Dataset Information

FVIII peptides presented on HLA-DP and identification of an A3 domain peptide binding with high affinity to the commonly expressed HLA-DP4

ABSTRACT: 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 anti- gen presenting cells (APC), B- and T-helper lymphocytes. APC present FVIII-derived peptides on major histocompatibility complex class II (MHC-II) to CD4+ T cells. 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 monocyte-derived dendritic cells (moDC) from HLA-typed healthy donors. Using this method, we iden- tified 176 to 1,352 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 evalu- ated 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 HLA-DP4. Interest- ingly, 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood

DISEASE(S): Autosomal Hemophilia A

SUBMITTER: Arie Hoogendijk

LAB HEAD: A.J. Hoogendijk

PROVIDER: PXD069096 | Pride | 2025-10-03

REPOSITORIES: Pride

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FVIII peptides presented on HLA-DP and identification of an A3 domain peptide binding with high affinity to the commonly expressed HLA-DP4.

Miranda Mariarosaria M Hansen Bjarke Endel BE Wehbi Batoul B Porcheddu Valeria V Van Alphen Floris P J FPJ Kaijen Paul P Fijnvandraat Karin K Lacroix-Desmazes Sebastien S Van den Biggelaar Maartje M Maillere Bernard B Voorberg Jan J Consortium Educ E

Haematologica 20241212 6

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 (APC), B- and T-helper lymphocytes. APC present FVIII-derived peptides on major histocompatibility complex class II (MHC-II) to CD4+ T cells. We previously established a mass spectrometry-based approach to delineate the FVIII repertoire ...[more]

PMID: 39665218

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Project description:HLA-DR molecules are highly expressed in synovial tissue (ST), the target of the immune response in chronic inflammatory arthritides, including in rheumatoid arthritis (RA) and Lyme arthritis (LA). In the current study, we identified HLA-DR-presented self-peptides (T cell epitopes) in ST, synovial fluid mononuclear cells (SF), and peripheral blood mononuclear cells (PB) from five patients with RA and eight with LA. Altogether, from 22 samples, 1,532 non-redundant HLA-DR-presented peptides were identified that were derived from 778 source proteins. Moreover, as the study progressed, application of newer, high sensitivity LC-MS instruments resulted in the identification of larger numbers of HLA-DR-presented peptides. Surprisingly, the source proteins for HLA-DR-presented peptides were as likely to have intracellular as extracellular locations. Although the number of peptides identified was greater in ST than in SF or PB, 68% of the peptides identified in SF were found in ST, and 55% of the peptides in PB were found in ST. Two RA patients had the same HLA-DR genotype (DRB1*0401 and 0101), and 44% of the peptides identified in these two patients were the same. In contrast, among the patients with RA or LA who had no shared HLA-DR alleles, only 6% of the peptides were the same. In the RA patients, HLA-DR-presented peptides were identified from source proteins that are thought to serve as potential autoantigens: collagen, enolase, fibrinogen, fibronectin, immunoglobulin and vimentin. Interestingly, peptides from these same source proteins were also commonly found in LA patients. However, citrullinated T cell epitopes were not identified in any patient. Thus, LC-MS/MS techniques are now sensitive enough to identify large numbers of T cell epitopes from tissue or fluids in individual patients. Importantly, analysis of SF or PB allowed us to identify a broader range of HLA-DR-presented self-peptides from individual patients and from patients seen earlier in the disease.

			Action	DRS
	DonorA_FVIII_HLA-DP.raw	Raw
	DonorA_FVIII_HLA-DR.raw	Raw
	DonorB_FVIII_HLA-DP.raw	Raw
	DonorB_FVIII_HLA-DR.raw	Raw
	DonorC_FVIII_HLA-DP.raw	Raw