scholarly journals Spliced HLA bound peptides; a Black-Swan event in Immunology

2021 ◽  
Author(s):  
Pouya Faridi ◽  
Mohammadreza .Dorvash ◽  
Anthony Purcell
Keyword(s):  
Global Analysis ◽  
Critical Role ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Peptide Ligands ◽  
Considerable Proportion ◽  
Immune Recognition ◽  
Leukocyte Antigens ◽  
Long Time ◽  
Hla Molecules

Peptides that bind to and are presented on the cell surface by Human Leukocyte Antigens (HLA) molecules play a critical role in adaptive immunity. For a long time, it was believed all of the HLA bound peptides were generated through simple proteolysis of linear sequences of cellular proteins, and therefore, are templated in the genome and proteome. However, evidence for untemplated peptide ligands of HLA molecules has accumulated over the last two decades, with a recent global analysis of HLA-bound peptides suggesting that a considerable proportion of HLA bound peptides are potentially generated through splicing/fusion of discontinuous peptide segments from one or two distinct proteins. In this review, we will review recent discoveries and debates on the contribution of spliced peptides to the HLA class I immunopeptidome, consider biochemical rules for splicing, and the potential role of these spliced peptides in immune recognition.

scholarly journals Role of Human Leukocyte Antigens at the Feto-Maternal Interface in Normal and Pathological Pregnancy: An Update

2020 ◽  
Vol 21 (13) ◽  
pp. 4756
Author(s):  
Chiara Tersigni ◽  
Federica Meli ◽  
Caterina Neri ◽  
Azzurra Iacoangeli ◽  
Rita Franco ◽  
...  
Keyword(s):  
Immune System ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Immune Recognition ◽  
Protective Mechanisms ◽  
Maternal Immune System ◽  
Hla Class I Molecules ◽  
Classical Pattern ◽  
Hla Molecules

The successful maternal tolerance of the semi-allogeneic fetus provides an apparent immunologic paradox. Indeed, deep invasion of placental trophoblast cells into maternal uterine tissue and the following growth of the fetus have to be tolerated by a pregnant woman’s immune system. Among the various possible protective mechanisms that may be involved in human pregnancy, the expression of a non-classical pattern of human leukocyte antigen (HLA) class I molecules and the complete lack of expression of HLA class II molecules in placental tissues seem to be the most relevant mechanisms of fetal escape from maternal immune recognition. The importance of HLA molecules in fetal toleration by the maternal immune system is highlighted by pregnancy complications occurring in cases of abnormal HLA molecule expression at the maternal–fetal interface. In this review, we summarize evidences about the role of placental HLA molecules in normal and pathological pregnancies.

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 Generation of HLA Universal Megakaryocytes and Platelets by Genetic Engineering

2021 ◽  
Vol 12 ◽  
Author(s):  
Constanca Figueiredo ◽  
Rainer Blasczyk
Keyword(s):  
Genetic Engineering ◽  
New Technologies ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Genetically Engineered ◽  
Leukocyte Antigens ◽  
Cell Sources ◽  
Technical Advances

Patelet transfusion refractoriness remains a relevant hurdle in the treatment of severe alloimmunized thrombocytopenic patients. Antibodies specific for the human leukocyte antigens (HLA) class I are considered the major immunological cause for PLT transfusion refractoriness. Due to the insufficient availability of HLA-matched PLTs, the development of new technologies is highly desirable to provide an adequate management of thrombocytopenia in immunized patients. Blood pharming is a promising strategy not only to generate an alternative to donor blood products, but it may offer the possibility to optimize the therapeutic effect of the produced blood cells by genetic modification. Recently, enormous technical advances in the field of in vitro production of megakaryocytes (MKs) and PLTs have been achieved by combining progresses made at different levels including identification of suitable cell sources, cell pharming technologies, bioreactors and application of genetic engineering tools. In particular, use of RNA interference, TALEN and CRISPR/Cas9 nucleases or nickases has allowed for the generation of HLA universal PLTs with the potential to survive under refractoriness conditions. Genetically engineered HLA-silenced MKs and PLTs were shown to be functional and to have the capability to survive cell- and antibody-mediated cytotoxicity using in vitro and in vivo models. This review is focused on the methods to generate in vitro genetically engineered MKs and PLTs with the capacity to evade allogeneic immune responses.

