Comparative profiling of HLA-DR and HLA-DQ associated factor VIII peptides presented by monocyte-derived dendritic cells

Peyron, Ivan; Hartholt, Robin B.; Pedró-Cos, Laura; Alphen, Floris van; Brinke, Anja ten; Lardy, Neubury M.; Meijer, Alexander B.; Voorberg, Jan

doi:10.3324/haematol.2017.175083

Cited by 19 publications

(28 citation statements)

References 39 publications

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“…HLA-DR and HLA-DQ molecules were purified employing monoclonal antibodies directed against HLA-DR (L243) and HLA-DQ (SPV-L3), 22 and the eluates were analyzed by mass-spectrometry. In agreement with our previous reports, 19 , 23 , 25 peptides derived from endogenously expressed as well as internalized proteins were presented on HLA-DR and HLA-DQ ( Online Supplementary Table S1A and B , respectively). A subset of peptides was derived from proteins that are found within the endolysosomal compartment; these include HLA-DR itself, several proteases (such as cathepsin B) and endocytic receptors (such as the macrophage mannose receptor and prolow-density lipoprotein receptor-related protein 1).…”

Section: Resultssupporting

confidence: 92%

“…Mo-DCs from the same panel of donors were recently analyzed for the presentation of FVIII-derived peptides on HLA-DQ. 25 Mo-DCs were incubated with 1 μg/mL LPS and 1% fetal calf serum to allow for their maturation. HLA-DR and HLA-DQ molecules were purified employing monoclonal antibodies directed against HLA-DR (L243) and HLA-DQ (SPV-L3), 22 and the eluates were analyzed by mass-spectrometry.…”

Section: Resultsmentioning

confidence: 99%

“…This is most likely explained by the higher expression of HLA-DR on dendritic cells when compared to HLA-DQ. 25 , 34 , 35 Furthermore, this could also result from an overall lower binding affinity of peptides for HLA-DQ when compared to HLA-DR. Indeed, the NetMHCIIpan3.1 prediction tool suggests a higher binding affinity of ADAMTS13-derived peptides to HLA-DR when compared to HLA-DQ.…”

Section: Discussionmentioning

confidence: 99%

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Mass spectrometry-assisted identification of ADAMTS13-derived peptides presented on HLA-DR and HLA-DQ

et al. 2018

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Formation of microthrombi is a hallmark of acquired thrombotic thrombocytopenic purpura. These microthrombi originate from insufficient processing of ultra large von Willebrand factor multimers by ADAMTS13 due to the development of anti-ADAMTS13 autoantibodies. Several studies have identified the major histocompatibility complex class II alleles HLA-DRB1*11, HLA-DQB1*03 and HLA-DQB1*02:02 as risk factors for acquired thrombotic thrombocytopenic purpura development. Previous research in our department indicated that ADAMTS13 CUB2 domain-derived peptides FINVAPHAR and LIRDTHSLR are presented on HLA-DRB1*11 and HLA-DRB1*03, respectively. Here, we describe the repertoire of ADAMTS13 peptides presented on HLA-DQ. In parallel, the repertoire of ADAMTS13-derived peptides presented on HLA-DR was monitored. Using HLA-DR- and HLA-DQ-specific antibodies, we purified HLA/peptide complexes from ADAMTS13-pulsed monocyte-derived dendritic cells. Using this approach, we identified ADAMTS13-derived peptides presented on HLA-DR for all 9 samples analyzed; ADAMTS13-derived peptides presented on HLA-DQ were identified in 4 out of 9 samples. We were able to confirm the presentation of the CUB2 domain-derived peptides FINVAPHAR and LIRDTHSLR on HLA-DR. In total, 12 different core-peptide sequences were identified on HLA-DR and 8 on HLA-DQ. For HLA-DR11, several potential new core-peptides were found; 4 novel core-peptides were exclusively identified on HLA-DQ. Furthermore, an in silico analysis was performed using the EpiMatrix and JanusMatrix tools to evaluate the eluted peptides, in the context of HLA-DR, for putative effector or regulatory T-cell responses at the population level. The results from this study provide a basis for the identification of immuno-dominant epitopes on ADAMTS13 involved in the onset of acquired thrombotic thrombocytopenic purpura.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Mass spectrometry-assisted identification of ADAMTS13-derived peptides presented on HLA-DR and HLA-DQ

et al. 2018

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“…However, recent data have suggested that residues within the C1 and C2 domain are associated with the uptake of FVIII by dendritic cells, which can elicit an immune response. 28 In addition, amino acid 2085 is located on a peptide that is frequently associated with histocompatibility leukocyte antigen (HLA) molecules, 29 and the two de novo mutations 2157 and 2159 are located in a T cell epitope. 30 Therefore, whether the JF12 modifications affect inhibitor formation or any other immunological properties will require further evaluation.…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Coagulation Activity Determining Elements in Canine Factor VIII

