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- Hagert, C., et al.
(författare)
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Chronic Active Arthritis Driven by Macrophages Without Involvement of T Cells : A Novel Experimental Model of Rheumatoid Arthritis
- 2018
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Ingår i: Arthritis & Rheumatology. - Hoboken : Wiley. - 2326-5191 .- 2326-5205 .- 1529-0131. ; 70:8, s. 1343-1353
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To develop a new chronic rheumatoid arthritis model that is driven by the innate immune system. METHODS: Injection of a cocktail of 4 monoclonal antibodies against type II collagen, followed on days 5 and 60 by intraperitoneal injections of mannan (from Saccharomyces cerevisiae), was used to induce development of chronic arthritis in B10.Q mice. The role of the innate immune system as compared to the adaptive immune system in this arthritis model was investigated using genetically modified mouse strains. RESULTS: A new model of chronic relapsing arthritis was characterized in B10.Q mice, in which a persistently active, chronic disease was found. This relapsing disease was driven by macrophages lacking the ability to mount a reactive oxygen species response against pathogens, and was associated with the classical/alternative pathway, but not the lectin pathway, of complement activation. The disease was independent of Fcgamma receptor type III, and also independent of the activity of adaptive immune cells (B and T cells), indicating that the innate immune system, involving complement activation, could be the sole driver of chronicity. CONCLUSION: Chronic active arthritis can be driven innately by macrophages without the involvement of T and B cells in the adaptive immune system.
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- Kelkka, T, et al.
(författare)
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Superoxide dismutase 3 limits collagen-induced arthritis in the absence of phagocyte oxidative burst
- 2012
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Ingår i: Mediators of inflammation. - : Hindawi Limited. - 1466-1861 .- 0962-9351. ; 2012, s. 730469-
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular superoxide dismutase (SOD3), an enzyme mediating dismutation of superoxide into hydrogen peroxide, has been shown to reduce inflammation by inhibiting macrophage migration into injured tissues. In inflamed tissues, superoxide is produced by the phagocytic NOX2 complex, which consists of the catalytic subunit NOX2 and several regulatory subunits (e.g., NCF1). To analyze whether SOD3 can regulate inflammation in the absence of functional NOX2 complex, we injected an adenoviral vector overexpressing SOD3 directly into the arthritic paws ofNcf1*/*mice with collagen-induced arthritis. SOD3 reduced arthritis severity in both oxidative burst-deficientNcf1*/*mice and also in wild-type mice. The NOX2 complex independent anti-inflammatory effect of SOD3 was further characterized in peritonitis, and SOD3 was found to reduce macrophage infiltration independently of NOX2 complex functionality. We conclude that the SOD3-mediated anti-inflammatory effect on arthritis and peritonitis operates independently of NOX2 complex derived oxidative burst.
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- Lonnblom, E, et al.
