scholarly journals The HLA Ligand Atlas - A resource of natural HLA ligands presented on benign tissues

2019 ◽  
Author(s):  
Ana Marcu ◽  
Leon Bichmann ◽  
Leon Kuchenbecker ◽  
Daniel Johannes Kowalewski ◽  
Lena Katharina Freudenmann ◽  
...  
Keyword(s):  
Immune Cells ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Hla Ligand ◽  
Initial Release ◽  
Hla Ligands ◽  
Extensive Collection ◽  
Tumor Association ◽  
Genomic Regions

ABSTRACTThe human leukocyte antigen (HLA) complex controls adaptive immunity by presenting defined fractions of the intracellular and extracellular protein content to immune cells. Here, we describe the HLA Ligand Atlas, an extensive collection of mostly matched HLA-I and -II ligandomes from 225 benign samples (29 tissues, 21 subjects). The initial release covers 51 HLA-I and 86 HLA-II allotypes presenting 89,853 HLA-I- and 140,861 HLA-II ligands. We observe that the immunopeptidomes differ considerably between tissues and individuals on both source protein and HLA-ligand level. 1,407 HLA-I ligands stem from non-canonical genomic regions. We highlight the importance of comparatively analyzing both benign and malignant tissues to inform tumor association, based on a case study in three glioblastoma patients. The resource provides insights into applied and basic immune-associated questions in the context of cancer immunotherapy, infection, transplantation, allergy, and autoimmunity. It is publicly available at www.hla-ligand-atlas.org.

scholarly journals Hierarchy of resistance to cervical neoplasia mediated by combinations of killer immunoglobulin-like receptor and human leukocyte antigen loci

2005 ◽  
Vol 201 (7) ◽  
pp. 1069-1075 ◽  
Author(s):  
Mary Carrington ◽  
Sophia Wang ◽  
Maureen P. Martin ◽  
Xiaojiang Gao ◽  
Mark Schiffman ◽  
...  
Keyword(s):  
Cell Activation ◽  
Nk Cell ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Cervical Neoplasia ◽  
Leukocyte Antigen ◽  
Hla Ligand ◽  
Increased Risk ◽  
Ligand Interactions ◽  
Cell Inhibition

Killer immunoglobulin-like receptor (KIR) recognition of specific human histocompatibility leukocyte antigen (HLA) class I allotypes contributes to the array of receptor–ligand interactions that determine natural killer (NK) cell response to its target. Contrasting genetic effects of KIR/HLA combinations have been observed in infectious and autoimmune diseases, where genotypes associated with NK cell activation seem to be protective or to confer susceptibility, respectively. We show here that combinations of KIR and HLA loci also affect the risk of developing cervical neoplasia. Specific inhibitory KIR/HLA ligand pairs decrease the risk of developing neoplasia, whereas the presence of the activating receptor KIR3DS1 results in increased risk of disease, particularly when the protective inhibitory combinations are missing. These data suggest a continuum of resistance conferred by NK cell inhibition to susceptibility involving NK cell activation in the development of cervical neoplasia and underscore the pervasive influence of KIR/HLA genetic variation in human disease pathogenesis.

scholarly journals A facile immunopeptidomics workflow for capturing the HLA-I ligandome with PEAKS XPro

2021 ◽  
Author(s):  
Kyle S. Hoffman ◽  
Baozhen Shan ◽  
Jonathan R. Krieger
Keyword(s):  
Cancer Vaccines ◽  
De Novo ◽  
Consensus Sequence ◽  
Human Leukocyte ◽  
Sequence Motif ◽  
Cell Surfaces ◽  
Leukocyte Antigen ◽  
Uniprot Database ◽  
Hla Ligands ◽  
Mass Spectrometry Dataset

AbstractIdentifying antigens displayed specifically on tumour cell surfaces by human leukocyte antigen (HLA) proteins is important for the development of immunotherapies and cancer vaccines. The difficulty in capturing an HLA ligandome stems from the fact that many HLA ligands are derived from splicing events or contain mutations, hindering their identification in a standard database search. To address this challenge, we developed an immunopeptidomics workflow with PEAKS XPro that uses de novo sequencing to uncover such peptides and identifies mutations for neoantigen discovery. We demonstrate the utility of this workflow by re-analyzing HLA-I ligandome datasets and reveal a vast diversity in peptide sequences among clones derived from a colorectal cancer tumour. Over 8000 peptides predicted to bind HLA-I molecules were identified by de novo sequencing only (not found in the UniProt database) and make up over 50% of identified peptides from each sample. Lastly, tumour-specific mutations and consensus sequence motif characteristics are defined. This workflow is widely applicable to any immunopeptidomic mass spectrometry dataset and does not require custom database generation for neoantigen discovery.

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.

