scholarly journals Deep learning boosts sensitivity of mass spectrometry-based immunopeptidomics

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mathias Wilhelm ◽  
Daniel P. Zolg ◽  
Michael Graber ◽  
Siegfried Gessulat ◽  
Tobias Schmidt ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Deep Learning ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Great Promise ◽  
Published Data ◽  
Tryptic Peptides ◽  
Leukocyte Antigen ◽  
Learning Framework ◽  
Immune Oncology

AbstractCharacterizing the human leukocyte antigen (HLA) bound ligandome by mass spectrometry (MS) holds great promise for developing vaccines and drugs for immune-oncology. Still, the identification of non-tryptic peptides presents substantial computational challenges. To address these, we synthesized and analyzed >300,000 peptides by multi-modal LC-MS/MS within the ProteomeTools project representing HLA class I & II ligands and products of the proteases AspN and LysN. The resulting data enabled training of a single model using the deep learning framework Prosit, allowing the accurate prediction of fragment ion spectra for tryptic and non-tryptic peptides. Applying Prosit demonstrates that the identification of HLA peptides can be improved up to 7-fold, that 87% of the proposed proteasomally spliced HLA peptides may be incorrect and that dozens of additional immunogenic neo-epitopes can be identified from patient tumors in published data. Together, the provided peptides, spectra and computational tools substantially expand the analytical depth of immunopeptidomics workflows.

scholarly journals The molecular basis of how buried human leukocyte antigen polymorphism modulates natural killer cell function

2020 ◽  
Vol 117 (21) ◽  
pp. 11636-11647 ◽  
Author(s):  
Philippa M. Saunders ◽  
Bruce J. MacLachlan ◽  
Phillip Pymm ◽  
Patricia T. Illing ◽  
Yuanchen Deng ◽  
...  
Keyword(s):  
Human Leukocyte Antigen ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Peptide Binding ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Cell Recognition ◽  
Leukocyte Antigen ◽  
Binding Cleft

Micropolymorphisms within human leukocyte antigen (HLA) class I molecules can change the architecture of the peptide-binding cleft, leading to differences in peptide presentation and T cell recognition. The impact of such HLA variation on natural killer (NK) cell recognition remains unclear. Given the differential association of HLA-B*57:01 and HLA-B*57:03 with the control of HIV, recognition of these HLA-B57 allomorphs by the killer cell immunoglobulin-like receptor (KIR) 3DL1 was compared. Despite differing by only two polymorphic residues, both buried within the peptide-binding cleft, HLA-B*57:01 more potently inhibited NK cell activation. Direct-binding studies showed KIR3DL1 to preferentially recognize HLA-B*57:01, particularly when presenting peptides with positively charged position (P)Ω-2 residues. In HLA-B*57:01, charged PΩ-2 residues were oriented toward the peptide-binding cleft and away from KIR3DL1. In HLA-B*57:03, the charged PΩ-2 residues protruded out from the cleft and directly impacted KIR3DL1 engagement. Accordingly, KIR3DL1 recognition of HLA class I ligands is modulated by both the peptide sequence and conformation, as determined by the HLA polymorphic framework, providing a rationale for understanding differences in clinical associations.

scholarly journals Multiple sclerosis: disease modifying therapy and the human leukocyte antigen

2018 ◽  
Vol 76 (10) ◽  
pp. 697-704 ◽  
Author(s):  
Lineu Cesar Werneck ◽  
Paulo José Lorenzoni ◽  
Cláudia Suemi Kamoi Kay ◽  
Rosana Herminia Scola
Keyword(s):  
Multiple Sclerosis ◽  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Class I ◽  
Interferon Β ◽  
Leukocyte Antigen ◽  
Specific Subset ◽  
Hla Type ◽  
Disease Modifying

ABSTRACT Objective: To investigate the potential relationship between the human leukocyte antigen (HLA) type (class I and II) and the response to several disease-modifying therapies (DMTs) in patients with multiple sclerosis (MS). Methods: We analyzed clinical data of 87 patients with MS at the beginning and end of each type of DMT including the disease duration, Expanded Disability Status Scale and Multiple Sclerosis Severity Score (MSSS). Genotyping of HLA-DRB1, HLA-DPB1, HLA-DQB1, HLA-A, HLA-B and HLA-C alleles were identified using high-resolution techniques. Statistical correlation between the HLA type and response to DMTs was done using the initial and final MSSS. Results: Statistical relationships (p < 0.05) were found for only 15 of 245 alleles tested. There was a reduction in the MSSS for patients treated with corticosteroids (DRB1*15:01, DPB1*04:01, DQB1*02:01 and DQB1*03:01), azathioprine (DRB1*03:01, DPB1*04:01, DQB1*03:02, DQB1*06:02, HLA-C*07:02), interferon β-1a 22 mcg (DRB1*11:04, DQB1*03:01 and DQB1*03:02), interferon β-1a 30 mcg (DPB1*02:01, HLA-C*05:01) and interferon β-1b (DQB1*02:01). Conclusion: These findings suggest a few relationships between the HLA and response to DMTs in the disability for some types of HLA class I and II alleles in a specific subset of MS patients.