Firrman

Wang

et al. 2020

Molecular Therapy - Methods & Clinical Development

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It is well known that canine factor VIII (cFVIII) has a higher specific activity than does human FVIII (hFVIII), and it has been previously demonstrated that cFVIII light chain is able to enhance hFVIII activity. The goal of this study was to first determine which amino acids in cFVIII light chain were responsible for enhancing hFVIII activity, and second to use these amino acids to develop a hFVIII variant with enhanced functional activity. We systemically screened segments of cFVIII light chain by testing an array of human-canine light chain hybrids and found that canine amino acids 1857-2147 were key to this enhancement. Each canine amino acid within this span was screened individually using a negative selection method, which led to the identification of 12 aa (JF12) in the FVIII light chain that could enhance activity. Substitution of the corresponding 12 aa into hFVIII (hFVIIIJF12BDD) elevated the specific activity profile in vitro. Furthermore, hFVIIIJF12BDD expressed an in vivo-displayed increased coagulation activity compared to wild-type, while maintaining normal secretion efficiency. In conclusion, we identified the amino acids in cFVIII that are the key determinants for higher specific activity and may be the basis for future development of therapeutic treatments for hemophilia A.

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“…Studies in which monocyte-derived dendritic cells were pulsed with FVIII, followed by peptide elution and identification by LC-mass spectrometry, have yielded valuable insights into the repertoires of FVIII-derived peptides that can be presented on various MHC class II, and thereby made available for potential recognition by CD4 + T cells (60)(61)(62)(63)(64)(65). Together with complementary studies characterizing CD4 + T-cell responses, which are discussed in detail later in this review, this provides detailed information identifying naturally processed FVIII peptides.…”

Section: Fviii Uptake Processing and Presentationmentioning

confidence: 99%

Tolerating Factor VIII: Recent Progress

et al. 2020

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Development of neutralizing antibodies against biotherapeutic agents administered to prevent or treat various clinical conditions is a longstanding and growing problem faced by patients, medical providers and pharmaceutical companies. The hemophilia A community has deep experience with attempting to manage such deleterious immune responses, as the lifesaving protein drug factor VIII (FVIII) has been in use for decades. Hemophilia A is a bleeding disorder caused by genetic mutations that result in absent or dysfunctional FVIII. Prophylactic treatment consists of regular intravenous FVIII infusions. Unfortunately, 1/4 to 1/3 of patients develop neutralizing anti-FVIII antibodies, referred to clinically as "inhibitors," which result in a serious bleeding diathesis. Until recently, the only therapeutic option for these patients was "Immune Tolerance Induction," consisting of intensive FVIII administration, which is extraordinarily expensive and fails in ∼30% of cases. There has been tremendous recent progress in developing novel potential clinical alternatives for the treatment of hemophilia A, ranging from encouraging results of gene therapy trials, to use of other hemostatic agents (either promoting coagulation or slowing down anti-coagulant or fibrinolytic pathways) to "bypass" the need for FVIII or supplement FVIII replacement therapy. Although these approaches are promising, there is widespread agreement that preventing or reversing inhibitors remains a high priority. Risk profiles of novel therapies are still unknown or incomplete, and FVIII will likely continue to be considered the optimal hemostatic agent to support surgery and manage trauma, or to combine with other therapies. We describe here recent exciting studies, most still pre-clinical, that address FVIII immunogenicity and suggest novel interventions to prevent or reverse inhibitor development. Studies of FVIII uptake, processing and presentation on antigen-presenting cells, epitope mapping, and the roles of complement, heme, von Willebrand factor, glycans, and the microbiome in FVIII immunogenicity are elucidating mechanisms of primary and secondary immune responses and suggesting additional novel targets. Promising tolerogenic therapies include development of FVIII-Fc fusion proteins, nanoparticle-based therapies, oral tolerance, and engineering of regulatory or cytotoxic T cells to render them FVIII-specific. Importantly, these studies are highly applicable to other scenarios where establishing immune tolerance to a defined antigen is a clinical priority.

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Comparative profiling of HLA-DR and HLA-DQ associated factor VIII peptides presented by monocyte-derived dendritic cells

Cited by 19 publications

References 39 publications

Mass spectrometry-assisted identification of ADAMTS13-derived peptides presented on HLA-DR and HLA-DQ

Mass spectrometry-assisted identification of ADAMTS13-derived peptides presented on HLA-DR and HLA-DQ

Identification of Key Coagulation Activity Determining Elements in Canine Factor VIII

Tolerating Factor VIII: Recent Progress

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