scholarly journals Identification of Flucloxacillin-Haptenated HLA-B*57:01 Ligands: Evidence of Antigen Processing and Presentation

2020 ◽  
Vol 177 (2) ◽  
pp. 454-465 ◽  
Author(s):  
James C Waddington ◽  
Xiaoli Meng ◽  
Patricia T Illing ◽  
Arun Tailor ◽  
Kareena Adair ◽  
...  
Keyword(s):  
Antigen Processing ◽  
Protein Modification ◽  
Human Leukocyte ◽  
Peptide Ligands ◽  
Drug Induced ◽  
Leukocyte Antigen ◽  
Lactam Antibiotic ◽  
Hla Ligands ◽  
Antigen Presenting ◽  
Antigen Processing And Presentation

Abstract Flucloxacillin is a β-lactam antibiotic associated with a high incidence of drug-induced liver reactions. Although expression of human leukocyte antigen (HLA)-B*57:01 increases susceptibility, little is known of the pathological mechanisms involved in the induction of the clinical phenotype. Irreversible protein modification is suspected to drive the reaction through the modification of peptides that are presented by the risk allele. In this study, the binding of flucloxacillin to immune cells was characterized and the nature of the peptides presented by HLA-B*57:01 was analyzed using mass spectrometric-based immunopeptidomics methods. Flucloxacillin modification of multiple proteins was observed, providing a potential source of neoantigens for HLA presentation. Of the peptides eluted from flucloxacillin-treated C1R-B*57:01 cells, 6 putative peptides were annotated as flucloxacillin-modified HLA-B*57:01 peptide ligands (data are available via ProteomeXchange with identifier PXD020137). To conclude, we have characterized naturally processed drug-haptenated HLA ligands presented on the surface of antigen presenting cells that may drive drug-specific CD8+ T-cell responses.

scholarly journals CIITA-transduced glioblastoma cells uncover a rich repertoire of clinically relevant tumor-associated HLA-II antigens

2020 ◽  
pp. mcp.RA120.002201
Author(s):  
Greta Forlani ◽  
Justine Michaux ◽  
HuiSong Pak ◽  
Florian Huber ◽  
Elodie Lauret Marie Joseph ◽  
...  
Keyword(s):  
Cell Lines ◽  
Tumor Antigens ◽  
Therapeutic Potential ◽  
Human Leukocyte ◽  
Class Ii ◽  
Leukocyte Antigen ◽  
Hla Ligands ◽  
Tumor Types ◽  
Antigen Presenting ◽  
Cancer Immunotherapies

CD4+ T cell responses are crucial for inducing and maintaining effective anti-cancer immunity, and the identification of human leukocyte antigen class II (HLA-II) cancer-specific epitopes is key to the development of potent cancer immunotherapies. In many tumor types, and especially in glioblastoma (GBM), HLA-II complexes are hardly ever naturally expressed. Hence, little is known about immunogenic HLA-II epitopes in GBM. With stable expression of the class II major histocompatibility complex transactivator (CIITA) coupled to a detailed and sensitive mass spectrometry based immunopeptidomics analysis, we here uncovered a remarkable breadth of the HLA-ligandome in HROG02, HROG17 and RA GBM cell lines. The effect of CIITA expression on the induction of the HLA-II presentation machinery was striking in each of the three cell lines, and it was significantly higher compared to interferon gamma (IFNɣ) treatment. In total, we identified 16,123 unique HLA-I peptides and 32,690 unique HLA-II peptides. In order to genuinely define the identified peptides as true HLA ligands, we carefully characterized their association with the different HLA allotypes. In addition, we identified 138 and 279 HLA-I and HLA-II ligands, respectively, most of which are novel in GBM, derived from known GBM-associated tumor-antigens that have been used as source proteins for a variety of GBM vaccines. Our data further indicate that CIITA-expressing GBM cells acquired an antigen presenting cell-like phenotype as we found that they directly present external proteins as HLA-II ligands. Not only that CIITA-expressing GBM cells are attractive models for antigen discovery endeavors, but also such engineered cells have great therapeutic potential through massive presentation of a diverse antigenic repertoire.

