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Trends in Microbiology Feb 2018The M protein is the major surface-associated virulence factor of group A Streptococcus (GAS) and an antigenically variable target of host immunity. How selection... (Review)
Review
The M protein is the major surface-associated virulence factor of group A Streptococcus (GAS) and an antigenically variable target of host immunity. How selection pressures to escape immune recognition, maintain indispensable functions, and mask vulnerabilities have shaped the sequences of the >220M protein types is unclear. Recent experiments have shed light on this question by showing that, hidden within the antigenic variability of many M protein types, are sequence patterns conserved for recruiting human C4b-binding protein (C4BP). Other host factors may be recruited in a similar manner by conserved but hidden sequence patterns in the M protein. The identification of such patterns may be applicable to the development of a GAS vaccine.
Topics: Antigenic Variation; Antigens, Bacterial; Antimicrobial Cationic Peptides; Bacterial Outer Membrane Proteins; Carrier Proteins; Complement C4b-Binding Protein; Complement Factor H; Histones; Host-Pathogen Interactions; Humans; Protein Binding; Staphylococcal Vaccines; Streptococcus pyogenes; Virulence Factors; Cathelicidins
PubMed: 28867148
DOI: 10.1016/j.tim.2017.08.002 -
Molecular Immunology Sep 2019Endoplasmic Reticulum aminopeptidase 1 (ERAP1) is an intracellular enzyme that can generate or destroy potential peptide ligands for MHC class I molecules. ERAP1... (Review)
Review
Endoplasmic Reticulum aminopeptidase 1 (ERAP1) is an intracellular enzyme that can generate or destroy potential peptide ligands for MHC class I molecules. ERAP1 activity influences the cell-surface immunopeptidome and epitope immunodominance patterns but in complex and poorly understood manners. Two main distinct pathways have been proposed to account for ERAP1's effects on the nature and quantity of MHCI-bound peptides: i) ERAP1 trims peptides in solution, generating the correct length for binding to MHCI or overtrimming peptides so that they are too short to bind, and ii) ERAP1 trims peptides while they are partially bound onto MHCI in manner that leaves the peptide amino terminus accessible. For both pathways, once an appropriate length peptide is generated it could bind conventionally to MHCI, competing with further trimming by ERAP1. The two pathways, although not necessarily mutually exclusive, provide distinct vantage points for understanding of the rules behind the generation of the immunopeptidome. Resolution of the mechanistic details of ERAP1-mediated antigenic peptide generation can have important consequences for pharmacological efforts to regulate the immunopeptidome for therapeutic applications, and for understanding association of ERAP1 alleles with susceptibility to autoimmune disease and cancer. We review current evidence in support of these two pathways and discuss their relative importance and potential complementarity.
Topics: Aminopeptidases; Animals; Antigen Presentation; Antigens; Epitopes; Histocompatibility Antigens Class I; Humans; Ligands; Peptides; Signal Transduction
PubMed: 29678301
DOI: 10.1016/j.molimm.2018.03.026 -
Mini Reviews in Medicinal Chemistry Jul 2010The development of an adequate immune response against pathogens is mediated by molecular interactions between different cell types. Among them, binding of antigenic... (Review)
Review
The development of an adequate immune response against pathogens is mediated by molecular interactions between different cell types. Among them, binding of antigenic peptides to the Major Histocompatibility Complex (MHC) molecule expressed on the membrane of antigen presenting cells (APCs), and their subsequent recognition by the T cell receptor have been demonstrated to be crucial for developing an adequate immune response. The present review compiles computational quantum chemistry studies about the electrostatic potential variations induced on the MHC binding region by peptide's amino acids, carried out with the aim of describing MHC-peptide binding interactions. The global idea is that the electrostatic potential can be represented in terms of a series expansion (charge, dipole, quadrupole, hexadecapole, etc.) whose three first terms provide a good local approximation to the molecular electrostatic 'landscape' and to the variations induced on such landscape by targeted modifications on the residues of the antigenic peptide. Studies carried out in four MHC class II human allele molecules, which are the most representative alleles of their corresponding haplotypes, showed that each of these molecules have conserved as well as specific electrostatic characteristics, which can be correlated at a good extent with the peptide binding profiles reported experimentally for these molecules. The information provided by such characteristics would help increase our knowledge about antigen binding and presentation, and could ultimately contribute to developing a logical and rational methodology for designing chemically synthesized, multi-antigenic, subunit-based vaccines, through the application of quantum chemistry methods.
