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- Thiagarajan, D, et al.
(författare)
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IGG1 ANTIBODIES AGAINST PHOSPHORYLCHOLINE ARE NEGATIVELY ASSOCIATED WITH DISEASE ACTIVITY, DISEASE DAMAGE, CARDIOVASCULAR DISEASE AND ATHEROSCLEROSIS IN SLE: POTENTIAL UNDERLYING MECHANISMS.
- 2020
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 338-339
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Phosphorylcholine (PC) is an important component in cellular membranes and in lipoproteins that is exposed and recognized by the immune system, when cells undergo apoptosis or lipoproteins like LDL undergo oxidation. PC is also exposed in some microorganisms including nematodes and bacteria (non-self). We reported that IgM anti-PC is associated with protection in atherosclerosis, SLE, RA and other chronic inflammatory conditions.1We also reported potential underlying protective mechanisms: 1: increase in clearance of human dead cells,22: inhibition of uptake of oxLDL in macrophages, 3: inhibition of cell death.14: anti-inflammatory; 5: promotion of polarization of T regulatory cells in SLE-patients´ T cells from a low level and also in plaque T cells.3We generated in-house fully human IgG1 anti-PC clones for experimental studies to study anti-PC properties in humans. In contrast to mice, anti-PC are not germ-line encoded with a dominant clone.4Objectives:We here study IgG1 and IgG2 anti-PC, with focus on atherosclerosis and SLE and properties of fully human IgG1 clones, in relation to SLE.Methods:We determined anti-PC by ELISA in 116 SLE-patients and 110 age- and sex-matched controls. For functional studies, we used three in-house generated, fully human monoclonal IgG1 anti-PC (A01, D05, E01). Apoptosis was induced in Jurkat T-cells and pre-incubated with A01, D05, E01 or isotype control IgG1 and effects on efferocytosis by human macrophages studied. Anti-PC peptide/protein characterization was determined using a proteomics de novo sequencing approach.Results:IgG1 but not IgG2 anti-PC levels were higher among SLE patients (p=0.02). IgG1 anti-PC was negatively associated with SLICC and SLEDAI (OR: 2,978 CI: 0.876-10.098, OR: 5.108 CI 1.3 20.067 respectively) and negatively associated with CVD, atherosclerotic plaques and echolucent (potentially vulnerable plaques) but the association for the two former was not significant after controlling for confounders. D05 had maximum effect on macrophage efferocytosis efficiency, followed by A01 and E01. The monoclonal antibodies showed differential binding specificity to PC and PC associated neo-epitopes. Peptide analysis showed difference in the CDR3 region of the three anti-PC IgG1 clones which are crucial for recognition of PC on apoptotic cell surface and other neo-epitopes.Conclusion:Anti-PC IgG1 is negatively associated with disease activity, and disease damage in SLE, but the negative association with CVD is also dependent on confounding risk factors. One potential underlying mechanism could be increased clearance of dead cells.References:[1]Frostegard J. Immunity, atherosclerosis and cardiovascular disease.BMC Med. 2013;11:117.[2]Rahman M, Sing S, Golabkesh Z, Fiskesund R, Gustafsson T, Jogestrand T, Frostegard AG, Hafstrom I, Liu A and Frostegard J. IgM antibodies against malondialdehyde and phosphorylcholine are together strong protection markers for atherosclerosis in systemic lupus erythematosus: Regulation and underlying mechanisms.Clin Immunol. 2016;166-167:27-37.[3]Sun J, Lundstrom SL, Zhang B, Zubarev RA, Steuer J, Gillgren P, Rahman M, Ajeganova S, Liu A and Frostegard J. IgM antibodies against phosphorylcholine promote polarization of T regulatory cells from patients with atherosclerotic plaques, systemic lupus erythematosus and healthy donors.Atherosclerosis. 2018;268:36-48.[4]Fiskesund R, Steen J, Amara K, Murray F, Szwajda A, Liu A, Douagi I, Malmstrom V and Frostegard J. Naturally occurring human phosphorylcholine antibodies are predominantly products of affinity-matured B cells in the adult.J Immunol. 2014;192:4551-9.Disclosure of Interests: :Divya Thiagarajan: None declared, Roland Fiskesund: None declared, Johanna Steen: None declared, Mizanur Rahman: None declared, Susanna Lundström: None declared, Johan Frostegård Grant/research support from: Unconditional competitive grant from Amgen, related only to PCSK9, not the topic of this abstract
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- Thiagarajan, D, et al.
