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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 -
Frontiers in Immunology 2022Recruitment and activation of CD8 T cells occur through specific triggering of T cell receptor (TCR) by peptide-bound human leucocyte antigen (HLA) ligands. Within the...
Recruitment and activation of CD8 T cells occur through specific triggering of T cell receptor (TCR) by peptide-bound human leucocyte antigen (HLA) ligands. Within the generated trimeric TCR-peptide:HLA complex, the molecular binding affinities between peptide and HLA, and between TCR and peptide:HLA both impact T cell functional outcomes. However, how their individual and combined effects modulate immunogenicity and overall T cell responsiveness has not been investigated systematically. Here, we established two panels of human tumor peptide variants differing in their affinity to HLA. For precise characterization, we developed the "blue peptide assay", an upgraded cell-based approach to measure the peptide:HLA affinity. These peptide variants were then used to investigate the cross-reactivity of tumor antigen-specific CD8 T cell clonotypes derived from blood of cancer patients after vaccination with either the native or an affinity-optimized Melan-A/MART-1 epitope, or isolated from tumor infiltrated lymph nodes (TILNs). Vaccines containing the native tumor epitope generated T cells with better functionality, and superior cross-reactivity against potential low affinity escape epitopes, as compared to T cells induced by vaccines containing an HLA affinity-optimized epitope. Comparatively, Melan-A/MART-1-specific TILN cells displayed functional and cross-reactive profiles that were heterogeneous and clonotype-dependent. Finally, we took advantage of a collection of T cells expressing affinity-optimized NY-ESO-1-specific TCRs to interrogate the individual and combined impact of peptide:HLA and TCR-pHLA affinities on overall CD8 T cell responses. We found profound and distinct effects of both biophysical parameters, with additive contributions and absence of hierarchical dominance. Altogether, the biological impact of peptide:HLA and TCR-pHLA affinities on T cell responses was carefully dissected in two antigenic systems, frequently targeted in human cancer immunotherapy. Our technology and stepwise comparison open new insights into the rational design and selection of vaccine-associated tumor-specific epitopes and highlight the functional and cross-reactivity profiles that endow T cells with best tumor control capacity.
Topics: CD8-Positive T-Lymphocytes; Epitopes; Histocompatibility Antigens Class II; Humans; MART-1 Antigen; Neoplasms; Peptides; Receptors, Antigen, T-Cell
PubMed: 36032094
DOI: 10.3389/fimmu.2022.973986 -
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 -
PLoS Computational Biology 2012The Complementarity Determining Regions (CDRs) of antibodies are assumed to account for the antigen recognition and binding and thus to contain also the antigen binding...
The Complementarity Determining Regions (CDRs) of antibodies are assumed to account for the antigen recognition and binding and thus to contain also the antigen binding site. CDRs are typically discerned by searching for regions that are most different, in sequence or in structure, between different antibodies. Here, we show that ~20% of the antibody residues that actually bind the antigen fall outside the CDRs. However, virtually all antigen binding residues lie in regions of structural consensus across antibodies. Furthermore, we show that these regions of structural consensus which cover the antigen binding site are identifiable from the sequence of the antibody. Analyzing the predicted contribution of antigen binding residues to the stability of the antibody-antigen complex, we show that residues that fall outside of the traditionally defined CDRs are at least as important to antigen binding as residues within the CDRs, and in some cases, they are even more important energetically. Furthermore, antigen binding residues that fall outside of the structural consensus regions but within traditionally defined CDRs show a marginal energetic contribution to antigen binding. These findings allow for systematic and comprehensive identification of antigen binding sites, which can improve the understanding of antigenic interactions and may be useful in antibody engineering and B-cell epitope identification.
Topics: Alanine; Antibodies; Antigen-Antibody Complex; Antigens; Automation; B-Lymphocytes; Binding Sites; Binding Sites, Antibody; Complementarity Determining Regions; Epitopes; Humans; Molecular Conformation; Mutation; Reproducibility of Results
PubMed: 22383868
DOI: 10.1371/journal.pcbi.1002388 -
Communications Biology Nov 2022Understanding the antigenic signatures of all human coronaviruses (HCoVs) Spike (S) proteins is imperative for pan-HCoV epitopes identification and broadly effective...