scholarly journals Monospecific and Polyreactive Monoclonal Antibodies against Human Leukocyte Antigen-E: Diagnostic and Therapeutic Relevance

2021 ◽  
Author(s):  
Mepur H. Ravindranath ◽  
Fatiha E.L. Hilali
Keyword(s):  
Amino Acid ◽  
Nk Cells ◽  
Major Histocompatibility Complex Gene ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Amino Acid Sequences ◽  
Leukocyte Antigens ◽  
Hla Class I Molecules ◽  
Specific Localization ◽  
High Degree

A monoclonal antibody (mAb) binds to an antigen recognizing an epitope (a sequence of amino acids). A protein antigen may carry amino acid sequence unique to that antigen as well as sequences found in other proteins. Human leukocyte antigens (HLA), a family of proteins expressed by the Major Histocompatibility Complex gene family represent a special case, in that it displays a high degree of polymorphism. Every HLA molecule possesses both specific (private) epitopes and epitopes shared (public) with other HLA class Ia and class Ib molecules. HLA-E is overexpressed in cancer cells more than any other HLA Class I molecules. Therefore specific localization of HLA-E with mAbs is pivotal for developing targeted therapy against cancer. However, the commercially available mAbs for immunodiagnosis are polyreactive. We have developed anti-HLA-E mAbs and distinguished monospecific from polyreactive mAbs using Luminex multiplex single antigen bead (SAB) assay. HLA-E-binding of monospecific-mAbs was also inhibited by E-restricted epitopes. The amino acid sequences in the region of the epitopes bind to CD94/NKG2A receptors on CD8+ T cells and NK cells and block their antitumor functions. Monospecific-HLA-E mAbs recognizing the epitopes sequences can interfere with the binding to restore the anti-tumor efficacy of NK cells. Also, monospecific-mAbs augment the proliferation of CD4-/CD+ cytotoxic T-lymphocytes. Therefore, anti-HLA-E monospecific-mAb can serve as a double-edged sword for eliminating tumor cells.

scholarly journals B2M gene knockout in HEK293T cells by non-viral delivery of CRISPR-Cas9 for the induction of universal cell

2021 ◽  
Author(s):  
Maryam Ranjbar ◽  
Farshid Amiri ◽  
Marjan Nourigorji ◽  
Farid Torabizadeh ◽  
Mahintaj Dara ◽  
...  
Keyword(s):  
Gene Knockout ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Immune Rejection ◽  
Guide Rna ◽  
Leukocyte Antigens ◽  
Intron 1 ◽  
Exon 1 ◽  
Polymerase Chain ◽  
Viral Transfer

Abstract Allogeneic stem cells have been introduced as a potential approach to generate grafts in regenerative medicine. But the clinical usage of them is limited due to the risk of immune rejection that is induced by the incompatibility of human leukocyte antigens (HLAs) between donors and recipients. To overcome this limitation, we knocked out the β2 microglobulin (B2M) gene which is crucial for HLA class I expression, using CRISPR/Cas9 approach. Non-viral transfer of two gRNAs targeting exon 1 and intron 1 in B2M gene caused in large and predictable deletion in region between two loci, which was defined by sequencing and polymerase chain reaction (PCR). Furthermore, results revealed that roughly 11.11% and 22.22% of the GFP expressing cells reflecting a homozygous and heterozygous pattern of genomic modifications. We demonstrated that the dual guide RNA approach is a simple and efficient method for gene disruption. Significantly, these engineered hypoimmunogenic cells could be proposed as universal cells that are not distinguishable to the recipient immune system in cell therapy and transplantation.

