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B cell-derived anti-beta 2 glycoprotein I antibody contributes to hyperhomocysteinaemia-aggravated abdominal aortic aneurysm

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Fangyu Shao, Yutong Miao, Yan Zhang, Lulu Han, Xiaolong Ma, Jiacheng Deng, Changtao Jiang, Wei Kong, Qingbo Xu, Juan Feng, Xian Wang

Original languageEnglish
Pages (from-to)1897-1909
Number of pages13
JournalCardiovascular Research
Volume116
Issue number11
DOIs
Published1 Sep 2020

King's Authors

Abstract

Aims Overactivated B cells secrete pathological antibodies, which in turn accelerate the formation of abdominal aortic aneurysms (AAAs). Hyperhomocysteinaemia (HHcy) aggravates AAA in mice; however, the underlying mechanisms remain largely elusive. In this study, we further investigated whether homocysteine (Hcy)-activated B cells produce antigen-specific antibodies that ultimately contribute to AAA formation. Methods ELISA assays showed that HHcy induced the secretion of anti-beta 2 glycoprotein I (anti-b 2GPI) antibody from B and results cells both in vitro and in vivo. Mechanistically, Hcy increased the accumulation of various lipid metabolites in B cells tested by liquid chromatography-tandem mass spectrometry, which contributed to elevated anti-b 2GPI IgG secretion. By using the toll-like receptor 4 (TLR4)-specific inhibitor TAK-242 or TLR4-deficient macrophages, we found that culture supernatants from Hcy-activated B cells and HHcy plasma IgG polarized inflammatory macrophages in a TLR4-dependent manner. In addition, HHcy markedly increased the incidence of elastase- and CaPO 4-induced AAA in male BALB/c mice, which was prevented in lMT mice. To further determine the importance of IgG in HHcy-aggravated AAA formation, we purified plasma IgG from HHcy or control mice and then transferred the IgG into lMT mice, which were subsequently subjected to elastase- or CaPO 4-induced AAA. Compared with lMT mice that received plasma IgG from control mice, lMT mice that received HHcy plasma IgG developed significantly exacerbated elastase- or CaPO 4-induced AAA accompanied by increased elastin degradation, MMP2/9 expression, and anti-b 2GPI IgG deposition in vascular lesions, as shown by immunofluorescence histochemical staining. Conclusion Our findings reveal a novel mechanism by which Hcy-induced B cell-derived pathogenic anti-b 2GPI IgG might, at least in part, contribute to HHcy-aggravated chronic vascular inflammation and AAA formation.

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