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

<jats:sec><jats:title>Objective</jats:title><jats:p>Immunoglobulin M antibodies against phosphorylcholine (anti‐<jats:styled-content style="fixed-case">PC</jats:styled-content>s) may be protective in atherosclerosis, cardiovascular disease (<jats:styled-content style="fixed-case">CVD</jats:styled-content>), and systemic lupus erythematosus (<jats:styled-content style="fixed-case">SLE</jats:styled-content>). We study immunoglobulin G1 (IgG1) and immunoglobulin G2 (IgG2) anti‐<jats:styled-content style="fixed-case">PC</jats:styled-content>s, with a focus on atherosclerosis and <jats:styled-content style="fixed-case">SLE</jats:styled-content>.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We determined anti‐<jats:styled-content style="fixed-case">PC</jats:styled-content>s by using the enzyme‐linked immunosorbent assay in 116 patients with <jats:styled-content style="fixed-case">SLE</jats:styled-content> and 110 age‐ and sex‐matched controls. For functional studies, we used three in‐house–generated, fully human monoclonal IgG1 anti‐<jats:styled-content style="fixed-case">PC</jats:styled-content>s (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‐<jats:styled-content style="fixed-case">PC</jats:styled-content> peptide/protein characterization was determined using a proteomics de novo sequencing approach.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>IgG1, but not IgG2, anti‐<jats:styled-content style="fixed-case">PC</jats:styled-content> levels were higher among patients with <jats:styled-content style="fixed-case">SLE</jats:styled-content> (<jats:italic>P</jats:italic> = 0.02). IgG1 anti‐<jats:styled-content style="fixed-case">PC</jats:styled-content>s were negatively associated with Systemic Lupus International Collaborating Clinics (<jats:styled-content style="fixed-case">SLICC</jats:styled-content>) damage index and Systemic Lupus Erythematosus Disease Activity Index (<jats:styled-content style="fixed-case">SLEDAI</jats:styled-content>) scores (odds ratio [<jats:styled-content style="fixed-case">OR</jats:styled-content>]: 2.978 [confidence interval (<jats:styled-content style="fixed-case">CI</jats:styled-content>): 0.876‐10.098] and <jats:styled-content style="fixed-case">OR</jats:styled-content>: 5.108 [<jats:styled-content style="fixed-case">CI</jats:styled-content> 1.3‐20.067], respectively) and negatively associated with <jats:styled-content style="fixed-case">CVD</jats:styled-content>, 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 <jats:styled-content style="fixed-case">PC</jats:styled-content> and <jats:styled-content style="fixed-case">PC</jats:styled-content>‐associated neoepitopes. A peptide analysis showed a difference in the complementarity‐determining region 3 of the three IgG1 anti‐<jats:styled-content style="fixed-case">PC</jats:styled-content> clones that are crucial for recognition of <jats:styled-content style="fixed-case">PC</jats:styled-content> on apoptotic cell surfaces and other neoepitopes.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>IgG1 anti‐<jats:styled-content style="fixed-case">PC</jats:styled-content>s are negatively associated with disease activity and disease damage in <jats:styled-content style="fixed-case">SLE</jats:styled-content>, but the negative association with <jats:styled-content style="fixed-case">CVD</jats:styled-content> is also dependent on confounding risk factors. One potential underlying mechanism could be increased clearance of dead cells.</jats:p></jats:sec>