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

Abstract

Objective Immunoglobulin 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. Methods We 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. Results IgG1, 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. Conclusion IgG1 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.

Identification of IgG1 isotype phosphorylcholine antibodies for the treatment of inflammatory cardiovascular diseases

“…PC‐mAb(T15) treatment led to retarded accelerated atherosclerosis and a less inflammatory phenotype, involving reduction in ER stress markers. In line with this, recent findings indicate that a fully human IgG1 clone against PC promotes clearance of dead cells and that IgG1 but not IgG2 anti‐PC is associated with protection in relation to atherosclerosis [ 42 ].…”

Antibodies against phosphorylcholine in hospitalized versus non-hospitalized obese subjects

“…In general, these findings have been confirmed by other researchers 20 – 25 , and extended to other chronic diseases as osteoarthritis 24 . Less is known about other subclasses and isotypes of anti-PC than IgM, even though we determined that IgG1, but not IgG2, shows comparable associations with protection as IgM, in atherosclerosis 13 , SLE 26 , and for mortality in CKD 11 .…”

“…Mechanisms related to atherosclerosis include IgM anti-PC induced inhibition of uptake of oxLDL by macrophages, which could be an important factor in plaque build-up and development 14 . Since accumulation of dead cells is a major feature of atherosclerosis, IgM anti-PC-induced inhibition of cell death caused by an important inflammatory phospholipid, lysophosphatidylcholine 13 and increased clearance of dead cells by both IgM 7 and IgG1 anti-PC 26 could also play a causative and protective role, inhibiting plaque development.…”

Mini Review: Structure and Function of Nematode Phosphorylcholine-Containing Glycoconjugates

“…Anti-PC antibodies have been found to reduce inflammation in ischemic mouse models and are plentiful in human subjects at low risk of atherosclerosis (92)(93)(94). In addition, in the context of rheumatic disease, an inverse correlation between anti-PC antibodies and, organ damage and disease activity in SLE patients has been demonstrated (95,96). Although the exact mechanism(s) underlying the protective effects of anti-PC antibodies is still under investigation, anti-inflammatory and cardioprotective benefits of anti-PC antibodies in SLE and also Sjögren's syndrome and mixed connective tissue disease are associated with regulatory T cell polarisation, oxidised low density lipoprotein uptake inhibition and enhanced apoptotic cell clearance (96)(97)(98)(99).…”

“…In addition, in the context of rheumatic disease, an inverse correlation between anti-PC antibodies and, organ damage and disease activity in SLE patients has been demonstrated (95,96). Although the exact mechanism(s) underlying the protective effects of anti-PC antibodies is still under investigation, anti-inflammatory and cardioprotective benefits of anti-PC antibodies in SLE and also Sjögren's syndrome and mixed connective tissue disease are associated with regulatory T cell polarisation, oxidised low density lipoprotein uptake inhibition and enhanced apoptotic cell clearance (96)(97)(98)(99). Interestingly, IgM anti-PC antibodies are greatly increased in response to ES-62 in murine models of lupus and in high calorie diet (HCD)-fed mice (82,89).…”