Topics: HLA Antigens; Histocompatibility Antigens; Humans; Peptides; Protein Binding; Quantum Theory; Static Electricity; Vaccines
PubMed: 20394575
DOI: 10.2174/138955710791572488 -
Scientific Reports Aug 2022A rapid rise in antibiotic resistance by bacterial pathogens is due to these pathogens adaptation to the changing environmental conditions. Antibiotic resistance...
A rapid rise in antibiotic resistance by bacterial pathogens is due to these pathogens adaptation to the changing environmental conditions. Antibiotic resistance infections can be reduced by a number of ways such as development of safe and effective vaccine. Klebsiella aerogene is a gram-negative, rod-shaped bacterium resistant to a variety of antibiotics and no commercial vaccine is available against the pathogen. Identifying antigens that can be easily evaluated experimentally would be crucial to successfully vaccine development. Reverse vaccinology (RV) was used to identify vaccine candidates based on complete pathogen proteomic information. The fully sequenced proteomes include 44,115 total proteins of which 43,316 are redundant and 799 are non-redundant. Subcellular localization showed that only 1 protein in extracellular matrix, 7 were found in outer-membrane proteins, and 27 in the periplasm space. A total of 3 proteins were found virulent. Next in the B-cell-derived T-cell epitopes mapping phase, the 3 proteins (Fe2 enterobactin, ABC transporter substrate-binding protein, and fimbriae biogenesis outer membrane usher protein) were tested positive for antigenicity, toxicity, and solubility. GPGPG linkers were used to prepare a vaccine construct composed of 7 epitopes and an adjuvant of toxin B subunit (CTBS). Molecular docking of vaccine construct with major histocompatibility-I (MHC-I), major histocompatibility-II (MHC-II), and Toll-like receptor 4 (TLR4) revealed vaccine robust interactions and stable binding pose to the receptors. By using molecular dynamics simulations, the vaccine-receptors complexes unveiled stable dynamics and uniform root mean square deviation (rmsd). Further, binding energies of complex were computed that again depicted strong intermolecular bindings and formation of stable conformation.
Topics: Bacterial Vaccines; Computational Biology; Enterobacter aerogenes; Epitopes; Epitopes, T-Lymphocyte; Molecular Docking Simulation; Molecular Dynamics Simulation; Proteomics; Vaccines, Subunit
PubMed: 36002561
DOI: 10.1038/s41598-022-18610-0 -
The Yale Journal of Biology and Medicine 1990Recognition and application of blood group differences on human red cells permitted the development of safe procedures for blood transfusion. Blood group antigens are... (Review)
Review
Recognition and application of blood group differences on human red cells permitted the development of safe procedures for blood transfusion. Blood group antigens are markers on surface-exposed red cell proteins or the sugar moiety of glycoproteins or glycolipids. Apart from their presumed biological function, some antigens have been identified as receptors for host/parasite interactions. Thus, carbohydrates that determine P antigenicity are the binding receptor for certain strains of pyelonephritic coliforms. Other pathogenic coliforms bind to the membrane structure that carries the Dra antigen. A structure associated with Duffy antigens is the attachment receptor for the parasite of Plasmodium vivax malaria, while Plasmodium falciparum parasites bind to structures associated with membrane glycophorins. Structure/function relationships have been established by the finding that lack of Rh protein in red cells of Rhnull phenotype is associated with stomatocytic cell morphology and a hemolytic state. Absence of glycophorin C, and the Gerbich blood group antigens that it carries, is associated with elliptocytic red cells. Absence of Kx antigen protein in the Kell system is associated with the McLeod blood group phenotype, with acanthocytic cell morphology and reduced in vivo survival. McLeod individuals also have late-onset muscular dystrophy and neurological disorders.
Topics: Bacterial Outer Membrane Proteins; Blood Group Antigens; Carrier Proteins; Glycophorins; HLA-DR Antigens; Host-Parasite Interactions; Humans; Kell Blood-Group System; Receptors, Cell Surface
PubMed: 2293504
DOI: No ID Found -
MAbs 2020The neonatal Fc receptor (FcRn) is a key membrane protein that plays an integral role in serum immunoglobulin (IgG) recycling, which extends the half-life of antibody....
