IgM natural antibody T15/E06 in atherosclerosis

Zou, Jin; Wang, Gang; Li, Heng; Tang, Chao-Ke

doi:10.1016/j.cca.2020.01.024

Cited by 9 publications

(7 citation statements)

References 116 publications

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“…A previous study demonstrated that natural IgM recognizing oxidized phospholipids deposit in plaques and play a protective role in atherosclerosis ( 52 ). To determine whether the infusion of C2scFv-Crry has any effect on endogenous natural antibody deposition, we analyzed the level of total IgM and IgG in the plaque after C2scFv-Crry treatment.…”

Section: Resultsmentioning

confidence: 99%

Complement Inhibition Targeted to Injury Specific Neoepitopes Attenuates Atherogenesis in Mice

Dai

Liu

Ren

et al. 2021

Front. Cardiovasc. Med.

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Rationale: Previous studies have indicated an important role for complement in atherosclerosis, a lipid-driven chronic inflammatory disease associated to oxidative stress in the vessel wall. However, it remains unclear how complement is activated in the process of atherogenesis. An accepted general model for complement activation in the context of ischemia reperfusion injury is that ischemia induces the exposure of neoepitopes that are recognized by natural self-reactive IgM antibodies, and that in turn activate complement.Objective: We investigated whether a similar phenomenon may be involved in the pathogenesis of atherosclerosis, and whether interfering with this activation event, together with inhibition of subsequent amplification of the cascade at the C3 activation step, can provide protection against atherogenesis.Methods and Results: We utilized C2scFv-Crry, a novel construct consisting of a single chain antibody (scFv) linked to Crry, a complement inhibitor that functions at C3 activation. The scFv moiety was derived from C2 IgM mAb that specifically recognizes phospholipid neoepitopes known to be expressed after ischemia. C2scFv-Crry targeted to the atherosclerotic plaque of Apoe−/− mice, demonstrating expression of the C2 neoepitope. C2scFv-Crry administered twice per week significantly attenuated atherosclerotic plaque in the aorta and aortic root of Apoe−/− mice fed with a high-fat diet (HFD) for either 2 or 4 months, and treatment reduced C3 deposition and membrane attack complex formation as compared to vehicle treated mice. C2scFv-Crry also inhibited the uptake of oxidized low-density-lipoprotein (oxLDL) by peritoneal macrophages, which has been shown to play a role in pathogenesis, and C2scFv-Crry-treated mice had decreased lipid content in the lesion with reduced oxLDL levels in serum compared to vehicle-treated mice. Furthermore, C2scFv-Crry reduced the deposition of endogenous total IgM in the plaque, although it did not alter serum IgM levels, further indicating a role for natural IgM in initiating complement activation.Conclusion: Neoepitope targeted complement inhibitors represent a novel therapeutic approach for atherosclerosis.

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Section: Resultsmentioning

confidence: 99%

Complement Inhibition Targeted to Injury Specific Neoepitopes Attenuates Atherogenesis in Mice

Dai

Liu

Ren

et al. 2021

Front. Cardiovasc. Med.

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“…There are several innate immune system receptors recognizing PC including proteins, scavenger receptors of phagocytic cells and natural antibodies (IgM anti‐PC) [ 6 ]; in general, these receptors are part of the system for clearance of damaged particles and cells (efferocytosis) [ 7 ]. The murine T15/E06 IgM antibody is well known to inhibit oxLDL uptake into macrophages [ 8 ] and enhance efferocytosis [ 9 , 10 ]. A pathophysiological role of PC‐containing oxPLs in atherosclerosis and ischaemia–reperfusion injury was shown by the protective effect of anti‐PC lacking effector function [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

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

Vries¹,

Ewing

Jong³

et al. 2021

J Intern Med

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“…Produced in inflammatory tissues, including atherosclerotic lesions, oxidized phospholipids are proinflammatory and promote the development of atherosclerosis and nonalcoholic steatohepatitis 78 . Numerous studies have indicated the potential of EO6/T15 antibodies to protect against atherosclerosis and nonalcoholic steatohepatitis by recognizing phosphorylcholine in oxidized phospholipids 79,[80][81][82] . In future work, it will be important to determine whether E34Δ mice show increased susceptibility to cardiovascular disease or nonalcoholic steatohepatitis.…”

Section: Discussionmentioning

confidence: 99%

Enhancer-instructed epigenetic landscape and chromatin compartmentalization dictate a primary antibody repertoire protective against specific bacterial pathogens

Barajas-Mora

Lee

et al. 2023

Nat Immunol

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Antigen receptor loci are organized into variable (V), diversity (D) and joining ( J) gene segments that rearrange to generate antigen receptor repertoires. Here, we identified an enhancer (E34) in the murine immunoglobulin kappa (Igk) locus that instructed rearrangement of V κ genes located in a sub-topologically associating domain, including a V κ gene encoding for antibodies targeting bacterial phosphorylcholine. We show that E34 instructs the nuclear repositioning of the E34 sub-topologically associating domain from a recombination-repressive compartment to a recombination-permissive compartment that is marked by equivalent activating histone modifications. Finally, we found that E34-instructed V κ -J κ rearrangement was essential to combat Streptococcus pneumoniae but not methicillin-resistant Staphylococcus aureus or influenza infections. We propose that the merging of V κ genes with J κ elements is instructed by one-dimensional epigenetic information imposed by enhancers across V κ and J κ genomic regions. The data also reveal how enhancers generate distinct antibody repertoires that provide protection against lethal bacterial infection.B cells generate diverse antibody repertoires through somatic recombination of distinct gene segments. Antibodies are encoded by the immunoglobulin heavy chain (Igh) locus, and by the immunoglobulin kappa (Igk) or the immunoglobulin lambda (Igl) loci. The Igh locus is segregated into variable (V), diversity (D), joining ( J) and constant (C) regions. The Igk and Igl loci are composed of V, J and C regions. Igh and Igl locus recombination occurs by deletion, while Igk rearrangement is mediated by deletion or inversion 1 . Immunoglobulin loci rearrangement is mediated by the Recombination-Activating gene 1 (Rag1) and Rag2 enzymes which cleave recombination signal sequences (RSSs) flanking the V, D and J gene segments 1 . During B cell development, rearrangement is mostly sequential. At the pro-B cell stage, D H -J H rearrangement precedes that of V H -D H J H joining. Pro-B cells that undergo V κ gene rearrangement largely give rise to B1a cells, but the majority of V κ -J κ rearrangement is initiated at the pre-B cell stage 2,3 . If V κ -J κ rearrangement is nonproductive or auto-reactive, V κ regions continue to recombine until a functional non-self-reactive V κ -J κ gene product is generated or proceeds to generate V λ -J λ joints 4 .

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IgM natural antibody T15/E06 in atherosclerosis

Cited by 9 publications

References 116 publications

Complement Inhibition Targeted to Injury Specific Neoepitopes Attenuates Atherogenesis in Mice

Complement Inhibition Targeted to Injury Specific Neoepitopes Attenuates Atherogenesis in Mice

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

Enhancer-instructed epigenetic landscape and chromatin compartmentalization dictate a primary antibody repertoire protective against specific bacterial pathogens

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