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

26 Citations (Scopus)

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

Fingerprint

Heart Valves
Swine
Pericardium
Aortic Valve
Polysaccharides
Pulmonary Valve
Mammals
Heterophile Antigens
Sialic Acids
N-Acetylneuraminic Acid
Heterografts
Horses
Immunohistochemistry
High Pressure Liquid Chromatography
Carbohydrates
Antigens
Antibodies

Keywords

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

ASJC Scopus subject areas

  • Immunology
  • Transplantation

Cite this

Reuven, E. M., Leviatan Ben-Arye, S., Marshanski, T., Breimer, M. E., Yu, H., Fellah-Hebia, I., ... Padler-Karavani, V. (2016). Characterization of immunogenic Neu5Gc in bioprosthetic heart valves. Xenotransplantation, 23(5), 381-392. https://doi.org/10.1111/xen.12260

Characterization of immunogenic Neu5Gc in bioprosthetic heart valves. / Reuven, Eliran Moshe; Leviatan Ben-Arye, Shani; Marshanski, Tal; Breimer, Michael E.; Yu, Hai; Fellah-Hebia, Imen; Roussel, Jean Christian; Costa, Cristina; Galiñanes, Manuel; Mañez, Rafael; Le Tourneau, Thierry; Soulillou, Jean Paul; Cozzi, Emanuele; Chen, Xi; Padler-Karavani, Vered.

In: Xenotransplantation, Vol. 23, No. 5, 01.09.2016, p. 381-392.

Research output: Contribution to journalArticle

Reuven, EM, Leviatan Ben-Arye, S, Marshanski, T, Breimer, ME, Yu, H, Fellah-Hebia, I, Roussel, JC, Costa, C, Galiñanes, M, Mañez, R, Le Tourneau, T, Soulillou, JP, Cozzi, E, Chen, X & Padler-Karavani, V 2016, 'Characterization of immunogenic Neu5Gc in bioprosthetic heart valves', Xenotransplantation, vol. 23, no. 5, pp. 381-392. https://doi.org/10.1111/xen.12260
Reuven EM, Leviatan Ben-Arye S, Marshanski T, Breimer ME, Yu H, Fellah-Hebia I et al. Characterization of immunogenic Neu5Gc in bioprosthetic heart valves. Xenotransplantation. 2016 Sep 1;23(5):381-392. https://doi.org/10.1111/xen.12260
Reuven, Eliran Moshe ; Leviatan Ben-Arye, Shani ; Marshanski, Tal ; Breimer, Michael E. ; Yu, Hai ; Fellah-Hebia, Imen ; Roussel, Jean Christian ; Costa, Cristina ; Galiñanes, Manuel ; Mañez, Rafael ; Le Tourneau, Thierry ; Soulillou, Jean Paul ; Cozzi, Emanuele ; Chen, Xi ; Padler-Karavani, Vered. / Characterization of immunogenic Neu5Gc in bioprosthetic heart valves. In: Xenotransplantation. 2016 ; Vol. 23, No. 5. pp. 381-392.
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T1 - Characterization of immunogenic Neu5Gc in bioprosthetic heart valves

AU - Reuven, Eliran Moshe

AU - Leviatan Ben-Arye, Shani

AU - Marshanski, Tal

AU - Breimer, Michael E.

AU - Yu, Hai

AU - Fellah-Hebia, Imen

AU - Roussel, Jean Christian

AU - Costa, Cristina

AU - Galiñanes, Manuel

AU - Mañez, Rafael

AU - Le Tourneau, Thierry

AU - Soulillou, Jean Paul

AU - Cozzi, Emanuele

AU - Chen, Xi

AU - Padler-Karavani, Vered

PY - 2016/9/1

Y1 - 2016/9/1

N2 - 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.

AB - 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.

KW - immunology

KW - Neu5Gc

KW - transplantation

KW - valvular heart disease

KW - xeno-antigens

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