(författare)
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AUTOANTIBODIES TO JOINT PROTEINS AS NOVEL BIOMARKERS FOR THE DIAGNOSIS OF UNTREATED EARLY RHEUMATOID ARTHRITIS
- 2022
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 546-546
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Autoantibodies to citrullinated protein (ACPA; measured as anti-CCP; aCCP) and rheumatoid factor (RF) appear years before clinical onset of RA and are essential tools in today’s classification criteria for RA. In animal models, antibodies to joint specific proteins (JP) can induce arthritis, and they are also present at onset of RA [1]. As there is a need for increased precision for early diagnosis of RA as well as identification of different subtypes of the disease, we aim to assess whether autoantibodies to native or modified JP can be used for early and precise diagnosis of RA.ObjectivesTo study whether antibodies to JP, alone or in combination with ACPA/RF, could increase the diagnostic sensitivity and specificity in untreated early (ue)RA patients.MethodsAntibodies to JP were analysed in serum from patients in three independent ueRA cohorts as well as from population controls without rheumatic diseases (WINGA, Gothenburg and MFM-ÅUS, Malmö n=1062). ERAp (n=66), the smallest and most recent cohort was chosen for screening, and BARFOT and TIRA-2 (n=1939) for validation. We have developed a bead-based multianalyte flow immunoassay [2] and screened approx. 350 peptides derived from JPs of interest. We included monoclonal antibodies as assay calibrators and determined limit of detection (LoD). To assess positivity for autoantibodies to JP of interest above LoD, we used 5MAD (median absolute deviation) of the control populations as the cut-off.ResultsIn the ERAp cohort, 5 autoantibodies discriminated RA patients from controls with 81% sensitivity and 100% specificity (Table 1). The same autoantibodies had 68% sensitivity and 98% specificity in the combined BARFOT and TIRA-2 cohorts. Together with RF and aCCP, only 2 of the 5 autoantibodies added statistically significant diagnostic value, increasing the sensitivity from 48% to 61% with 99% specificity. In aCCP- and RF-negative ueRA patients (n=536), the novel biomarkers identified 22.5% of the patients with 99% specificity compared to controls.Table 1.Diagnostic capacity of the joint-specific antibodiesTest panelPerformanceGroup of patientsaCCP+RF+JP+SensitivitySpecificityAUC(ROC)ERApAll patients (n=66)--X81%100%89%RF and aCCP-neg patients (n=7)1------BARFOT and TIRA-2, combined dataAll patients (N=1939)--X68%98%86%All patients (N=1939)X--58%99%78%All patients (N=1939)2XX-48%100%84%All patients (N=1939)2, 3XXX61%99%86%RF and/or aCCP-pos patients (N=1403)--X84%99%93%RF and aCCP-neg patients (N=536)--X22%99%67%RA, literature valuesAnti-CCP testXN/AN/A53–71%95–96%N/A1Not analysed due to lack of power2This patient population is both aCCP+ and RF+3Only 2 of the 5 autoantibodies added statistically significant to the diagnostic valueAUC, Area under the curve; ROC, receiver operating characteristic curve; N/A, not applicable. Controls without rheumatic diseases: N=935 for BARFOT / TIRA-2 and N=27 for ERAp.ConclusionAutoantibodies to JP discriminate ueRA patients better then aCCP and RF alone and add an increased diagnostic value in particular for seronegative patients.References[1]Holmdahl, R., V. Malmstrom, and H. Burkhardt, Autoimmune priming, tissue attack and chronic inflammation - the three stages of rheumatoid arthritis. Eur J Immunol, 2014. 44(6): p. 1593-9.[2]Viljanen, J., et al., Synthesis of an Array of Triple-Helical Peptides from Type II Collagen for Multiplex Analysis of Autoantibodies in Rheumatoid Arthritis. ACS Chem Biol, 2020. 15(9): p. 2605-2615. Correction: ACS Chem Biol, 2020. 15(11): p. 3072AcknowledgementsBARFOT study group.Disclosure of InterestsErik Lönnblom: None declared, Monica Leu Agelii: None declared, Outi Sareila Employee of: Part time employee in Vacara AB, Ingiäld Hafström: None declared, Maria Andersson: None declared, Lei Cheng: None declared, Göran Bergström: None declared, Anna-Karin H Ekwall: None declared, Anna Rudin: None declared, Alf Kastbom: None declared, Christopher Sjowall: None declared, Bingze Xu: None declared, Lennart T.H. Jacobsson: None declared, Johan Viljanen: None declared, Jan Kihlberg: None declared, Inger Gjertsson: None declared, Rikard Holmdahl Shareholder of: Rikard Holmdahl the founder of Vacara AB.
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- Sareila, O, et al.
(författare)
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NOX2 complex-derived ROS as immune regulators
- 2011
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Ingår i: Antioxidants & redox signaling. - : Mary Ann Liebert Inc. - 1557-7716 .- 1523-0864. ; 15:8, s. 2197-2208
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Tidskriftsartikel (refereegranskat)
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