Atherosclerosis

2018

DOI: 10.1016/j.atherosclerosis.2017.11.010

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IgM antibodies against phosphorylcholine promote polarization of T regulatory cells from patients with atherosclerotic plaques, systemic lupus erythematosus and healthy donors

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Susanna L. Lundström

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Studies Of T-regulatory Cells1

Igm Protein and Peptide Characterization Sample Preparation1

Proteomic Comparative Analysis Of Polyclonal Anti-pc and Ant1

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Cited by 36 publications

(29 citation statements)

References 43 publications

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“…In our study the levels of Tregs were normalized by IgM anti-PC treatment which was raised to the same levels as healthy controls 28 . Tregs are known to be decreased in MCTD and could be a contributing factor in disease pathogenesis and development 41 .…”

Section: Discussionmentioning

confidence: 52%

“…www.nature.com/scientificreports www.nature.com/scientificreports/ regulatory cells, both in from atherosclerotic plaques and SLE-patients 28 . In SLE, Tregs were lower than among controls which is in line with previous studies where Tregs were negatively associated with SLE 40 .…”

Section: Discussionmentioning

confidence: 99%

“…Generation of Tregs were performed as described previously 28 . Briefly, peripheral blood mononuclear cells (PBMCs) were isolated from healthy donors, according to the manufacturer's protocol (Ficoll-Paque PLUS, GE Healthcare, Buckinghamshire, United Kingdom).…”

Section: Studies Of T-regulatory Cellsmentioning

confidence: 99%

“…ing of the anti-MDA and the anti-PC IgM samples have been described elsewhere 15,28 . Data processing was performed using Spotlight proteomics approach 29 .…”

Section: Igm Protein and Peptide Characterization Sample Preparationmentioning

confidence: 99%

“…We have previously published quantitative LC-MS/MS peptide sequencing data from the anti-PC variable region 28 and the anti-MDA variable region 15 .…”

Section: Proteomic Comparative Analysis Of Polyclonal Anti-pc and Antmentioning

confidence: 99%

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IgM antibodies against malondialdehyde and phosphorylcholine in different systemic rheumatic diseases

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et al. 2020

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the pReciSeSADS clinical consortium*, Marta Alarcon-Riquelme 1,3 & Johan frostegård 1 ✉ 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.

“…In our study the levels of Tregs were normalized by IgM anti-PC treatment which was raised to the same levels as healthy controls 28 . Tregs are known to be decreased in MCTD and could be a contributing factor in disease pathogenesis and development 41 .…”

Section: Discussionmentioning

confidence: 52%

“…www.nature.com/scientificreports www.nature.com/scientificreports/ regulatory cells, both in from atherosclerotic plaques and SLE-patients 28 . In SLE, Tregs were lower than among controls which is in line with previous studies where Tregs were negatively associated with SLE 40 .…”

Section: Discussionmentioning

confidence: 99%

“…Generation of Tregs were performed as described previously 28 . Briefly, peripheral blood mononuclear cells (PBMCs) were isolated from healthy donors, according to the manufacturer's protocol (Ficoll-Paque PLUS, GE Healthcare, Buckinghamshire, United Kingdom).…”

Section: Studies Of T-regulatory Cellsmentioning

confidence: 99%

“…ing of the anti-MDA and the anti-PC IgM samples have been described elsewhere 15,28 . Data processing was performed using Spotlight proteomics approach 29 .…”

Section: Igm Protein and Peptide Characterization Sample Preparationmentioning

confidence: 99%

“…We have previously published quantitative LC-MS/MS peptide sequencing data from the anti-PC variable region 28 and the anti-MDA variable region 15 .…”

Section: Proteomic Comparative Analysis Of Polyclonal Anti-pc and Antmentioning

confidence: 99%

See 3 more Smart Citations

IgM antibodies against malondialdehyde and phosphorylcholine in different systemic rheumatic diseases

¹

,

²

,

³

et al. 2020

Self Cite

View full text Add to dashboard Cite

the pReciSeSADS clinical consortium*, Marta Alarcon-Riquelme 1,3 & Johan frostegård 1 ✉ 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.

