IgM antibodies against malondialdehyde and phosphorylcholine are together strong protection markers for atherosclerosis in systemic lupus erythematosus: Regulation and underlying mechanisms.
Phosphorylcholine (PC) and malondialdehyde (MDA) are generated during lipid peroxidation and form adducts with proteins as albumin as studied herein. Atherosclerosis and cardiovascular disease (CVD) are increased in systemic lupus erythematosus (SLE). We here investigate the role and regulation of IgM antibodies against PC (anti-PC) and MDA (anti-MDA).



IgM anti-PC and anti-MDA in SLE patients (n=114) were compared with age- and sex-matched population-based controls (n=108). Common carotid intima-media thickness (IMT) and plaque occurrence were determined by B-mode ultrasound. Plaques were graded according to echogenicity (potentially vulnerability). Production of IgM anti-PC and anti-MDA by B cells was determined by ELISA and ELISPOT. The effect of anti-PC and anti-MDA on macrophage uptake of apoptotic cells and oxidative stress was studied by flow cytometry.



Above 66rd percentile together, IgM anti-PC and anti-MDA were striking protection markers for plaque prevalence and echolucency in SLE (OR: 0.08, CI: 0.01-0.46 and OR: 0.10, CI: 0.01-0.82), respectively, and risk markers for plaque prevalence when below 33rd percentile: OR: 3.79, CI: (1.10-13.00). In vitro, IgM anti-PC and anti-MDA were much higher when B cells were co-cultured with CD3 T cells. Anti-HLA-, anti-CD40 antibody or CD40 silencing abolished these effects. Uptake of apoptotic cells was increased by IgM anti-PC and anti-MDA. MDA induced increased oxidative stress, which was inhibited by IgM anti-MDA.



Unexpectedly, both IgM anti-MDA and IgM anti-PC are T-cell dependent and especially together, are strong protection markers for atherosclerosis in SLE. Underlying mechanisms include increased phagocytosis of apoptotic cells and decrease of oxidative stress.
IMM, Unit of Immunology and Chronic Disease, Karolinska Institutet, 171 65 Stockholm, Sweden.
Mizanur
M
Rahman
IMM, Unit of Immunology and Chronic Disease, Karolinska Institutet, 171 65 Stockholm, Sweden.
Sudhir
S
Sing
IMM, Unit of Immunology and Chronic Disease, Karolinska Institutet, 171 65 Stockholm, Sweden.
Zahra
Z
Golabkesh
IMM, Unit of Immunology and Chronic Disease, Karolinska Institutet, 171 65 Stockholm, Sweden.
Roland
R
Fiskesund
Department of Laboratory Medicine, Division of Clinical Physiology, Karolinska Institutet at Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden.
Thomas
T
Gustafsson
Department of Laboratory Medicine, Division of Clinical Physiology, Karolinska Institutet at Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden.
Tomas
T
Jogestrand
IMM, Unit of Immunology and Chronic Disease, Karolinska Institutet, 171 65 Stockholm, Sweden.
Anna G
AG
Frostegård
Department of Rheumatology, Karolinska Institutet at Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden.
Ingiäld
I
Hafström
IMM, Unit of Immunology and Chronic Disease, Karolinska Institutet, 171 65 Stockholm, Sweden.
Anquan
A
Liu
IMM, Unit of Immunology and Chronic Disease, Karolinska Institutet, 171 65 Stockholm, Sweden. Electronic address: johan.frostegard@ki.se.
Johan
J
Frostegård
D000328:Adult; D017209:Apoptosis / Q000276:immunology; D050197:Atherosclerosis / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D059168:Carotid Intima-Media Thickness; D002478:Cells, Cultured; D018920:Coculture Techniques; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology* / Q000378:metabolism; D019169:Jurkat Cells; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000276:immunology* / Q000378:metabolism; D008875:Middle Aged; D018384:Oxidative Stress / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology; D010767:Phosphorylcholine / Q000276:immunology* / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000000981:diagnostic imaging / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014463:Ultrasonography
D015415:Biomarkers; D017252:CD3 Complex; D007075:Immunoglobulin M; D010767:Phosphorylcholine; D008315:Malondialdehyde
Antibodies; Atherosclerosis; Malondialdehyde; Phosphorylcholine; Systemic lupus erythematosus; T-cells; Vulnerable plaque