TY - JOUR
T1 - B cell-derived anti-beta 2 glycoprotein I antibody contributes to hyperhomocysteinaemia-aggravated abdominal aortic aneurysm
AU - Shao, Fangyu
AU - Miao, Yutong
AU - Zhang, Yan
AU - Han, Lulu
AU - Ma, Xiaolong
AU - Deng, Jiacheng
AU - Jiang, Changtao
AU - Kong, Wei
AU - Xu, Qingbo
AU - Feng, Juan
AU - Wang, Xian
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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.
AB - 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.
KW - Abdominal aortic aneurysm
KW - Anti-b GPI IgG
KW - B cells
KW - Homocysteine
UR - http://www.scopus.com/inward/record.url?scp=85088791942&partnerID=8YFLogxK
U2 - 10.1093/cvr/cvz288
DO - 10.1093/cvr/cvz288
M3 - Article
C2 - 31782769
AN - SCOPUS:85088791942
SN - 0008-6363
VL - 116
SP - 1897
EP - 1909
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 11
ER -