Computer-aided human leukocyte antigen association studies: A case study for psoriasis and severe alopecia areata

2010 ◽  
Vol 71 (8) ◽  
pp. 783-788 ◽  
Author(s):  
Daniele Catanzaro ◽  
Marc Andrien ◽  
Martine Labbé ◽  
Michel Toungouz-Nevessignsky
Keyword(s):  
Human Leukocyte Antigen ◽  
Alopecia Areata ◽  
Association Studies ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Computer Aided

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 Frequent expression of human leukocyte antigen class I and the status of intratumoral immune cells in alveolar soft part sarcoma

2017 ◽  
Vol 13 (4) ◽  
pp. 2169-2176 ◽  
Author(s):  
Akira Ogose ◽  
Hiroyuki Kawashima ◽  
Tetsuo Hotta ◽  
Takashi Ariizumi ◽  
Tetsuro Yamagishi ◽  
...  
Keyword(s):  
Human Leukocyte Antigen ◽  
Immune Cells ◽  
Human Leukocyte Antigen Class ◽  
Soft Part ◽  
Human Leukocyte ◽  
Class I ◽  
Alveolar Soft Part Sarcoma ◽  
Leukocyte Antigen ◽  
The Status ◽  
Leukocyte Antigen Class I

scholarly journals Targeted Delivery of the HLA-B∗27-Binding Peptide into the Endoplasmic Reticulum Suppresses the IL-23/IL-17 Axis of Immune Cells in Spondylarthritis

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Hui-Chun Yu ◽  
Kuang-Yung Huang ◽  
Ming-Chi Lu ◽  
Hsien-Lu Huang ◽  
Su-Qin Liu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Immune Cells ◽  
Targeted Delivery ◽  
Th17 Cells ◽  
Therapeutic Strategy ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Disulfide Linkage ◽  
Leukocyte Antigen ◽  
Binding Peptides

Ankylosing spondylitis (AS) is highly associated with the expression of human leukocyte antigen-B27 (HLA-B∗27). HLA-B∗27 heavy chain (B27-HC) has an intrinsic propensity to fold slowly, leading to the accumulation of the misfolded B27-HC in the endoplasmic reticulum (ER) and formation of the HLA-B∗27 HC homodimer, (B27-HC)2, by a disulfide linkage at Cys-67. (B27-HC)2displayed on the cell surface can act as a ligand of the killer-cell Ig-like receptor (KIR3DL2). (B27-HC)2binds to KIR3DL2 of NK and Th17 cells and activates both cells, resulting in the activation of the IL-23/IL-17 axis to launch the inflammatory reaction in AS patients. However, activation of the IL-23/IL-17 axis originally derived from the HLA-B∗27 misfolding in the ER needs to be characterized. In this study, we delivered two HLA-B∗27-binding peptides, KRGILTLKY and SRYWAIRTR, into the ER by using a tat-derived peptide (GRKKRRQRRR)-His6-ubiquitin (THU) vehicle. Both peptides are derived from the human actin and nucleoprotein of influenza virus, respectively. Our results demonstrated that targeted delivery of both HLA-B∗27-binding peptides into the ER can promote the HLA-B∗27 folding, decrease the levels of (B27-HC)2, and suppress the activation of the IL-23/IL-17 axis in response to lipopolysaccharide. Our findings can provide a new therapeutic strategy in AS.

scholarly journals Distribution of HLA-A, -B, and -C Alleles and HLA/KIR Combinations in Han Population in China

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Yunsong Shen ◽  
Danfeng Cao ◽  
Yalin Li ◽  
J. K. Kulski ◽  
Lei Shi ◽  
...  
Keyword(s):  
Yunnan Province ◽  
Southwest China ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Han Population ◽  
Leukocyte Antigen ◽  
Significant Difference ◽  
Hla Ligands ◽  
Polymerase Chain ◽  
Two Populations

We investigated polymorphisms of the human leukocyte antigen (HLA) class I (A, B, and C) loci of a Han population (n, 239) from the Yunnan province, Southwest China, using high-resolution polymerase chain reaction-Luminex (PCR-Luminex) typing. We combined the HLA data from this study with the KIR genotypes from a previous study of this Han population to analyze the combination of KIR/HLA ligands. A total of 27 HLA-A, 54 HLA-B, and 31 HLA-C alleles were found in this population. The frequencies ofA*11:01,A*24:02,B*40:01,B*46:01,C*01:02,C*03:04, andC*07:02 were all > 10%. The following haplotypes were common, with frequencies > 5%: 1 A-B (A*02:07-B*46:01), 2 A-C (A*02:07-C*01:02, andA*11:01-C*07:02), 4 C-B (B*13:01-C*03:04,B*40:01-C*07:02,B*46:01-C*01:02 andB*58:01-C*03:02), and 1 A-C-B (A*02:07-C*01:02-B*46:01). Analysis of KIR3D and their ligands HLA-A3/A11 and HLA-Bw4 showed that the frequencies of 3DL2+-A3/A11+and 3DL2+-A3/A11−were 0.527 and 0.473, and the frequencies of 3DL1+-Bw4+, 3DL1+-Bw4−, 3DL1−-Bw4+, and 3DL1−-Bw4−were 0.552, 0.397, 0.038, and 0.013, respectively. The results of KIR/HLA-C combination analysis showed that all individuals had at least one inhibitory or activating KIR/HLA-C pair, and one KIR/HLA-C pair was the most frequent (157/239), followed by two pairs (46/239), three pairs (33/239), and no pairs (3/239). Comparison of KIR gene and HLA gene and their pair frequency between Yunnan Han and the isolated Han (FYDH) who also lived in Yunnan province showed no significant difference (P>0.05) in KIR frequencies, but significant differences (P<0.05) for some HLA allele frequencies. In addition, there was no significant difference (P>0.05) between the two populations for KIR/HLA pairs.

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