scholarly journals Differential Gene Expression Analysis of Placentas with Increased Vascular Resistance and Pre-Eclampsia Using Whole-Genome Microarrays

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
M. Centlow ◽  
C. Wingren ◽  
C. Borrebaeck ◽  
M. J. Brownstein ◽  
S. R. Hansson
Keyword(s):  
Antigen Processing ◽  
Human Leukocyte ◽  
Placental Tissue ◽  
Whole Genome ◽  
Nf Kappa B ◽  
Antibody Microarrays ◽  
Expression Of Genes ◽  
Increased Risk ◽  
Antigen Presenting ◽  
Antigen Processing And Presentation

Pre-eclampsia is a pregnancy complication characterized by hypertension and proteinuria. There are several factors associated with an increased risk of developing pre-eclampsia, one of which is increased uterine artery resistance, referred to as “notching”. However, some women do not progress into pre-eclampsia whereas others may have a higher risk of doing so. The placenta, central in pre-eclampsia pathology, may express genes associated with either protection or progression into pre-eclampsia. In order to search for genes associated with protection or progression, whole-genome profiling was performed. Placental tissue from 15 controls, 10 pre-eclamptic, 5 pre-eclampsia with notching, and 5 with notching only were analyzed using microarray and antibody microarrays to study some of the same gene product and functionally related ones. The microarray showed 148 genes to be significantly altered between the four groups. In the preeclamptic group compared to notch only, there was increased expression of genes related to chemotaxis and the NF-kappa B pathway and decreased expression of genes related to antigen processing and presentation, such as human leukocyte antigen B. Our results indicate that progression of pre-eclampsia from notching may involve the development of inflammation. Increased expression of antigen-presenting genes, as seen in the notch-only placenta, may prevent this inflammatory response and, thereby, protect the patient from developing pre-eclampsia.

scholarly journals Toxic epidermal necrolysis

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 951 ◽  
Author(s):  
Wolfram Hoetzenecker ◽  
Tarun Mehra ◽  
Ieva Saulite ◽  
Martin Glatz ◽  
Peter Schmid-Grendelmeier ◽  
...  
Keyword(s):  
Cell Death ◽  
Mortality Rate ◽  
Toxic Epidermal Necrolysis ◽  
Human Leukocyte ◽  
Best Supportive Care ◽  
Drug Induced ◽  
Leukocyte Antigen ◽  
Mucosal Involvement ◽  
Keratinocyte Cell ◽  
Life Threatening

Toxic epidermal necrolysis (TEN) is a rare, life-threatening drug-induced skin disease with a mortality rate of approximately 30%. The clinical hallmark of TEN is a marked skin detachment caused by extensive keratinocyte cell death associated with mucosal involvement. The exact pathogenic mechanism of TEN is still uncertain. Recent advances in this field have led to the identification of several factors that might contribute to the induction of excessive apoptosis of keratinocytes. In addition, specific human leukocyte antigen types seem to be associated with certain drugs and the development of TEN. As well-controlled studies are lacking, patients are treated with various immunomodulators (e.g. intravenous immunoglobulin) in addition to the best supportive care.

scholarly journals Drug‐Induced Liver Injury due to Flucloxacillin: Relevance of Multiple Human Leukocyte Antigen Alleles

2019 ◽  
Vol 106 (1) ◽  
pp. 245-253 ◽  
Author(s):  
Paola Nicoletti ◽  
Guruprasad P. Aithal ◽  
Thomas C. Chamberlain ◽  
Sally Coulthard ◽  
Mohammad Alshabeeb ◽  
...  
Keyword(s):  
Liver Injury ◽  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Leukocyte Antigen

scholarly journals Single-cell derived tumor organoids display diversity in HLA class I peptide presentation

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Laura C. Demmers ◽  
Kai Kretzschmar ◽  
Arne Van Hoeck ◽  
Yotam E. Bar-Epraïm ◽  
Henk W. P. van den Toorn ◽  
...  
Keyword(s):  
Damage Control ◽  
Colorectal Cancer Patient ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Peptide Ligands ◽  
Class I ◽  
Viable Option ◽  
Leukocyte Antigen ◽  
Peptide Presentation ◽  
Tumor Mutational Burden