(författare)
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IGM ANTIBODIES AGAINST MALONDIALDEHYDE AND PHOSPHORYLCHOLINE IN DIFFERENT SYSTEMIC RHEUMATIC DISEASES
- 2020
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 571-571
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- IgM antibodies against phosphorylcholine (anti-PC) and malondialdehyde (anti-MDA) may have protective properties in both atherosclerosis and rheumatic disease, especially anti-PC. Low levels of IgM anti-PC is associated with SLE itself and also with atherosclerotic plaques1and with being a non-responder to biologics in RA.1We determined mechanisms by which anti-PC (and to some extent anti-MDA) could be protective: 1: anti-inflammatory; 2: inhibition of uptake of oxLDL in macrophages, 3: inhibition of cell death.14: increase in clearance of human dead cells,25: anti-PC promotes polarization of T regulatory cells in SLE-patients´ T cells from a low level and also in cells from atherosclerotic plaques.3Objectives:To compare systemic rheumatic diseases in relation to natural anti-PC and anti-MDA, to develop novel classifications but also potential treatment against rheumatic disease. We here determine anti-PC and anti-MDA in different systemic rheumatic conditions and study there potential role properties.Methods:Anti-PC and anti-MDA was measured using ELISA in patients with SLE (374), RA (354), Mixed connective tissue disease (MCTD, 77), Systemic sclerosis (SSc, 331), Sjögren’s syndrome (SjS, 324), primary antiphospholipid syndrome (PAPs, 65), undifferentiated connective tissue disease (UCTD, 118) and 515 matched healthy controls (HC). Cardiovascular score (CV) was broadly defined based on clinical disease symptoms. Anti-PC and anti-MDA peptide/protein characterization were compared using a proteomics de novo sequencing approach. anti-MDA and anti-PC were extracted from total IgM. The proportion of Treg cells was determined by flow cytometry.Results:The maximal difference between cases and controls was shown for MCTD: significantly lower IgM Anti-PC but not anti-MDA among patients (median 49.3RU/ml vs 70.4 in healthy controls, p(t-test)=0.0037). IgM low levels were more prevalent in MCTD, SLE, SjS, SSc and UCTD. IgM anti-PC variable region profiles were different from and more homologous than anti-MDA. Anti-PC but not anti-MDA were significantly negatively correlated with CV in the whole patient group. In contrast to IgM anti-PC, anti-MDA did not promote polarization of Tregs.Conclusion:Anti-PC is decreased in MCTD and also in SLE, SjS and SSc but not in other studied diseases. Anti-PC may thus differentiate between these. In contrast, anti-MDA did not show these differences between diseases studied. Anti-PC level is negatively correlated with CV in the patient group cohort. In contrast to anti-PC, anti-MDA did not promote Treg polarization. These findings could have both diagnostic and therapeutic implications, one possibility being active or passive immunization with PC in some rheumatic conditions.References:[1]Frostegard J. Immunity, atherosclerosis and cardiovascular disease.BMC Med. 2013;11:117.[2]Rahman M, Sing S, Golabkesh Z, Fiskesund R, Gustafsson T, Jogestrand T, Frostegard AG, Hafstrom I, Liu A and Frostegard J. IgM antibodies against malondialdehyde and phosphorylcholine are together strong protection markers for atherosclerosis in systemic lupus erythematosus: Regulation and underlying mechanisms.Clin Immunol. 2016;166-167:27-37.[3]Sun J, Lundstrom SL, Zhang B, Zubarev RA, Steuer J, Gillgren P, Rahman M, Ajeganova S, Liu A and Frostegard J. IgM antibodies against phosphorylcholine promote polarization of T regulatory cells from patients with atherosclerotic plaques, systemic lupus erythematosus and healthy donors.Atherosclerosis. 2018;268:36-48.Acknowledgments:Preciseads Clinical ConsortiumDisclosure of Interests:Divya Thiagarajan: None declared, Susanna Lundström: None declared, Roman Zubarev: None declared, jitong Sun: None declared, Marta Alarcon-Riquelme: None declared, Johan Frostegård Grant/research support from: Unconditional competitive grant from Amgen, related only to PCSK9, not the topic of this abstract
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- Ajeganova, S, et al.
