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

ObjectiveImmunoglobulin 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.MethodsWe 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.ResultsIgG1, 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.ConclusionIgG1 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.What is already known about this subject?Low levels of immunoglobulin M antibodies against phosphorylcholine (anti-PCs) is more common in patients with systemic lupus erythematosus (SLE) compared with controls and is associated with increased prevalence of vulnerable plaque among patients with SLE. center dotWhat does this study add?Immunoglobulin G1 (IgG1) anti-PCs are negatively associated with disease activity, disease damage, cardiovascular disease, and measures of atherosclerosis in SLE. We have produced in-house, fully human monoclonal antibodies of the IgG1 isotype that increase apoptotic cell uptake efficiently and reduce inflammation induced by lipopolysaccharide. Effects varied depending on the clone used. A peptide analysis showed a difference in the complementarity-determining region 3 of the three IgG1 anti-PC clones that are crucial for the recognition of phosphorylcholine (PC) on apoptotic cell surfaces and other neoepitopes.How might this impact clinical practice or future developments?Measurement of IgG1 anti-PCs, along with other autoantibodies, could improve prevention in patients with SLE with vascular implications. Anti-PCs could be developed as a novel treatment in SLE, either as monoclonal antibodies or as a vaccine with PC.