Immunoglobulin G1 Antibodies Against Phosphorylcholine Are Associated With Protection in Systemic Lupus Erythematosus and Atherosclerosis: Potential Underlying Mechanisms

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et al. 2020

ACR Open Rheumatology

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Objective Immunoglobulin M antibodies against phosphorylcholine (anti‐PCs) may be protective in atherosclerosis, cardiovascular disease (CVD), and systemic lupus erythematosus (SLE). We study immunoglobulin G1 (IgG1) and immunoglobulin G2 (IgG2) anti‐PCs, with a focus on atherosclerosis and SLE. Methods We determined anti‐PCs by using the enzyme‐linked immunosorbent assay in 116 patients with SLE and 110 age‐ and sex‐matched controls. For functional studies, we used three in‐house–generated, fully human monoclonal IgG1 anti‐PCs (A01, D05, and E01). Apoptosis was induced in Jurkat T cells and preincubated with A01, D05, E01, or IgG1 isotype control, and effects on efferocytosis by human macrophages were 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 patients with SLE (P = 0.02). IgG1 anti‐PCs were negatively associated with Systemic Lupus International Collaborating Clinics (SLICC) damage index and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores (odds ratio [OR]: 2.978 [confidence interval (CI): 0.876‐10.098] and OR: 5.108 [CI 1.3‐20.067], respectively) and negatively associated with CVD, atherosclerotic plaques, and echolucent plaques (potentially vulnerable plaques), but the association for the two former was not significant after controlling for confounders. D05 had a maximum effect on macrophage efferocytosis efficiency, followed by A01 and E01. The monoclonal antibodies showed differential binding specificity to PC and PC‐associated neoepitopes. A peptide analysis showed a difference in the complementarity‐determining region 3 of the three IgG1 anti‐PC clones that are crucial for recognition of PC on apoptotic cell surfaces and other neoepitopes. Conclusion IgG1 anti‐PCs are 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.

Effects of Atorvastatin on T‐Cell Activation and Apoptosis in Systemic Lupus Erythematosus and Novel Simulated Interactions With C‐Reactive Protein and Interleukin 6

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et al. 2021

ACR Open Rheumatology

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Objective We study activation of T helper 17 (Th17) and regulatory T (Treg) cells and induction of apoptosis in cells from patients with systemic lupus erythematosus (SLE) compared with controls and effects of atorvastatin and its simulated interactions with other compounds. Methods Mononuclear cells from 10 patients with SLE and 10 controls were cultured in conditions that induce Th17 and/or Treg cell polarization and/or apoptosis and were studied by FACScan. Gene expression was determined by quantitative real‐time reverse transcription–polymerase chain reaction. Cytokines in plasma were determined by enzyme‐linked immunosorbent assay. The Search Tool for Interactions of Chemicals (STITCH) was used to retrieve information regarding the binding properties of atorvastatin. Results Among patients with SLE, the proportion of Th17 (CD4+IL17+) cells was higher compared with controls after activation, with Th17 or Treg polarizing cytokines, phorbol myristate acetate, and ionomycin. In contrast, Treg cells (CD4+CD25+CD127dim/−) frequencies were lower. CD95 stimulation induced relatively more apoptosis in Treg cells and less in Th17 cells, as compared with controls. Addition of atorvastatin normalized Th17/Treg cell balance and apoptosis induction. Accordingly, the ratio of RORC/FoxP3 decreased in patients with SLE. Interleukin 17 and interleukin 6 (IL‐6) levels were increased in patients with SLE. Atorvastatin interacted strongly with C‐reactive protein (CRP) and also significantly with IL‐6. Conclusion There is a higher proportion of Th17 cells and a lower proportion of Treg cells in patients with SLE after activation. Th17 cells were more resistant than Treg cells to CD95‐induced apoptosis in SLE. Atorvastatin normalized these effects. Our findings reveal a novel mechanism behind the imbalance of Th17/Treg cells with implications for treatment in SLE. We determine for the first time simulated interaction between atorvastatin, CRP, and IL‐6, implying a novel role of atorvastatin.

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