Abstract
BackgroundImmunoglobulin M (IgM) autoreactivity to malondialdehyde (MDA) protein modifications is part of the natural antibody repertoire in health and may have beneficial functions. In contrast, IgG anti-MDA are increased in chronic inflammation and autoimmunity and may instead have pathogenic properties.MethodsHerein, we investigated serum IgG anti-MDA levels by enzyme-linked immunosorbent assay (ELISA) in 398 systemic lupus erythematosus (SLE) patients in the Swedish Karolinska SLE cohort and compared these to findings in 225 US SLE patients from New York University and Johns Hopkins University.ResultsIn two independent cohorts, IgG anti-MDA levels correlated positively with disease activity by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI; p < 0.0001, Spearman R = 0.3). Meta-analysis found an odds ratio of 2.7 (confidence interval (CI) 1.9–3.9; p < 0.0001) for high anti-MDA IgG levels with active disease (SLEDAI ≥ 6). Furthermore, IgG anti-MDA correlated directly with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), soluble tumor necrosis factor receptors (sTNFR-1, sTNFR-2), and vascular cell adhesion molecule 1 (VCAM-1) measurements, and inversely with complement factors (C1q, C2, C3, C4). Importantly, IgG anti-MDA levels were significantly elevated in SLE patients with active nephritis (p = 0.0005) and correlated with cystatin C estimated glomerular filtration rate and albuminuria.ConclusionsElevated IgG anti-MDA in SLE patients was associated with high disease activity, with active lupus nephritis, and with biomarkers of systemic inflammation. This natural antibody reactivity may have potential prognostic utility, and may also actively contribute to pathogenesis.
Highlights
Immunoglobulin M (IgM) autoreactivity to malondialdehyde (MDA) protein modifications is part of the natural antibody repertoire in health and may have beneficial functions
While we had a striking difference in immunoglobulin G (IgG) antiMDA levels when comparing the combined US Systemic lupus erythematosus (SLE) cohort (225 patients from New York University (NYU) and John Hopkins) and the healthy blood donors (13.2 ± 16.4 NYU-relative units (RU)/ml vs 7.4 ± 5.8 NYURU/ml, p = 0.001), we did not find the same pattern in the Karolinska SLE cohort compared to the sex- and agematched population controls (50.3 ± 50.7 KI-RU/ml vs 41.9 ± 37.3 KI-RU/ml, p = 0.08) (Fig. 1)
We found a distinct difference between population controls and SLE patients that reached statistical significance (p = 0.01), a subgroup of the controls still had substantial anti-MDA levels (Fig. 1)
Summary
Immunoglobulin M (IgM) autoreactivity to malondialdehyde (MDA) protein modifications is part of the natural antibody repertoire in health and may have beneficial functions. Systemic lupus erythematosus (SLE) is a complex autoimmune disease associated with production of autoantibodies and damage to multiple organs [1]. MDAmodified protein, together with other oxidation-associated modifications, are primary targets recognized by IgM antibodies that are present from birth, referred to as natural autoantibodies [6,7,8]. These IgM have been postulated to have roles in maintaining homeostasis, in part by enhancing the clearance of apoptotic cells and harmful modified self-molecules (reviewed in [9, 10]). In vitro cell assays and studies in animal models have shown that these types of anti-oxidation neo-epitope-directed IgM can be directly anti-inflammatory [16,17,18]
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