scholarly journals Spondyloarthritis and the Human Leukocyte Antigen (HLA)-B*27 Connection

2021 ◽  
Vol 12 ◽  
Author(s):  
Chengappa G. Kavadichanda ◽  
Jie Geng ◽  
Sree Nethra Bulusu ◽  
Vir Singh Negi ◽  
Malini Raghavan
Keyword(s):  
Endoplasmic Reticulum ◽  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Clinical Aspects ◽  
Susceptibility Loci ◽  
New Bone Formation ◽  
High Association ◽  
Leukocyte Antigen ◽  
Heavy Chains

Heritability of Spondyloarthritis (SpA) is highlighted by several familial studies and a high association with the presence of human leukocyte antigen (HLA)-B*27. Though it has been over four decades since the association of HLA-B*27 with SpA was first determined, the pathophysiological roles played by specific HLA-B*27 allotypes are not fully understood. Popular hypotheses include the presentation of arthritogenic peptides, triggering of endoplasmic reticulum (ER) stress by misfolded HLA-B*27, and the interaction between free heavy chains or heavy chain homodimers of HLA-B*27 and immune receptors to drive IL-17 responses. Several non-HLA susceptibility loci have also been identified for SpA, including endoplasmic reticulum aminopeptidases (ERAP) and those related to the IL-23/IL-17 axes. In this review, we summarize clinical aspects of SpA including known characteristics of gut inflammation, enthesitis and new bone formation and the existing models for understanding the association of HLA-B*27 with disease pathogenesis. We also examine newer insights into the biology of HLA class I (HLA-I) proteins and their implications for expanding our understanding of HLA-B*27 contributions to SpA pathogenesis.

scholarly journals High resolution human leukocyte antigen (HLA) class I and class II allele typing in Mexican mestizo women with sporadic breast cancer: case-control study

BMC Cancer ◽  
2009 ◽  
Vol 9 (1) ◽  
Author(s):  
David Cantú de León ◽  
Delia Pérez-Montiel ◽  
Verónica Villavicencio ◽  
Alejandro García Carranca ◽  
Alejandro Mohar Betancourt ◽  
...  
Keyword(s):  
Sporadic Breast Cancer ◽  
Case Control Study ◽  
Human Leukocyte ◽  
Breast Cancer Case ◽  
Hla Class I ◽  
Case Control ◽  
Cancer Case ◽  
Mexican Mestizo ◽  
Leukocyte Antigen ◽  
Control Study

scholarly journals Mapping the tumour human leukocyte antigen (HLA) ligandome by mass spectrometry

Immunology ◽  
2018 ◽  
Vol 154 (3) ◽  
pp. 331-345 ◽  
Author(s):  
Lena Katharina Freudenmann ◽  
Ana Marcu ◽  
Stefan Stevanović
Keyword(s):  
Mass Spectrometry ◽  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Hla Ligandome

Seronegative Spondyloarthritis: Epidemiology, Pathogenesis, And Pathology

2018 ◽  
Author(s):  
Walter P Maksymowych
Keyword(s):  
Association Studies ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Population Based ◽  
Cell Phenotype ◽  
Imaging Data ◽  
Leukocyte Antigen ◽  
Seronegative Spondyloarthritis ◽  
Magnetic Resonance Imaging Mri

