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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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- 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: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 11010-
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Tidskriftsartikel (refereegranskat)abstract
- IgM antibodies against phosphorylcholine (anti-PC) and malondialdehyde (anti-MDA) may have protective properties in cardiovascular and rheumatic diseases. We here compare these antibodies in systemic rheumatic conditions and study their properties. 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. 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. Taken together, 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.
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- Thiagarajan, D, et al.
(författare)
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NATURAL ANTIBODIES AGAINST PHOSPHORYLCHOLINE AND MALONDIALDEHYDE DURING THE FIRST TWO YEARS OF LIFE: IMPLICATIONS FOR RHEUMATIC DISEASE
- 2020
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 1326-1326
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Antibodies against phosphorylcholine (anti-PC) have potentially protective properties in both atherosclerosis and rheumatic disease. IgM anti-PC could play a role in SLE being associated with protection, also in relation to atherosclerotic plaques and vulnerable plaques in SLE1and being a non-responder to biologics in RA.1We reported potential mechanisms by which anti-PC could be protective: 1:anti-inflammatory; 2: inhibits uptake of oxLDL in macrophages, 3: inhibits cell death.14: anti-PC (and anti-MDA) increases clearance of human dead cells which could be of importance not especially in SLE;25: anti-PC increases T regulatory cells in SLE-patients´ T cells from a low level and also in atherosclerosis, with implications for both conditions.3Also antibodies against malondialdehyde (anti-MDA) have interesting propertiesObjectives:It is not known how these antibodies develop early in life and what may cause low levels. The objective is to determine this.Methods:Antibodies were studied by ELISA in healthy pregnant women (n=105; Born into life study) and their newborn children. Women were recruited before conception. Informed consent, questionnaires from parents and plasma sample was collected from children at birth from cord blood, at 1-year and 2 years after birth. Extracted antibodies were compared using a proteomics de novo sequencing approach.Results:Children were born with very low levels of IgM anti-PC, while IgM anti-MDA was present at birth,. Both IgM anti-PC and anti-MDA increased during the first two years of life, but IgM anti-PC in contrast to IgM anti-MDA was still significantly lower than mothers´. IgG anti-PC decreased after 1 year, but reached similar levels as mothers´ after 2 years while IgG anti-MDA reached similar levels as mothers´ already after one year. Proteomics peptide sequencing analysis indicates large peptide sequence variation without specific clone expression during early stage of life compared to the adult stage for which specific peptide sequences dominated.Conclusion:IgM anti-PC levels develop much slower than anti-MDA and are still relatively low at 2 years. We hypothesize that anti-PC is developed by a combination of pre-programming and exposure to the external world, where infectious agents may play a role. For anti-MDA pre-programming is likely to play a major role and at an earlier stage than for anti-PC.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.Disclosure of Interests:Divya Thiagarajan: None declared, Susanna Lundström: None declared, Göran Pershagen: None declared, Catharina Almqvist Malmros: None declared, Ellika Andolf: None declared, Anna Hedman: None declared, Oscar Berg: None declared, Nina Oparina: 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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