Increased Plasma IgE Accelerate Atherosclerosis in Secreted IgM Deficiency

Tsiantoulas, Dimitrios; Bot, Ilze; Ozsvár-Kozma, Mária; Göderle, Laura; Perkmann, Thomas; Hartvigsen, Karsten; Conrad, Daniel H.; Kuiper, Johan; Mallat, Ziad; Binder, Christoph J.

doi:10.1161/circresaha.116.309606

Cited by 56 publications

(47 citation statements)

References 33 publications

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“…12 However, in sIgM −/− Ldlr −/− mice, impaired clearance of IgE promotes atherosclerosis, rather than direct local effects of IgM deficiency. 17 Compared with sIgM −/− mice, Ldlr…”

Section: 44mentioning

confidence: 99%

“…16 However, in a more recent study using soluble IgM (sIgM −/− )/Ldlr −/− mice, we demonstrated that the enhanced atherosclerosis was a result of IgE accumulation in the circulation because anti-IgE injections completely reversed the phenotype. 17 IgE accumulates because sIgM −/− mice have a significant reduction in IgE receptor (CD23)-expressing B cells, leading to mast cell activation and proatherogenic inflammation. This raises important questions about the direct role of IgM or related downstream biological events in mediating atheroprotection.…”

Section: Meet the First Author See P 198mentioning

confidence: 99%

“…37 Although no other studies have previously addressed the effects of a specific defect in plasma cells, 2 previous articles reported enhanced atherosclerosis in mice lacking the secreted form of IgM. 16,17 Indirect but compelling evidence for the importance of IgM is also provided by studies showing enhanced atherosclerosis in IL5-deficient mice that have reduced IgM 11 and reduced atherosclerosis in SiglecG-deficient mice that have increased IgM. 44 In addition, passive transfer of polyclonal IgM reduces atherosclerosis in ApoE −/− mice.…”

Section: 44mentioning

confidence: 99%

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X-Box Binding Protein-1 Dependent Plasma Cell Responses Limit the Development of Atherosclerosis

Sage

Nus

Chakraborty

et al. 2017

Circulation Research

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Rationale: Diverse B cell responses and functions may be involved in atherosclerosis. Protective antibody responses, such as those against oxidized lipid epitopes, are thought to mainly derive from T cell-independent innate B cell subsets. In contrast, both pathogenic and protective roles have been associated with T cell-dependent antibodies, and their importance in both humans and mouse models is still unclear.Objective: To specifically target antibody production by plasma cells and determine the impact on atherosclerotic plaque development in mice with and without CD4+ T cells. Methods and Results:We combined a model of specific antibody deficiency, B cell-specific CD79a-Cre x XBP1 (X-box binding protein-1) floxed mice (XBP1-conditional knockout), with antibody-mediated depletion of CD4+ T cells. Ldlr knockout mice transplanted with XBP1-conditional knockout (or wild-type control littermate) bone marrow were fed western diet for 8 weeks with or without anti-CD4 depletion. All groups had similar levels of serum cholesterol. In Ldlr/ XBP1-conditional knockout mice, serum levels of IgG, IgE, and IgM were significantly attenuated, and local antibody deposition in atherosclerotic plaque was absent. Antibody deficiency significantly accelerated atherosclerosis at both the aortic root and aortic arch. T cell and monocyte responses were not modulated, but necrotic core size was greater, even when adjusting for plaque size, and collagen deposition significantly lower. Anti-CD4 depletion in Ldlr/wild-type mice led to a decrease of serum IgG1 and IgG2c but not IgG3, as well as decreased IgM, associated with increased atherosclerosis and necrotic cores, and a decrease in plaque collagen. The combination of antibody deficiency and anti-CD4 depletion has no additive effects on aortic root atherosclerosis. Conclusions:

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Section: 44mentioning

confidence: 99%

Section: Meet the First Author See P 198mentioning

confidence: 99%

Section: 44mentioning

confidence: 99%

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X-Box Binding Protein-1 Dependent Plasma Cell Responses Limit the Development of Atherosclerosis

Sage

Nus

Chakraborty

et al. 2017

Circulation Research

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“…Approximately 30% of all natural IgM antibodies, recognizing diverse OSEs, were found to bind to atherosclerotic lesions and apoptotic cells in a mouse model [32]. Furthermore, genetic deficiency of secreted IgM ( sIgM -/- ) in mice dramatically accelerates atherosclerosis on the LDL receptor deficient ( Ldlr -/- ), atherosclerosis-susceptible mouse background, parallel with increased plasma IgE levels and perivascular accumulation of mast cells and neutrophils within the plaques [33]. In addition, the OSE-specific T15/E06 IgM blocks the recognition of the oxidized phospholipid POVPC (1-palmitoyl-2-(5-oxovaleroyl)- sn -glycero-3-phosphorylcholine) by the scavenger receptor CD36 [34], and the IL-6 secretion, induced by oxPAPC (oxidized 1‑palmitoyl-2-arachidonoyl- sn -glycero-3-phosphocholine) in macrophages [35].…”

Section: Lp(a) and Inflammation And Atherogenesismentioning

confidence: 99%

Lipoprotein(a) and its role in inflammation, atherosclerosis and malignancies

Orsó

Schmitz

2017

Clin Res Cardiol Suppl

103

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Lipoprotein (a) (Lp(a)) is a modified low-density lipoprotein (LDL) particle with an additional specific apolipoprotein (a), covalently attached to apolipoprotein B‑100 of LDL by a single thioester bond. Increased plasma Lp(a) level is a genetically determined, independent, causal risk factor for cardiovascular disease.The precise quantification of Lp(a) in plasma is still hampered by mass-sensitive assays, large particle variation, poor standardization and lack of assay comparability.The physiological functions of Lp(a) include wound healing, promoting tissue repair and vascular remodeling. Similarly to other lipoproteins, Lp(a) is also susceptible for oxidative modifications, leading to extensive formation of pro-inflammatory and pro-atherogenic oxidized phospholipids, oxysterols, oxidized lipid-protein adducts in Lp(a) particles, that perpetuate atherosclerotic lesion progression and intima-media thickening through induction of M1-macrophages, inflammation, autoimmunity and apoptosis. The oxidation-specific epitopes of modified lipoproteins are major targets of pre-immune, natural IgM antibodies, that may attenuate the pro-inflammatory and pro-atherogenic effects of Lp(a).Although the data are still insufficient, recent studies suggest a potential anti-neoplastic role of Lp(a).

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“…Notably, autoantibodies of the IgE isotypes develop in T H 2-driven immunity in patients with lupus and atopic dermatitis, [25][26][27] and increased IgE levels seem to play a role in atherosclerosis. 28 The cellular immune response to allografts is recognized to include features of T H 2 immunity in some rejection settings. [29][30][31] However, the occurrence and potential relevance of IgE in graft-directed immunity in transplantation has not been investigated thus far.…”

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confidence: 99%