Mizanur Rahman1, Sudhir Sing1, Zahra Golabkesh1, Roland Fiskesund1, Thomas Gustafsson2, Tomas Jogestrand2, Anna G Frostegård1, Ingiäld Hafström3, Anquan Liu1, Johan Frostegård4. 1. IMM, Unit of Immunology and Chronic Disease, Karolinska Institutet, 171 65 Stockholm, Sweden. 2. Department of Laboratory Medicine, Division of Clinical Physiology, Karolinska Institutet at Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden. 3. Department of Rheumatology, Karolinska Institutet at Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden. 4. IMM, Unit of Immunology and Chronic Disease, Karolinska Institutet, 171 65 Stockholm, Sweden. Electronic address: johan.frostegard@ki.se.
Abstract
OBJECTIVES: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVES: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). METHODS: IgM anti-PC and anti-MDA in SLEpatients (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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Xu Chen; Stefan Gustafsson; Thomas Whitington; Yan Borné; Erik Lorentzen; Jitong Sun; Peter Almgren; Jun Su; Robert Karlsson; Jie Song; Yi Lu; Yiqiang Zhan; Sara Hägg; Per Svensson; Karin E Smedby; Susan L Slager; Erik Ingelsson; Cecilia M Lindgren; Andrew P Morris; Olle Melander; Thomas Karlsson; Ulf de Faire; Kenneth Caidahl; Gunnar Engström; Lars Lind; Mikael C I Karlsson; Nancy L Pedersen; Johan Frostegård; Patrik K E Magnusson Journal: Hum Mol Genet Date: 2018-05-15 Impact factor: 6.150
Authors: Divya Thiagarajan; Anna G Frostegård; Sudhir Singh; Mizanur Rahman; Anquan Liu; Max Vikström; Karin Leander; Bruna Gigante; Mai-Lis Hellenius; Bo Zhang; Roman A Zubarev; Ulf de Faire; Susanna L Lundström; Johan Frostegård Journal: J Am Heart Assoc Date: 2016-12-20 Impact factor: 5.501