Abstract Tumor heterogeneity is a major cause of therapeutic resistance. Immunotherapy may exploit alternative vulnerabilities of drug-resistant cells, where tumor-specific human leukocyte antigen (HLA) peptide ligands are promising leads to invoke targeted anti-tumor responses. Here, we investigate the variability in HLA class I peptide presentation between different clonal cells of the same colorectal cancer patient, using an organoid system. While clone-specific differences in HLA peptide presentation were observed, broad inter-clone variability was even more prevalent (15–25%). By coupling organoid proteomics and HLA peptide ligandomics, we also found that tumor-specific ligands from DNA damage control and tumor suppressor source proteins were prominently presented by tumor cells, coinciding likely with the silencing of such cytoprotective functions. Collectively, these data illustrate the heterogeneous HLA peptide presentation landscape even within one individual, and hint that a multi-peptide vaccination approach against highly conserved tumor suppressors may be a viable option in patients with low tumor-mutational burden.

scholarly journals A Viral, Transporter Associated with Antigen Processing (TAP)-independent, High Affinity Ligand with Alternative Interactions Endogenously Presented by the Nonclassical Human Leukocyte Antigen E Class I Molecule

2012 ◽  
Vol 287 (42) ◽  
pp. 34895-34903 ◽  
Author(s):  
Elena Lorente ◽  
Susana Infantes ◽  
David Abia ◽  
Eilon Barnea ◽  
Ilan Beer ◽  
...  
Keyword(s):  
Human Leukocyte Antigen ◽  
Antigen Processing ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Class I ◽  
Structural Motif ◽  
Leukocyte Antigen ◽  
High Affinity ◽  
Hla Class I Molecules ◽  
Infected Cells

The transporter associated with antigen processing (TAP) enables the flow of viral peptides generated in the cytosol by the proteasome and other proteases to the endoplasmic reticulum, where they complex with nascent human leukocyte antigen (HLA) class I. Later, these peptide-HLA class I complexes can be recognized by CD8+ lymphocytes. Cancerous cells and infected cells in which TAP is blocked, as well as individuals with unusable TAP complexes, are able to present peptides on HLA class I by generating them through TAP-independent processing pathways. Here, we identify a physiologically processed HLA-E ligand derived from the D8L protein in TAP-deficient vaccinia virus-infected cells. This natural high affinity HLA-E class I ligand uses alternative interactions to the anchor motifs previously described to be presented on nonclassical HLA class I molecules. This octameric peptide was also presented on HLA-Cw1 with similar binding affinity on both classical and nonclassical class I molecules. In addition, this viral peptide inhibits HLA-E-mediated cytolysis by natural killer cells. Comparison between the amino acid sequences of the presenting HLA-E and HLA-Cw1 alleles revealed a shared structural motif in both HLA class molecules, which could be related to their observed similar cross-reactivity affinities. This motif consists of several residues located on the floor of the peptide-binding site. These data expand the role of HLA-E as an antigen-presenting molecule.

Additive effect of the HLA-DR15 haplotype on susceptibility to multiple sclerosis

2001 ◽  
Vol 7 (2) ◽  
pp. 91-93 ◽  
Author(s):  
H B Rasmussen ◽  
M A Kelly ◽  
J Clausen
Keyword(s):  
Multiple Sclerosis ◽  
Meta Analysis ◽  
Human Leukocyte ◽  
Surface Expression ◽  
Relative Effect ◽  
European Origin ◽  
Future Studies ◽  
Leukocyte Antigen ◽  
Density Surface ◽  
Antigen Presenting

Multiple sclerosis (MS) has been associated with the human leukocyte antigen DR15 allele in Caucasians of North and Central European origin. However, the relative effect of the DR15 homozygous and the DR15 heterozygous genotypes on the disease susceptibility is unclear. Based upon results from three North European studies we have examined this by meta-analysis. Our results suggested that the effect of the DRB1*1501, DQA1*0102, DQB1*0602 haplotype on the susceptibility to MS is additive, perhaps reflecting that development of the disease is facilitated by a high density surface expression of the antigen presenting molecules encoded by this haplotype. Possible implications of our finding to future studies of the genetic background of MS is discussed.

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