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Cited by 80Glycosylation and Glycoproteins ResearchXenotransplantation and immune responseCardiac Valve Diseases and Treatments

Characterization of immunogenic Neu5Gc in bioprosthetic heart valves

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Reuven, Eliran Moshe, Leviatan Ben‐Arye, Shani, Marshanski, Tal, Breimer, Michael E., Yu, Hai, Fellah‐Hebia, Imen, Roussel, Jean‐Christian, Costa, Cristina +7 more·2016·Xenotransplantation
DOI 10.1111/xen.12260PMC PMC5036590
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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.

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Authors
Reuven, E. M., Leviatan Ben‐Arye, S., Marshanski, T., Breimer, M. E., Yu, H., Fellah‐Hebia, I., Roussel, J., Costa, C., Galiñanes, M., Mañez, R., Le Tourneau, T., Soulillou, J., Cozzi, E., Chen, X., & Padler‐Karavani, V.
Affiliations
  • Tel Aviv University (IL)
  • Department of Cell Research and Immunology Tel Aviv University Tel Aviv Israel
  • University of Gothenburg (SE)
  • University of California, Davis (US)
  • Department of Thoracic and Cardiovascular Surgery Institut du Thorax University Hospital Nantes France
  • Centre Hospitalier Universitaire de Nantes (FR)
  • Institut d'Investigació Biomédica de Bellvitge (ES)
  • Vall d'Hebron Institut de Recerca (ES)
  • Infectious Diseases and Transplantation Division Bellvitge Biomedical Research Institute (IDIBELL) L'Hospitalet de Llobregat Barcelona Spain
  • Department of Cardiology Institut du Thorax University Hospital Nantes France
  • Inserm (FR)
  • University of Padua (IT)
Corresponding author
Padler‐Karavani, Vered
ORCID
Venue
Xenotransplantation
Publisher
Wiley
Published
2016-09
Volume
23
Issue
5
Pages
381-392
ISSN
  • 0908-665X (ISSN-L)
  • 1399-3089
DOI
10.1111/xen.12260
PMC
PMC5036590
OpenAlex
W2507761367
Cited by
80
References
1
Citations by year
2026: 3 · 2025: 8 · 2024: 6 · 2023: 9 · 2022: 10 · 2021: 3 · 2020: 9 · 2019: 12 · 2018: 11 · 2017: 8 · 2016: 1
FWCI
5.55
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 8 d)
Locations
  • Xenotransplantation (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • HAL (submittedVersion, other-oa)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
  • eScholarship (California Digital Library) (submittedVersion)
  • RECERCAT (Consorci de Serveis Universitaris de Catalunya) (submittedVersion, public-domain)
  • Padua Research Archive (University of Padova) (submittedVersion)
Funders
  • Leona M. and Harry B. Helmsley Charitable Trust
  • Seventh Framework Programme (PIIF‐GA‐2012‐327726, 603049)
  • National Institutes of Health (R01GM076360)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
  • Health Sciences › Medicine › Surgery › Xenotransplantation and immune response
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Valve Diseases and Treatments
Keywords
N-glycolylneuraminic acid, sialic acid, bioprosthetic heart valves, porcine aortic valve, porcine pericardium, bovine pericardium, glycan microarrays
MeSH terms
Animals, Antibodies, Bioprosthesis, Cattle, Heart Valves, Neuraminic Acids, Pericardium, Swine, Transplantation, Heterologous

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