Human IgM Antibodies to Malondialdehyde Conjugated With Albumin Are Negatively Associated With Cardiovascular Disease Among 60‐Year‐Olds

Abstract

BackgroundMalondialdehyde (MDA) is generated during lipid peroxidation as in oxidized low‐density lipoprotein, but antibodies against oxidized low‐density lipoprotein show variable results in clinical studies. We therefore studied the risk of cardiovascular disease (CVD) associated with IgM antibodies against MDA conjugated with human albumin (anti‐MDA).Methods and ResultsIn a 5‐ to 7‐year follow‐up of 60‐year‐old men and women from Stockholm County previously screened for cardiovascular risk factors (2039 men, 2193 women), 209 incident CVD cases (defined as new events of coronary heart disease, fatal and nonfatal myocardial infarction, ischemic stroke, and hospitalization for angina pectoris) and 620 age‐ and sex‐matched controls were tested for IgM anti‐MDA by ELISA. Antibody peptide/protein characterization was done using a proteomics de novo sequencing approach. After adjustment for smoking, body‐mass index, type 2 diabetes mellitus, hyperlipidemia, and hypertension, an increased CVD risk was observed in the low IgM anti‐MDA percentiles (below 10th and 25th) (odds ratio and 95% CI: 2.0; 1.19–3.36 and 1.67; 1.16–2.41, respectively). Anti‐MDA above the 66th percentile was associated with a decreased CVD risk (odds ratio 0.68; CI: 0.48–0.98). After stratification by sex, associations were only present among men. IgM anti‐MDA levels were lower among cases (median [interquartile range]: 141.0 [112.7–164.3] versus 147.4 [123.5–169.6]; P=0.0177), even more so among men (130.6 [107.7–155.3] versus 143.0 [120.1–165.2]; P=0.001). The IgM anti‐MDA variable region profiles are distinctly different and also more homologous in their content (correlates strongly with fewer peptides) than control antibodies (not binding MDA).ConclusionsIgM anti‐MDA is a protection marker for CVD. This finding could have diagnostic and therapeutic implications.

Schizophrenia Phenomenology Comprises a Bifactorial General Severity and a Single-group Factor, Which Are Differently Associated with Neurotoxic Immune and Immune-regulatory Pathways

“…Deficit schizophrenia, but not non-deficit schizophrenia, is accompanied by lowered IgM responses to oxidative specific epitopes (OSEs) including malondialdehyde (MDA) indicating that this condition is characterized by lowered natural IgM antibodies, which are a key component of innate immunity [18]. These IgM antibodies are produced by innate-like B1 and marginal zone B cells and have immune-regulatory, housekeeping, and anti-oxidant properties thereby protecting against an overzealous IRS and bacterial infections [21,22,23,24]. Finally, deficit schizophrenia is also accompanied by lowered activity levels of paraoxonase 1 (PON1) [Matsumoto et al, in preparation], a detoxifying and antioxidant enzyme that is strongly associated with high-density lipoproteins (HDLs) [25].…”

In Schizophrenia, Low Natural IgM Antibody Titers to Oxidative Specific Epitopes and Higher IgM Responses to Nitrated and Nitrosylated Proteins Strongly Predict Negative Symptoms, Neurocognitive Impairments and the Deficit Syndrome

“…Expressed on these surfaces, the neoepitopes are recognized by immunocytes and consequently autoimmune, including adaptive IgM isotype-mediated, responses may be generated directed against these neoepitopes [44][45][46]. In addition, natural IgM antibodies, which have specificity for many OSEs, including MDA, are present without antigenic contact and in fact are part of the innate first-line defense against microorganisms [16,17]. Increased MDA levels are frequently, but not always, observed in schizophrenia [47,48], while mood disorders including major depression and bipolar depression are characterized by increased MDA levels or increased IgM responses to MDA [49-51, in preparation].…”

“…For example, in women with perinatal depression, IgM isotype-mediated responses directed to MDA are inversely associated with multiple signs of nitro-oxidative stress and depressive symptoms as well [15]. IgM antibodies to MDA protect against cardio-vascular disorder, are a first line defense against micro-organisms, have anti-inflammatory activities and eliminate apoptotic cells thereby promoting tissuehomeostasis [16,17]. Nevertheless, no studies have examined IgM antibodies to OSEs (including MDA and azelaic acid) in deficit and non-deficit schizophrenia.…”

In Schizophrenia, Low Natural IgM Antibody Titers to Oxidative Specific Epitopes and Higher IgM Responses to Nitrated and Nitrosylated Proteins Strongly Predict Negative Symptoms, Neurocognitive Impairments and the Deficit Syndrome

“…For example, in women with perinatal depression, IgM isotype-mediated responses directed to MDA are inversely associated with multiple signs of nitro-oxidative stress and depressive symptoms as well [15]. IgM antibodies to MDA protect against cardio-vascular disorder, are a first line defense against micro-organisms, have anti-inflammatory activities and eliminate apoptotic cells thereby promoting tissuehomeostasis [16,17]. Nevertheless, no studies have examined IgM antibodies to OSEs (including MDA and azelaic acid) in deficit and non-deficit schizophrenia.…”