The neonatal Fc receptor (FcRn) is a key membrane protein that plays an integral role in serum immunoglobulin (IgG) recycling, which extends the half-life of antibody. In addition, FcRn is known to traffic antigen-bound immunoglobulins (Ag-IgGs), and to interact with immune complexes to facilitate the antigen cross-presentation of peptides derived from the immune complexes in antigen-presenting cells (APCs). Studies on the IgG-FcRn molecular interactions have primarily focused on the Fc region, and only recently have shown the potential impact of the antigen-binding fragment physiochemical properties on FcRn binding. However, the effect of the antigen physiochemical properties on IgG structure as it relates to Ag-IgG-FcRn binding is not well understood. Here we used an IgG-peptide antigen complex as a model system to investigate the structural effects of the antigen's physiochemical properties on the IgG structure, and the subsequent effects of Ag-IgG-FcRn interactions. We used hydroxyl radical footprinting-mass spectrometry to investigate the structural impact on an IgG upon antigen binding, and observed that the physicochemical properties of the antigen differentially induce conformational changes in the IgG FcRn binding region. The extent of these structural changes directly correlates to the magnitude of the affinity differences between the Ag-IgG complexes and FcRn. Moreover, the antigen's physicochemical properties differentially induce structural differences within the Ag-IgG-FcRn ternary complex. We also provide electron microscopy data that shows corroborating Fab-FcRn interactions, and confirms the hypothesis of potential 2:1 FcRn:IgG binding stoichiometry. These data demonstrate antigen-induced Fc structural rearrangements affect both the affinity toward FcRn and the trimeric antigen-IgG-FcRn complex, providing novel molecular insights in the first steps toward understanding interactions of FcRn-containing large(r)-sized immune complex.
Topics: Histocompatibility Antigens Class I; Humans; Immunoglobulin Fab Fragments; Immunoglobulin G; Receptors, Fc
PubMed: 32795110
DOI: 10.1080/19420862.2020.1802135 -
Current Opinion in Immunology Jun 2022T cell receptors (TCRs) and other receptors of the immune system recognize peptides presented by class I or class II major histocompatibility complex (MHC) proteins.... (Review)
Review
T cell receptors (TCRs) and other receptors of the immune system recognize peptides presented by class I or class II major histocompatibility complex (MHC) proteins. Although we generally distinguish between the MHC protein and its peptide, at an atomic level the two form a structural composite, which allows peptides to influence MHC properties and vice versa. One consequence is the peptide-dependent tuning of MHC structural dynamics, which contributes to protein structural adaptability and influences how receptors identify and bind targets. Peptide-dependent tuning of MHC protein dynamics can impact processes such as antigenicity, TCR cross-reactivity, and T cell repertoire selection. Motional tuning extends beyond the binding groove, influencing peptide selection and exchange, as well as interactions with other immune receptors. Here, we review recent findings showing how peptides can affect the dynamic and adaptable nature of MHC proteins. We highlight consequences for immunity and demonstrate how MHC proteins have evolved to be highly sensitive dynamic reporters, with broad immunological consequences.
Topics: Histocompatibility Antigens; Histocompatibility Antigens Class I; Humans; Lymphocyte Activation; Major Histocompatibility Complex; Peptides; Receptors, Antigen, T-Cell
PubMed: 35550277
DOI: 10.1016/j.coi.2022.102184 -
Human Vaccines & Immunotherapeutics Nov 2020Many types of cancers are prevalent in India and worldwide. Monoclonal antibodies (MAbs) are one of the major types of cancer therapeutics, which have included MAbs of...
Many types of cancers are prevalent in India and worldwide. Monoclonal antibodies (MAbs) are one of the major types of cancer therapeutics, which have included MAbs of hybridoma, chimeric, humanized, or human origin. MAbs are mostly generated currently by direct cloning from B cells. Bispecific antibodies (BAbs), as the name suggests, have two different antigen-binding domains in a single molecule and thus have dual functionality/specificity combined in a single antibody. In addition to the detection of two different antigenic molecules, the dual functionality of BAbs can be utilized to mount T-cell-mediated killing of tumor cells wherein one Fv binds to the tumor-specific antigen and the another recruits T cells to the site of action. Breast cancer and prostate cancer are among the most prevalent cancers in women and men, respectively. Biomarkers such as HER2 and ER/PR are expressed in breast cancer, while overexpression of hepsin and prostate-specific membrane antigen is observed in prostate cancer. Developing BAbs against these biomarkers may be a potent therapeutic option to target breast and prostate cancer, respectively. Therefore, an efficient method using recombinant DNA technology and mammalian cell culture platform is required to generate BAbs against specific diseases as biomarkers as well as for the generation of antibody-based therapeutics.
Topics: Animals; Antibodies, Bispecific; Antibodies, Monoclonal; Antigens, Neoplasm; Biomarkers; Humans; India; Male
PubMed: 32614706
DOI: 10.1080/21645515.2020.1738167 -
Iranian Biomedical Journal May 2020Breast cancer is one of the most prevalent cancers among women. Common cancer treatment methods are not effective enough, and there is a need for a more efficient...
