Characterization of immunogenic Neu5Gc in bioprosthetic heart valves

Eliran Moshe Reuven, Shani Leviatan Ben-Arye, Tal Marshanski, Michael E. Breimer, Hai Yu, Imen Fellah-Hebia, Jean Christian Roussel, Cristina Costa, Manuel Galiñanes, Rafael Mañez, Thierry Le Tourneau, Jean Paul Soulillou, Emanuele Cozzi, Xi Chen, Vered Padler-Karavani

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Background: The two common sialic acids (Sias) in mammals are N-acetylneuraminic acid (Neu5Ac) and its hydroxylated form N-glycolylneuraminic acid (Neu5Gc). Unlike most mammals, humans cannot synthesize Neu5Gc that is considered foreign and recognized by circulating antibodies. Thus, Neu5Gc is a potential xenogenic carbohydrate antigen in bioprosthetic heart valves (BHV) that tend to deteriorate in time within human patients. Methods: We investigated Neu5Gc expression in non-engineered animal-derived cardiac tissues and in clinically used commercial BHV, and evaluated Neu5Gc immunogenicity on BHV through recognition by human anti-Neu5Gc IgG. Results: Neu5Gc was detected by immunohistochemistry in porcine aortic valves and in porcine and bovine pericardium. Qualitative analysis of Sia linkages revealed Siaα2-3>Siaα2-6 on porcine/bovine pericardium while the opposite in porcine aortic/pulmonary valve cusps. Similarly, six commercial BHV containing either porcine aortic valve or porcine/bovine/equine pericardium revealed Siaα2-3>Siaα2-6 expression. Quantitative analysis of Sia by HPLC showed porcine/bovine pericardium express 4-fold higher Neu5Gc levels compared to the porcine aortic/pulmonary valves, with Neu5Ac at 6-fold over Neu5Gc. Likewise, Neu5Gc was expressed on commercial BHV (186.3±16.9 pmol Sia/μg protein), with Neu5Ac at 8-fold over Neu5Gc. Affinity-purified human anti-Neu5Gc IgG showing high specificity toward Neu5Gc-glycans (with no binding to Neu5Ac-glycans) on a glycan microarray, strongly bound to all tested commercial BHV, demonstrating Neu5Gc immune recognition in cardiac xenografts. Conclusions: We conclusively demonstrated Neu5Gc expression in native cardiac tissues, as well as in six commercial BHV. These Neu5Gc xeno-antigens were recognized by human anti-Neu5Gc IgG, supporting their immunogenicity. Altogether, these findings suggest BHV-Neu5Gc/anti-Neu5Gc may play a role in valve deterioration warranting further investigation.

Original languageEnglish (US)
Pages (from-to)381-392
Number of pages12
JournalXenotransplantation
Volume23
Issue number5
DOIs
StatePublished - Sep 1 2016

Keywords

  • immunology
  • Neu5Gc
  • transplantation
  • valvular heart disease
  • xeno-antigens

ASJC Scopus subject areas

  • Immunology
  • Transplantation

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    Reuven, E. M., Leviatan Ben-Arye, S., Marshanski, T., Breimer, M. E., Yu, H., Fellah-Hebia, I., Roussel, J. C., Costa, C., Galiñanes, M., Mañez, R., Le Tourneau, T., Soulillou, J. P., Cozzi, E., Chen, X., & Padler-Karavani, V. (2016). Characterization of immunogenic Neu5Gc in bioprosthetic heart valves. Xenotransplantation, 23(5), 381-392. https://doi.org/10.1111/xen.12260