Classification of spondyloarthritis (SpA) is aimed at including patients with radiographic evidence of sacroiliitis and those with early disease who do not yet meet radiographic criteria but have positive features on magnetic resonance imaging (MRI). Most studies report a prevalence of SpA of 0.1 to 0.6%. Human leukocyte antigen (HLA)-B27 contributes approximately 20% of the heritability of SpA, and non–major histocompatibility complex loci identified to date (n = 113) contribute another approximately 10%. To date, 160 subtypes of HLA-B*27 have been reported, although population-based disease association studies are limited to only a few subtypes. Subtypes HLA-B*27:05 and HLA-B*27:04 are examples of subtypes associated with disease, whereas HLA-B*27:06 and HLA-B*27:09 are nonassociated. Properties of the B27 molecule relevant to pathogenesis include antigen presentation, propensity to misfold, and formation of homodimers. Key pathways identified by genetic studies include the interleukin (IL)-23 and M1-aminopeptidase pathways. The latter pathway is involved in peptide trimming in the endoplasmic reticulum, changing both the length and amino acid composition of peptides available for HLA class I presentation. IL-23 is a key cytokine regulating expression of IL-17 in a specific T helper cell phenotype, Th17, and also a variety of cells of the innate immune system. The IL-23–IL-17 pathway has been directly implicated in inflammation at sites that are inflamed in SpA. Increasing evidence based on prospective clinical and imaging data supports a link between inflammation and ankylosis, especially if the resolution of inflammation is followed by the appearance of a particular type of reparative tissue, namely, fat metaplasia, on T1-weighted MRI. This review contains 8 figures, 5 tables and 33 references Key words: association, classification, genetics, heritability, innate immunity, prevalence, spondyloarthritis

Characteristics allelic of Human Leukocyte Antigen class I genotype and association with viral load and CD4 cell count in HIV-1 infected patients, Hanoi 2014 – 2016

2021 ◽  
Vol 31 (4) ◽  
pp. 43-50
Author(s):  
Tran Thi Minh Tam ◽  
Nguyen Thuy Linh ◽  
Phan Ha My ◽  
Nguyen Thi Lan Anh
Keyword(s):  
Viral Load ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Class I ◽  
Cd4 Cell Count ◽  
Leukocyte Antigen ◽  
Cell Counts ◽  
Cd4 Cell Counts ◽  
Cd4 Cell ◽  
Hiv 1

Human Leukocyte Antigen (HLA) class I plays a regulatory role in cellular immune response to HIV-1 infection. The role of HLA alleles in HIV progression via viral load and CD4 cell count is well known. HLA class I is polymorphic and distributed differently by nation. This descriptive cross-sectional study was performed on 303 HIV-1 infected patients in 2014 - 2016, with aims to (i) characterize HLA class I genotype with 4-digit nomenclature and (ii) identify specifc alleles in correlate with CD4 cell counts and HIV viral load. 117 allele genotypes have been identifed, including 28 HLA-A alleles, 54 HLA-B alleles and 35 HLA-C alleles. The results showed that the most prevalent alleles in the population include A*11:01 (30.7%), B*15:02 (15.2%) and C*08:01 (17.1%). The frequency of haplotype created from these alleles is 8.4%. A*02:03, B*46:01 related to gender and ethnicity respectively. In conclusion, the study provided detailed pattern of HLA class I expression in a study population of HIV-1 infected patients and reported for the frst time the associated B*51:01, C*14:02 alleles associated to an increase in CD4 cell counts.

scholarly journals A Unique Regulation Region in the 3′ UTR of HLA-G with a Promising Potential

2020 ◽  
Vol 21 (3) ◽  
pp. 900 ◽  
Author(s):  
Adi Reches ◽  
Orit Berhani ◽  
Ofer Mandelboim
Keyword(s):  
Human Leukocyte Antigen ◽  
Expression Pattern ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Leukocyte Antigen ◽  
Distinct Site ◽  
Human Leukocyte Antigen G ◽  
Classical Human Leukocyte Antigen

Human leukocyte antigen G (HLA-G) is a non-classical human leukocyte antigen (HLA) class I protein that interacts with inhibitory receptors and is commonly overexpressed in various cancers, thereby establishing itself as an inhibitory checkpoint immune ligand. It is also expressed in trophoblast cells during pregnancy and protects the fetus from immune rejection. Despite its crucial role and its intriguing expression pattern, the regulation of HLA-G’s expression is only partially understood. HLA-G’s mRNA is expressed in many tissues but the protein expression is restricted only to the cells mentioned above. Therefore, we suggest that HLA-G is post-transcriptionally regulated. Here, we reveal a distinctive site present only in the 3′ Untranslated region (UTR) of HLA-G, which might explain its unique expression pattern. Consequently, we attempted to find binding factors such as RNA binding proteins (RBPs) and microRNAS (miRs) that regulate HLA-G expression by interacting with this distinct site present in its 3′ UTR. Our research indicates that this site should be further studied in order to reveal its significance.

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