FVIII peptides presented on HLA-DP and identification of an A3 domain peptide binding with high affinity to the commonly expressed HLA-DP4
The development of neutralizing antibodies (inhibitors) against coagulation factor VIII (FVIII) poses a major challenge in hemophilia A (HA) treatment. The formation of FVIII inhibitors is a CD4+ T-cell dependent mechanism which includes antigen presenting cells (APCs), B- and T-helper lymphocytes....
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| Format: | Article |
| Language: | English |
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Ferrata Storti Foundation
2024-12-01
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| Series: | Haematologica |
| Online Access: | https://haematologica.org/article/view/11868 |
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| author | Mariarosaria Miranda Bjarke Endel Hansen Batoul Wehbi Valeria Porcheddu Floris P.J. van Alphen Paul Kaijen Karin Fijnvandraat Sebastien Lacroix-Desmazes Maartje van den Biggelaar Bernard Maillere Jan Voorberg EDUC8 Consortium |
| author_facet | Mariarosaria Miranda Bjarke Endel Hansen Batoul Wehbi Valeria Porcheddu Floris P.J. van Alphen Paul Kaijen Karin Fijnvandraat Sebastien Lacroix-Desmazes Maartje van den Biggelaar Bernard Maillere Jan Voorberg EDUC8 Consortium |
| author_sort | Mariarosaria Miranda |
| collection | DOAJ |
| description |
The development of neutralizing antibodies (inhibitors) against coagulation factor VIII (FVIII) poses a major challenge in hemophilia A (HA) treatment. The formation of FVIII inhibitors is a CD4+ T-cell dependent mechanism which includes antigen presenting cells (APCs), B- and T-helper lymphocytes. APCs present FVIII derived peptides on major histocompatibility complex class II (MHC-II) to CD4+ Tcells. We previously established a mass spectrometry based approach to delineate the FVIII repertoire presented on HLA-DR and HLA-DQ. In this study, specific attention was directed towards the identification of FVIII peptides presented on HLA-DP. A data-set of naturally processed FVIII peptides was generated by incubating human FVIII with immature monocytes-derived dendritic cells (moDCs) from HLA-typed healthy donors. Using this method, we identified 176 to 1352 different HLA-DP presented peptides per donor, including 26 different FVIII derived peptides. The most frequently presented peptides derived from the A3, and C2 domains of FVIII. Comparison of the FVIII repertoire presented on HLA-DP with that presented on HLA-DR revealed considerable overlap but also suggested preferential presentation of specific peptides on either HLA-DR or HLA-DP. Fourteen FVIII peptides presented on HLA-DP were synthesized and evaluated for their binding ability to the commonly expressed HLA-DP4 molecule which is highly prevalent in the Caucasian population. Peptide binding studies showed that 7 of 14 peptides competed with a reference peptide to HLADP4. Interestingly, an A3 domain derived peptide bound with high affinity to HLA-DP4 positioning this peptide as a prime candidate for the development of novel peptide-based tolerogenic strategies for FVIII inhibitors.
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| format | Article |
| id | doaj-art-1d3765a7344b47d59f82ebbd401adcb1 |
| institution | Kabale University |
| issn | 0390-6078 1592-8721 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Ferrata Storti Foundation |
| record_format | Article |
| series | Haematologica |
| spelling | doaj-art-1d3765a7344b47d59f82ebbd401adcb12024-12-12T19:43:09ZengFerrata Storti FoundationHaematologica0390-60781592-87212024-12-01999110.3324/haematol.2024.286204FVIII peptides presented on HLA-DP and identification of an A3 domain peptide binding with high affinity to the commonly expressed HLA-DP4Mariarosaria Miranda0Bjarke Endel Hansen1Batoul Wehbi2Valeria Porcheddu3Floris P.J. van Alphen4Paul Kaijen5Karin Fijnvandraat6Sebastien Lacroix-Desmazes7Maartje van den Biggelaar8Bernard Maillere9Jan Voorberg10EDUC8 Consortium11Department of Molecular Hematology, Sanquin Research and Landsteiner Laboratory, AmsterdamImmudex, Copenhagen, DenmarkUniversite Paris-Saclay, C EA, INRAE, Departement Medicaments et T echnologies pour la Sante, SIMoS, Gif-sur-Y vetteUniversite Paris-Saclay, C EA, INRAE, Departement Medicaments et T echnologies pour la