(författare)
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HIGHER LEVELS OF NATURAL ANTI-PHOSPHORYLCHOLINE ANTIBODIES ARE ASSOCIATED WITH LOWER RISK OF INCIDENT CARDIOVASCULAR EVENTS IN YOUNGER PATIENTS WITH RHEUMATOID ARTHRITIS
- 2020
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 939-939
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The increased cardiovascular (CV) risk in rheumatoid arthritis (RA), especially in seropositive RA, is not fully explained by traditional risk factors. Immuno-inflammatory mechanisms and autoantibodies could be involved in the pathogenesis of atherosclerotic disease. Recent studies have suggested that anti-phosporylcholine antibodies (anti-PC) of IgM subclass counteract the generation of senescent and IL-17+ T-cells, have atheroprotective effects and may play a role in formation and stabilization of atherosclerotic plaque.Objectives:To investigate the association between IgM anti-PC antibodies with cardiovascular (CV) morbidity in patients with RA in age and sex groups and by serostatus.Methods:The study population was derived from the BARFOT early RA cohort, recruited in 1994-1999. The outcome was CV events i.e. AMI, angina pectoris, coronary intervention, ischemic stroke and TIA tracked through the Swedish Hospital Discharge and the National Cause of Death Registries. The RA-disease measures and traditional risk factors were assessed according to the protocol. Sera collected at inclusion and the 2-year visit were analyzed with ELISA to determine levels of anti-PC IgM (Athera CVDefine kit, Athera Biotechnologies AB). The Kaplan-Meier estimates and Cox proportional-hazards regression models were applied. Analysis were stratified by median level of IgM anti-PC and performed within strata of age, sex and RA-autoantibodies.Results:In all, 654 patients with early RA, 68% women, mean (SD) age 55(14.7) years, DAS28 5.2(1.3), 60% RF-positive and 60% ACPA-positive without prevalent CVD were included in this analysis. The level of IgM anti-PC at baseline was median (IQR) of 60.9(36.4-94.9) and at 2 years 56.0(32.3-84.2) U/ml. During follow-up of > 10 years, 141 incident CV events (21.6%) were registered. The levels of anti-PC both at inclusion and after 2 years of observation were lower in participants who experienced CV event than in those who did not, p=0.020 and p=0.012.The CV event-free survival differed between patients with levels of anti-PC above median compared with those with levels below, p=0.003 by log-rank test. The risk for incident CV event showed a 0.6-fold hazard (95% CI, 0.4-0.8) among patients with higher anti-PC levels as compared with those with lower levels, p=0.003. In the age groups, the risk for incident CV event was lower in patients aged <55 years at inclusion than in those who were older, hazard ratio (HR) 0.40 (0.17-0.94), p=0.036. This result persisted when adjusted for sex and all traditional risk factors, HR 0.36 (0.14-0.92), p=0.032. Also, the risk for incident CV events was lower in patients with higher anti-PC levels in females, HR 0.61 (0-39-0.45), and double RF- and ACPA- negative patients, 0.44 (0.21-0.90), in crude analyses.The favourable effect of anti-PC at baseline and the CV outcome was not observed in ages >55 years, males, ACPA+ and RF+ patients. There were no significant association between anti-PC level at 2 years and outcome.Conclusion:These results suggest that higher levels of IgM anti-PC are associated with a lower risk of incident CV events over 10 years in younger patients. The favourable atheroprotective effect of IgM anti-PC may be a part of explanation of lower risk of atherosclerotic disease in younger persons, females and in those with seronegative RA.Acknowledgments :6th Framework Program of the European Union (grant LSHM-CT-2006-037227 CVDIMMUNE)Disclosure of Interests:Sofia Ajeganova: None declared, Maria Andersson: None declared, Johan Frostegård Grant/research support from: Unconditional competitive grant from Amgen, related only to PCSK9, not the topic of this abstract, Ingiäld Hafström: None declared
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- Ajeganova, S, et al.