Human Leukocyte Antigens (HLA) Class I and Class II on Sperm Cells Studied at the Serological, Cellular, and Genomic Levels

1987 ◽  
Vol 13 (4) ◽  
pp. 97-103 ◽  
Author(s):  
AMAL BISHARA ◽  
JORGE R. OKSENBERG ◽  
GADI FRANKEL ◽  
EHUD I.J. MARGALIOTH ◽  
EMANUEL PERSITZ ◽  
...  
Keyword(s):  
Human Leukocyte ◽  
Hla Class I ◽  
Class Ii ◽  
Class I ◽  
Sperm Cells ◽  
Human Leukocyte Antigens ◽  
Leukocyte Antigens

scholarly journals Battle between Host Immune Cellular Responses and HCMV Immune Evasion

2019 ◽  
Vol 20 (15) ◽  
pp. 3626 ◽  
Author(s):  
Manandhar ◽  
Hò ◽  
Pump ◽  
Blasczyk ◽  
Bade-Doeding
Keyword(s):  
Immune Evasion ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Human Organism ◽  
Transplant Recipients ◽  
Immune Effector ◽  
Effector Cells ◽  
Leukocyte Antigens ◽  
Wide Range ◽  
Infected Cells

Human cytomegalovirus (HCMV) is ubiquitously prevalent. HCMV infection is typically asymptomatic and controlled by the immune system in healthy individuals, yet HCMV can be severely pathogenic for the fetus during pregnancy and in immunocompromised persons, such as transplant recipients or HIV infected patients. HCMV has co-evolved with the hosts, developed strategies to hide from immune effector cells and to successfully survive in the human organism. One strategy for evading or delaying the immune response is maintenance of the viral genome to establish the phase of latency. Furthermore, HCMV immune evasion involves the downregulation of human leukocyte antigens (HLA)-Ia molecules to hide infected cells from T-cell recognition. HCMV expresses several proteins that are described for downregulation of the HLA class I pathway via various mechanisms. Here, we review the wide range of immune evasion mechanisms of HCMV. Understanding the mechanisms of HCMV immune evasion will contribute to the development of new customized therapeutic strategies against the virus.

scholarly journals Mass spectrometry based immunopeptidomics leads to robust predictions of phosphorylated HLA class I ligands

2019 ◽  
Author(s):  
Marthe Solleder ◽  
Philippe Guillaume ◽  
Julien Racle ◽  
Justine Michaux ◽  
HuiSong Pak ◽  
...  
Keyword(s):  
Human Leukocyte ◽  
Hla Class I ◽  
Class I ◽  
Immune Recognition ◽  
Post Translational Modifications ◽  
Synonymous Mutations ◽  
Alternative Mrna Splicing ◽  
Phosphorylated Peptides ◽  
Specific Alternative

AbstractThe presentation of peptides on class I human leukocyte antigen (HLA-I) molecules plays a central role in immune recognition of infected or malignant cells. In cancer, non-self HLA-I ligands can arise from many different alterations, including non-synonymous mutations, gene fusion, cancer-specific alternative mRNA splicing or aberrant post-translational modifications. Identifying HLA-I ligands remains a challenging task that requires either heavy experimental work for in-vivo identification or optimized bioinformatics tools for accurate predictions. To date, no HLA-I ligand predictor includes post-translational modifications. To fill this gap, we curated phosphorylated HLA-I ligands from several immunopeptidomics studies (including six newly measured samples) covering 72 HLA-I alleles, and retrieved a total of 2,066 unique phosphorylated peptides. We then expanded our motif deconvolution tool to identify precise binding motifs of phosphorylated HLA-I ligands. Our results reveal a clear enrichment of phosphorylated peptides among HLA-C ligands and demonstrate a prevalent role of both HLA-I motifs and kinase motifs on the presentation of phosphorylated peptides. This data further enabled us to develop and validate the first predictor of interactions between HLA-I molecules and phosphorylated peptides.

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