Sante, SIMoS, Gif-sur-Y vetteDepartment of Molecular Hematology, Sanquin Research and Landsteiner Laboratory, AmsterdamDepartment of Molecular Hematology, Sanquin Research and Landsteiner Laboratory, AmsterdamDepartment of Molecular Hematology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands; Amsterdam University Medical Center location University of Amsterdam, Department of Pediatric Hematology, AmsterdamInstitut National de la Sante et de la Recherche Medicale, Centre de Recherche des Cordeliers, CNRS, Sorbonne Universite, Universite Paris Cite, ParisDepartment of Molecular Hematology, Sanquin Research and Landsteiner Laboratory, AmsterdamUniversite Paris-Saclay, CEA, INRAE, Departement Medicaments et Technologies pourla Sante, SIMoS, Gif-sur-Y vetteDepartment of Molecular Hematology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands; Department of Experimental V ascular Medicine, Amsterdam University Medical C enter, AmsterdamFlora Peyvandi, Christoph Koenigs, Johannes Oldenburg, Yvette van Kooyk, Bernard Maillère, Sebastien Lacroix-Desmazes, Jan Voorberg The development of neutralizing antibodies (inhibitors) against coagulation factor VIII (FVIII) poses a major challenge in hemophilia A (HA) treatment. The formation of FVIII inhibitors is a CD4+ T-cell dependent mechanism which includes antigen presenting cells (APCs), B- and T-helper lymphocytes. APCs present FVIII derived peptides on major histocompatibility complex class II (MHC-II) to CD4+ Tcells. We previously established a mass spectrometry based approach to delineate the FVIII repertoire presented on HLA-DR and HLA-DQ. In this study, specific attention was directed towards the identification of FVIII peptides presented on HLA-DP. A data-set of naturally processed FVIII peptides was generated by incubating human FVIII with immature monocytes-derived dendritic cells (moDCs) from HLA-typed healthy donors. Using this method, we identified 176 to 1352 different HLA-DP presented peptides per donor, including 26 different FVIII derived peptides. The most frequently presented peptides derived from the A3, and C2 domains of FVIII. Comparison of the FVIII repertoire presented on HLA-DP with that presented on HLA-DR revealed considerable overlap but also suggested preferential presentation of specific peptides on either HLA-DR or HLA-DP. Fourteen FVIII peptides presented on HLA-DP were synthesized and evaluated for their binding ability to the commonly expressed HLA-DP4 molecule which is highly prevalent in the Caucasian population. Peptide binding studies showed that 7 of 14 peptides competed with a reference peptide to HLADP4. Interestingly, an A3 domain derived peptide bound with high affinity to HLA-DP4 positioning this peptide as a prime candidate for the development of novel peptide-based tolerogenic strategies for FVIII inhibitors. https://haematologica.org/article/view/11868 |
| spellingShingle | Mariarosaria Miranda Bjarke Endel Hansen Batoul Wehbi Valeria Porcheddu Floris P.J. van Alphen Paul Kaijen Karin Fijnvandraat Sebastien Lacroix-Desmazes Maartje van den Biggelaar Bernard Maillere Jan Voorberg EDUC8 Consortium FVIII peptides presented on HLA-DP and identification of an A3 domain peptide binding with high affinity to the commonly expressed HLA-DP4 Haematologica |
| title | FVIII peptides presented on HLA-DP and identification of an A3 domain peptide binding with high affinity to the commonly expressed HLA-DP4 |
| title_full | FVIII peptides presented on HLA-DP and identification of an A3 domain peptide binding with high affinity to the commonly expressed HLA-DP4 |
| title_fullStr | FVIII peptides presented on HLA-DP and identification of an A3 domain peptide binding with high affinity to the commonly expressed HLA-DP4 |
| title_full_unstemmed | FVIII peptides presented on HLA-DP and identification of an A3 domain peptide binding with high affinity to the commonly expressed HLA-DP4 |
| title_short | FVIII peptides presented on HLA-DP and identification of an A3 domain peptide binding with high affinity to the commonly expressed HLA-DP4 |
| title_sort | fviii peptides presented on hla dp and identification of an a3 domain peptide binding with high affinity to the commonly expressed hla dp4 |
| url | https://haematologica.org/article/view/11868 |
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