(författare)
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Patients with SLE have higher risk of cardiovascular events and mortality in comparison with controls with the same levels of traditional risk factors and intima-media measures, which is related to accumulated disease damage and antiphospholipid syndrome: a case-control study over 10 years
- 2021
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Ingår i: Lupus science & medicine. - : BMJ. - 2053-8790. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- SLE is a strong risk factor for premature cardiovascular (CV) disease and mortality. We investigated which factors could explain poor prognosis in SLE compared with controls.MethodsPatients with SLE and population controls without history of clinical CV events who performed carotid ultrasound examination were recruited for this study. The outcome was incident CV event and death. Event-free survival rates were compared using Kaplan-Meier curves. Relative HR (95% CI) was used to estimate risk of outcome.ResultsPatients (n=99, 87% female), aged 47 (13) years and with a disease duration of 12 (9) years, had mild disease at inclusion, Systemic Lupus Erythematosus Diseases Activity Index score of 3 (1–6) and Systemic Lupus International Collaborating Clinics (SLICC) Damage Index score of 0 (0–1). The controls (n=109, 91% female) were 49 (12) years old. Baseline carotid intima-media thickness (cIMT) did not differ between the groups, but plaques were more prevalent in patients (p=0.068). During 10.1 (9.8-10.2) years, 12 patients and 4 controls reached the outcome (p=0.022). Compared with the controls, the risk of the adverse outcome in patients increased threefold to fourfold taking into account age, gender, history of smoking and diabetes, family history of CV, baseline body mass index, waist circumference, C reactive protein, total cholesterol, high-density lipoprotein, low-density lipoprotein, dyslipidaemia, cIMT and presence of carotid plaque. In patients, higher SLICC score and SLE-antiphospholipid syndrome (SLE-APS) were associated with increased risk of the adverse outcome, with respective HRs of 1.66 (95% CI 1.20 to 2.28) and 9.08 (95% CI 2.71 to 30.5), as was cIMT with an HR of 1.006 (95% CI 1.002 to 1.01). The combination of SLICC and SLE-APS with cIMT significantly improved prediction of the adverse outcome (p<0.001).ConclusionIn patients with mild SLE of more than 10 years duration, there is a threefold to fourfold increased risk of CV events and death compared with persons who do not have SLE with similar pattern of traditional CV risk factors, cIMT and presence of carotid plaque. SLICC, SLE-APS and subclinical atherosclerosis may indicate a group at risk of worse outcome in SLE.
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- Ajeganova, S, et al.
(författare)
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Similar progression of carotid intima-media thickness in 7-year surveillance of patients with mild SLE and controls, but this progression is still promoted by dyslipidaemia, lower HDL levels, hypertension, history of lupus nephritis and a higher prednisolone usage in patients
- 2020
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Ingår i: Lupus science & medicine. - : BMJ. - 2053-8790. ; 7:1, s. e000362-
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Tidskriftsartikel (refereegranskat)abstract
- To compare progression of subclinical atherosclerosis and factors promoting it in patients with SLE and controls.MethodsConsecutive patients with SLE and age-matched, sex-matched population controls from the SLEVIC cohort were assessed at inclusion and after 7 years with standardised data collection and carotid ultrasound. Effect of risk factors on carotid intima–media thickness (cIMT) progression was examined with adjusted linear mixed models.ResultsA total of 77 patients and 74 controls, 68% and 61% of the original cohort, completed follow-up. The patients were (mean) 47 years old, 90% were women, and controls were 51 years old, 92% women. Patients had disease duration of (mean) 11 years, mild disease activity and low severity at both assessments. Baseline cIMT did not differ between the groups. An average absolute cIMT progression was 0.009 mm/year in patients and 0.011 mm/year in controls, intergroup difference p=0.9.Of factors at inclusion, dyslipidaemia, lower levels of high-density lipoprotein (HDL) and carotid plaque in patients and controls, and higher systolic blood pressure, total cholesterol:HDL and LDL:HDL ratios and triglycerides in patients were associated with cIMT progression. Of factors at follow-up, hypertension and blood lipids in patients and HDL in controls were significantly associated with cIMT progression. History of lupus nephritis and a higher average dose of prednisolone used since diagnosis were associated with cIMT progression in patients. Associations of risk factors with cIMT progression were stronger in presence of plaques.ConclusionWe observed a statistically comparable progression of cIMT in patients with mild SLE and controls over 7 years, which implies that progression of subclinical atherosclerosis in some patients with SLE could follow that of the general population. Traditional cardiovascular (CV) risk factors, history of lupus nephritis and higher use of corticosteroids promote cIMT progression in SLE. Detection of carotid plaque may add to CV risk stratification.
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