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Elicited and pre‐existing anti‐Neu5Gc antibodies differentially affect human endothelial cells transcriptome

Ludmilla Le Berre 1, 2 Richard Danger 1, 2 Hoa Le Mai 3, 2 Ron Amon 4 Shani Leviatan Ben‐arye Sarah Bruneau 1, 2 Thomas Sénage 5 Hélène Perreault 6 Milan Teraiya 6 Thi van Ha Nguyen 1, 2 Thierry Le Tourneau 7 Hai yu 8 Xi Chen 8 Cesare Galli 9 Jean‐christian Roussel 5 Rafael Mañez 10, 11 Cristina E. Costa 10 Sophie Brouard 1, 2 Manuel Galiñanes 12 Kristina M Harris 13 Stephen E Gitelman 14 Emanuele Cozzi 15 Béatrice Charreau 1, 2 Vered Padler‐karavani 4 Jean‐paul Soulillou 1, 2 
Abstract : Humans cannot synthesizeN-glycolylneuraminic acid (Neu5Gc) but dietary Neu5Gc can be absorbed and deposited on endothelial cells (ECs) and diet-induced anti-Neu5Gc antibodies (Abs) develop early in human life. While the interaction of Neu5Gc and diet‐induced anti‐Neu5Gc Abs occurs in all normal individuals, endothelium activa-tion by elicited anti‐Neu5Gc Abs following a challenge with animal‐derived materials, such as following xenotransplantation, had been postulated. Ten primary human EC preparations were cultured with affinity‐purified anti‐Neu5Gc Abs from human sera obtained before or after exposure to Neu5Gc‐glycosylated rabbit IgGs (elicited Abs). RNAs of each EC preparation stimulated in various conditions by purified Abs were exhaustively sequenced. EC transcriptomic patterns induced by elicited anti-Neu5Gc Abs, compared with pre‐existing ones, were analyzed. qPCR, cytokines/chemokines release, and apoptosis were tested on some EC preparations. The data showed that anti‐Neu5Gc Abs induced 967 differentially expressed (DE) genes. Most DE genes are shared following EC activation by pre‐existing or anti‐human T‐cell globulin (ATG)‐elicited anti‐Neu5Gc Abs. Compared with pre‐existing anti‐Neu5Gc Abs, which are normal component of ECs environment, elicited anti‐Neu5Gc Abs down‐regulated 66 genes, including master genes of EC function. Furthermore, elicited anti-Neu5Gc Abs combined with complement‐containing serum down‐regulated most transcripts mobilized by serum alone. Both types of anti‐Neu5Gc Abs‐induced a dose‐ and com-plement‐dependent release of selected cytokines and chemokines. Altogether, these data show that, compared with pre‐existing anti‐Neu5Gc Abs, ATG‐elicited anti‐Neu5Gc Abs specifically modulate genes related to cytokine responses, MAPkinase cascades, chemotaxis, and integrins and do not skew the EC transcriptome toward a pro-inflammatory profile in vitro.
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Submitted on : Tuesday, October 29, 2019 - 11:45:54 AM
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Ludmilla Le Berre, Richard Danger, Hoa Le Mai, Ron Amon, Shani Leviatan Ben‐arye, et al.. Elicited and pre‐existing anti‐Neu5Gc antibodies differentially affect human endothelial cells transcriptome. Xenotransplantation, Wiley, 2019, pp.e12535. ⟨10.1111/xen.12535⟩. ⟨inserm-02337077⟩



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