BACKGROUND
Breast cancer is one of the most prevalent cancers among women. Common cancer treatment methods are not effective enough, and there is a need for a more efficient treatment procedure. Cancer vaccine is a novel immunotherapy method that stimulates humoral and/or cellular immunity against cancer. Placenta-specific protein 1 (PLAC1) is a cancer/testis antigen, prevalent in breast cancer and rarely found in normal tissues. FliC, as a bacterial adjuvant, when fused to PLAC1 can elicit humoral and cellular responses. Therefore, PLAC1-fliC is a chimeric protein, which can be considered a suitable candidate against breast cancer.
METHODS
ProtParam was used to evaluate the physicochemical properties of PLAC1-fliC. Second structures were determined using the GOR V server. PLAC1-fliC 3D structure was modeled by Phyre2, and it was refined using GalaxyWEB. The refined model was submitted to RAMPAGE, PROCHECK, and ProSA-web for validation. Antigenicity and allergenicity of the construct were predicted by ANTIGENpro, VaxiJen, AllergenFP, and SDAP databases. Then MHC-I- and MHC-II-binding epitopes of PLAC1-fliC were forecasted by NetMHC 4.0 and NetMHCII 2.3 Servers. Finally, Ellipro and CTLpred were employed to predict B-cell and cytotoxic T lymphocyte epitopes.
RESULTS
The construct was evaluated as a stable fusion protein, which could be antigenic and could stimulate B and T cells against breast cancer.
CONCLUSION
PLAC1-fliC, as a cancer vaccine candidate, might be suitable and specific for breast cancer, which could evoke humoral and cellular immunity against this type of tumor.
Topics: Amino Acid Sequence; Antigens, Neoplasm; Breast Neoplasms; Cancer Vaccines; Computer Simulation; Epitopes, B-Lymphocyte; Epitopes, T-Lymphocyte; Female; HLA Antigens; Humans; Peptides; Pregnancy Proteins; Protein Structure, Secondary; Reproducibility of Results
PubMed: 31952435
DOI: 10.29252/ibj.24.3.173 -
Cancer Immunology, Immunotherapy : CII Jul 2023Immunotherapeutic strategies aimed at enhancing tumor cell killing by tumor-specific T cells hold great potential for reducing tumor burden and prolonging survival of...
Identification of antigenic epitopes recognized by tumor infiltrating lymphocytes in high grade serous ovarian cancer by multi-omics profiling of the auto-antigen repertoire.
Immunotherapeutic strategies aimed at enhancing tumor cell killing by tumor-specific T cells hold great potential for reducing tumor burden and prolonging survival of cancer patients. Although many potential tumor antigens have been described, identifying relevant targets when designing anti-cancer vaccines or targeted cell therapies remains a challenge. To identify novel, potentially immunogenic candidate tumor antigens, we performed integrated tumor transcriptomic, seromic, and proteomic analyses of high grade serous ovarian cancer (HGSC) patient tumor samples. We identified tumor neo-antigens and over-expressed antigens using whole exome and RNA sequencing and examined these in relation to patient-matched auto-antibody repertoires. Focusing on MHC class I epitopes recognized by CD8 T cells, HLA-binding epitopes were identified or predicted from the highly expressed, mutated, or auto-antibody target antigen, or MHC-associated peptides (MAPs). Recognition of candidate antigenic peptides was assessed within the tumor-infiltrating T lymphocyte (TIL) population expanded from each patient. Known tumor-associated antigens (TAA) and cancer/testis antigens (CTA) were commonly found in the auto-antibody and MAP repertoires and CD8 TILs recognizing epitopes from these antigens were detected, although neither expression level nor the presence of auto-antibodies correlated with TIL recognition. Auto-antibodies against tumor-mutated antigens were found in most patients, however, no TIL recognition of the highest predicted affinity neo-epitopes was detected. Using high expression level, auto-antibody recognition, and epitope prediction algorithms, we identified epitopes in 5 novel antigens (MOB1A, SOCS3, TUBB, PRKAR1A, CCDC6) recognized by HGSC patient TILs. Furthermore, selection of epitopes from the MAP repertoire identified 5 additional targets commonly recognized by multiple patient TILs. We find that the repertoire of TIL specificities includes recognition of highly expressed and immunogenic self-antigens that are processed and presented by tumors. These results indicate an ongoing autoimmune response against a range of self-antigens targeted by HGSC TILs.
Topics: Male; Humans; Female; Lymphocytes, Tumor-Infiltrating; Epitopes; CD8-Positive T-Lymphocytes; Proteomics; Multiomics; Antigens, Neoplasm; Peptides; Ovarian Neoplasms; Autoantigens; Epitopes, T-Lymphocyte
PubMed: 36943460
DOI: 10.1007/s00262-023-03413-7