Understanding the antigenic signatures of all human coronaviruses (HCoVs) Spike (S) proteins is imperative for pan-HCoV epitopes identification and broadly effective vaccine development. To depict the currently elusive antigenic signatures of α-HCoVs S proteins, we isolated a panel of antibodies against the HCoV-229E S protein and characterized their epitopes and neutralizing potential. We found that the N-terminal domain of HCoV-229E S protein is antigenically dominant wherein an antigenic supersite is present and appears conserved in HCoV-NL63, which holds potential to serve as a pan-α-HCoVs epitope. In the receptor binding domain, a neutralizing epitope is captured in the end distal to the receptor binding site, reminiscent of the locations of the SARS-CoV-2 RBD cryptic epitopes. We also identified a neutralizing antibody that recognizes the connector domain, thus representing the first S2-directed neutralizing antibody against α-HCoVs. The unraveled HCoVs S proteins antigenic similarities and variances among genera highlight the challenges faced by pan-HCoV vaccine design while supporting the feasibility of broadly effective vaccine development against a subset of HCoVs.
Topics: Humans; Spike Glycoprotein, Coronavirus; SARS-CoV-2; COVID-19; Coronavirus 229E, Human; Antigens, Viral; Epitopes; Antibodies, Neutralizing
PubMed: 36333470
DOI: 10.1038/s42003-022-04160-8 -
Virology Jan 2021Human norovirus virus-like particles (VLPs) are assumed to be morphologically and antigenically similar to virion particles. The norovirus virion is assembled from 180...
Human norovirus virus-like particles (VLPs) are assumed to be morphologically and antigenically similar to virion particles. The norovirus virion is assembled from 180 copies of the capsid protein (VP1) and exhibits T = 3 icosahedral symmetry. In this study, we showed that the vaccine candidate GII.4c VP1 formed T = 1 and T = 3 VLPs, but mainly assembled into T = 4 icosahedral particles that were composed of 240 VP1 copies. In contrast, another clinically important genotype, GII.17, almost exclusively folded into T = 3 VLPs. Interestingly, the GII.4c T = 1 particles had higher binding capacities to norovirus-specific Nanobodies than to GII.4c T = 3 and T = 4 particles. Our data indicated that the occluded Nanobody-binding epitopes on the T = 1 particles were more accessible compared to the larger T = 3 and T = 4 particles. Overall, this new data revealed that GII.4c VLPs had a preference for forming the T = 4 icosahedral symmetry and future studies with varied sized norovirus VLPs should take caution when examining antigenicity.
Topics: Animals; Antigens, Viral; Capsid Proteins; Cryoelectron Microscopy; Epitopes; HEK293 Cells; Humans; Norovirus; Sf9 Cells; Single-Domain Antibodies; Vaccines, Virus-Like Particle; Viral Vaccines
PubMed: 33202318
DOI: 10.1016/j.virol.2020.10.005 -
Journal of Biosciences 2021The COVID-19 pandemic that emerged around December 2019 claimed millions of lives. For vaccine development, S protein on viral envelope that binds to ACE2 receptor on... (Review)
Review
The COVID-19 pandemic that emerged around December 2019 claimed millions of lives. For vaccine development, S protein on viral envelope that binds to ACE2 receptor on cells for entry was identified as vaccine candidate. S protein consists of Receptor Binding Motif (RBM) in the S1 subunit followed by the S2 subunit with an intermediate furin cleavage site. A stabilized version of S protein with 2 proline residues was used as antigen. Overall, most vaccines exhibited efficacy between 80 and 95%. However, being a RNA virus that is prone to mutations along with selection pressure on S protein and frequent use of convalescent plasma led to evolution of variants. These variants are responsible for multiple waves of infection observed globally. In our review, we discuss current data on vaccines and its efficacy in neutralizing SARS-CoV-2 from Wuhan and its variants. Further, our docked mutations observed in variants on the ACE2-S complex cryo-EM structure show that mostly the S1 domain is under selection pressure where major mutations occur in the N terminal domain (NTD), RBM and junction near S1-S2 subunit. Therefore, this review would be a reference for development of new candidate antigen(s) with better efficacy against variants.
Topics: Amino Acid Motifs; Antibodies, Neutralizing; Antigens; Binding Sites; COVID-19; COVID-19 Vaccines; Global Health; Humans; India; Mutation; Pandemics; Proline; Protein Binding; Protein Domains; SARS-CoV-2; Vaccine Development
PubMed: 34857677
DOI: 10.1007/s12038-021-00226-7 -
BMC Bioinformatics Jun 2020In 2009, a novel influenza vaccine was distributed worldwide to combat the H1N1 influenza "swine flu" pandemic. However, antibodies induced by the vaccine display...
BACKGROUND
In 2009, a novel influenza vaccine was distributed worldwide to combat the H1N1 influenza "swine flu" pandemic. However, antibodies induced by the vaccine display differences in their specificity and cross-reactivity dependent on pre-existing immunity. Here, we present a computational model that can capture the effect of pre-existing immunity on influenza vaccine responses. The model predicts the region of the virus hemagglutinin (HA) protein targeted by antibodies after vaccination as well as the level of cross-reactivity induced by the vaccine. We tested our model by simulating a scenario similar to the 2009 pandemic vaccine and compared the results to antibody binding data obtained from human subjects vaccinated with the monovalent 2009 H1N1 influenza vaccine.
