospholipid syndrome (APS) and organ damage among 526 Swedish SLE patients meeting ACR-97. Patients with rheumatoid arthritis (n=100), primary Sjogren's syndrome (n=50) and blood donors (n=507) served as controls. Anti-phospholipid antibodies (aPL) were analysed by fluoroenzyme-immunoassays detecting aCL/anti-(2)GPI. Seventy-six (14%) SLE cases fulfilled the Sydney APS-criteria, and 1 aCL/anti-(2)GPI isotype (IgG/IgA/IgM) occurred in 138 SLE patients (26%). Forty-five (9%) of the SLE cases had IgA-aCL, 20 of whom (4%) lacked IgG-/IgM-aCL. Seventy-four (14%) tested positive for IgA anti-(2)GPI, 34 (6%) being seronegative regarding IgG/IgM anti-(2)GPI. Six (1%) had APS manifestations but were seropositive regarding IgA-aCL and/or IgA anti-(2)GPI in the absence of IgG/IgM-aPL and LA. Positive LA and IgG-aPL tests were associated with most APS-related events and organ damage. Exclusive IgA anti-(2)GPI occurrence associated inversely with Caucasian ethnicity [odds ratio (OR)=021, 95% confidence interval (CI)=006-072) and photosensitivity (OR=019, 95% CI=005-072). Nephritis, smoking, LA-positivity and statin/corticosteroid-medication associated strongly with organ damage, whereas hydroxychloroquine-medication was protective. In conclusion, IgA-aPL is not rare in SLE (16%) and IgA-aPL analysis may have additional value among SLE cases with suspected APS testing negative for other isotypes of aPL and LA.

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
anti-phospholipid antibodies, anti-phospholipid syndrome, autoantibodies, immunoglobulin A, systemic lupus erythematosus
National Category
Rheumatology and Autoimmunity Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-363214 (URN)10.1111/cei.13180 (DOI)000445601500004 ()30208508 (PubMedID)
Funder
Swedish Research CouncilSwedish Society for Medical Research (SSMF)Swedish Society of MedicineSwedish Rheumatism AssociationSwedish Heart Lung FoundationStockholm County Council
Available from: 2018-10-17 Created: 2018-10-17 Last updated: 2018-10-17Bibliographically approved
Frodlund, M., Vikerfors, A., Elvin, K., Rönnelid, J., Svenungsson, E. & Sjowall, C. (2018). Immunoglobulin A anti-phospholipid antibodies in Swedish cases with systemic lupus erythematosus: associations with disease phenotypes, vascular events, and damage accrual. Scandinavian Journal of Rheumatology, 47, 48-48
Open this publication in new window or tab >>Immunoglobulin A anti-phospholipid antibodies in Swedish cases with systemic lupus erythematosus: associations with disease phenotypes, vascular events, and damage accrual
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2018 (English)In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 47, p. 48-48Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2018
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-363888 (URN)000442295400073 ()
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2018-11-12Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-1186-3226

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