RESULTS
We found that both specificity and cross-reactivity of the antibodies induced by the 2009 H1N1 influenza HA protein were affected by the viral strain the individual was originally exposed. Specifically, the level of antigenic relatedness between the original exposure HA antigen and the 2009 HA protein affected antigenic-site immunodominance. Moreover, antibody cross-reactivity was increased when the individual's pre-existing immunity was specific to an HA protein antigenically distinct from the 2009 pandemic strain. Comparison of simulation data with antibody binding data from human serum samples demonstrated qualitative and quantitative similarities between the model and real-life immune responses to the 2009 vaccine.
CONCLUSION
We provide a novel method to evaluate expected outcomes in antibody specificity and cross-reactivity after influenza vaccination in individuals with different influenza HA antigen exposure histories. The model produced similar outcomes as what has been previously reported in humans after receiving the 2009 influenza pandemic vaccine. Our results suggest that differences in cross-reactivity after influenza vaccination should be expected in individuals with different exposure histories.
Topics: Amino Acid Sequence; Antibodies, Viral; Antigens, Viral; Computer Simulation; Cross Reactions; Hemagglutinin Glycoproteins, Influenza Virus; Humans; Influenza A Virus, H1N1 Subtype; Influenza Vaccines; Models, Immunological
PubMed: 32560624
DOI: 10.1186/s12859-020-03594-3 -
Gut Microbes Jan 2017Recent discoveries on the role of commensal microbiota have significantly changed our understanding of human physiology. The host-microbiota interplay is now an... (Review)
Review
Recent discoveries on the role of commensal microbiota have significantly changed our understanding of human physiology. The host-microbiota interplay is now an important aspect to take into account to understand immune responses and immunological diseases. Autoimmune uveitis is a sight-threatening disease that arises without a known infectious etiology. It is unknown where and how autoreactive T cells become primed to trigger disease in the eye, which is an immune privileged site. We recently reported data supporting the notion that retina-specific T cells receive a signal in the gut from commensal microbiota-derived cross-reactive antigen(s) and trigger autoimmune uveitis in the R161H mouse model. Here we discuss our published findings, as well as our recent attempts to identify the responsible microbe(s) by using different antibiotic treatments, 16S rDNA sequencing and homology searches for candidate antigenic mimic(s) of the retinal antigen.
Topics: Animals; Antigens; Autoimmune Diseases; Autoimmunity; Gastrointestinal Microbiome; Humans; Retina; T-Lymphocytes; Uveitis
PubMed: 28045579
DOI: 10.1080/19490976.2016.1273996 -
Frontiers in Immunology 2020Whole genome/exome sequencing data for tumors are now abundant, and many tumor antigens, especially mutant antigens (neoantigens), have been identified for cancer...
Whole genome/exome sequencing data for tumors are now abundant, and many tumor antigens, especially mutant antigens (neoantigens), have been identified for cancer immunotherapy. However, only a small fraction of the peptides from these antigens induce cytotoxic T cell responses. Therefore, efficient methods to identify these antigenic peptides are crucial. The current models of major histocompatibility complex (MHC) binding and antigenic prediction are still inaccurate. In this study, 360 9-mer peptides with verified immunological activity were selected to construct a prediction of tumor neoantigen (POTN) model, an immunogenic prediction model specifically for the human leukocyte antigen-A2 allele. Based on the physicochemical properties of amino acids, such as the residue propensity, hydrophobicity, and organic solvent/water, we found that the predictive capability of POTN is superior to that of the prediction programs SYPEITHI, IEDB, and NetMHCpan 4.0. We used POTN to screen peptides for the cancer-testis antigen located on the X chromosome, and we identified several peptides that may trigger immunogenicity. We synthesized and measured the binding affinity and immunogenicity of these peptides and found that the accuracy of POTN is higher than that of NetMHCpan 4.0. Identifying the properties related to the T cell response or immunogenicity paves the way to understanding the MHC/peptide/T cell receptor complex. In conclusion, POTN is an efficient prediction model for screening high-affinity immunogenic peptides from tumor antigens, and thus provides useful information for developing cancer immunotherapy.
Topics: Antigens, Neoplasm; HLA-A2 Antigen; Humans; Male; Models, Immunological; Peptides; Testicular Neoplasms
PubMed: 33133063
DOI: 10.3389/fimmu.2020.02193