Immune Epitope Research Articles

Bioinformatic Analysis of Immunodominant Peptides of Rabies Virus (<i>Rabies lyssavirus, Rhabdoviridae</i>)

There is a need to develop a new generation of anti-rabies vaccines that provide a protective level of antibodies after a single injection. Prospects for solving this problem are opened by the latest developments in the field of “reverse vaccinology”. The main parameter that determines the effectiveness of recombinant vaccines is the design of the antigen-coding sequence. In this regard, the aim of the work was to conduct a bioinformatic analysis of rabies virus (Rabies lyssavirus, Rhabdoviridae) peptides to identify immunogenic epitopes.Materials and methods. Analysis of 5 candidate protein sequences of more than 100 strains and epizootic isolates of the rabies virus was performed using standard in silico prediction methods using Immune Epitope Database (IEDB) (NIH, USA).Results and discussion. As a result of the analysis of primary amino acid sequences, carried out using the most commonly used bioinformatics tools, the number of immunogenic epitopes and the types of immune response detected (T- and B-cell epitopes, class I MHCbinding epitopes) were established for viral proteins: glycoprotein (G), nucleoprotein (N), phosphoprotein (P), matrix protein (M), RNA-dependent RNA polymerase (L). In the amino acid structure of these proteins, N- and O-glycosylation sites, signal peptides, and transmembrane domains were additionally identified. In order to predict the safety and efficacy of these proteins as components of recombinant vaccines, an in silico assessment of their physicochemical properties was carried out. Despite the fact that the predominant number of epitopes is concentrated in the structure of the glycoprotein, the epitopes of other proteins, ranging according to the level of antigenicity and conservatism, may also be of interest as components of preventive drugs or diagnostics. The presented data can be used in the design of the insert during the construction of a candidate virus-vector vaccine or control positive samples in diagnostic methods based on the indication of viral genome fragments.

Reverse Vaccinology Analysis of B-cell Epitope against Nipah Virus using Fusion Protein

Nipah virus (NiV) is an RNA virus, a pathogenic paramyxovirus that causes nonlethal respiratory illness in pigs. It was originally reported in Malaysia in 1998. NiV is considered a potential outbreak threat because it is zoonotic. However, no vaccines or antiviral drugs have been found against NiV. Therefore, the main objective is to develop effective vaccines by characterizing the fusion protein of NiV. We used a reference sequence retrieved from the National Center for Biotechnology Information (NCBI), then 3D modeled it to obtain the conserved region of the fusion protein. The interaction between the conserved region and B-cell receptors has been evaluated through a molecular docking approach. The B-cell epitope was identified using the Immune Epitope Database (IEDB) web server. As a result, we recommend Pep_D FANCISVTCQCQ as an epitope-based peptide vaccine candidate against Nipah virus. Pep D is highly immunogenic and does not cause autoimmune reactions. Pep D has the lowest binding energy for BCR molecular complexes, which can activate the transduction signal and direct B-cell immune response. However, further studies are required for confirmation (in vitro and in vivo).

Correlative CD4 and CD8 T-cell immunodominance in humans and mice: Implications for preclinical testing

Antigen-specific T-cell recognition is restricted by Major Histocompatibility Complex (MHC) molecules, and differences between CD4 and CD8 immunogenicity in humans and animal species used in preclinical vaccine testing are yet to be fully understood. In this study, we addressed this matter by analyzing experimentally identified epitopes based on published data curated in the Immune Epitopes DataBase (IEDB) database. We first analyzed SARS-CoV-2 spike (S) and nucleoprotein (N), which are two common targets of the immune response and well studied in both human and mouse systems. We observed a weak but statistically significant correlation between human and H-2b mouse T-cell responses (CD8 S specific (r = 0.206, p = 1.37 × 10−13); CD4 S specific (r = 0.118, p = 2.63 × 10−5) and N specific (r = 0.179, p = 2.55 × 10−4)). Due to intrinsic differences in MHC molecules across species, we also investigated the association between the immunodominance of common Human Leukocyte Antigen (HLA) alleles for which HLA transgenic mice are available, namely, A*02:01, B*07:02, DRB1*01:01, and DRB1*04:01, and found higher significant correlations for both CD8 and CD4 (maximum r = 0.702, p = 1.36 × 10−31 and r = 0.594, p = 3.04−122, respectively). Our results further indicated that some regions are commonly immunogenic between humans and mice (either H-2b or HLA transgenic) but that others are human specific. Finally, we noted a significant correlation between CD8 and CD4 S- (r = 0.258, p = 7.33 × 1021) and N-specific (r = 0.369, p = 2.43 × 1014) responses, suggesting that discrete protein subregions can be simultaneously recognized by T cells. These findings were confirmed in other viral systems, providing general guidance for the use of murine models to test T-cell immunogenicity of viral antigens destined for human use.

Statistical Analysis and Tokenization of Epitopes to Construct Artificial Neoepitope Libraries.

Epitopes are specific regions on an antigen's surface that the immune system recognizes. Epitopes are usually protein regions on foreign immune-stimulating entities such as viruses and bacteria, and in some cases, endogenous proteins may act as antigens. Identifying epitopes is crucial for accelerating the development of vaccines and immunotherapies. However, mapping epitopes in pathogen proteomes is challenging using conventional methods. Screening artificial neoepitope libraries against antibodies can overcome this issue. Here, we applied conventional sequence analysis and methods inspired in natural language processing to reveal specific sequence patterns in the linear epitopes deposited in the Immune Epitope Database (www.iedb.org) that can serve as building blocks for the design of universal epitope libraries. Our results reveal that amino acid frequency in annotated linear epitopes differs from that in the human proteome. Aromatic residues are overrepresented, while the presence of cysteines is practically null in epitopes. Byte pair encoding tokenization shows high frequencies of tryptophan in tokens of 5, 6, and 7 amino acids, corroborating the findings of the conventional sequence analysis. These results can be applied to reduce the diversity of linear epitope libraries by orders of magnitude.

A Lysine Residue at the C-Terminus of MHC Class I Ligands Correlates with Low C-Terminal Proteasomal Cleavage Probability.

The majority of peptides presented by MHC class I result from proteasomal protein turnover. The specialized immunoproteasome, which is induced during inflammation, plays a major role in antigenic peptide generation. However, other cellular proteases can, either alone or together with the proteasome, contribute peptides to MHC class I loading non-canonically. We used an immunopeptidomics workflow combined with prediction software for proteasomal cleavage probabilities to analyze how inflammatory conditions affect the proteasomal processing of immune epitopes presented by A549 cells. The treatment of A549 cells with IFNγ enhanced the proteasomal cleavage probability of MHC class I ligands for both the constitutive proteasome and the immunoproteasome. Furthermore, IFNγ alters the contribution of the different HLA allotypes to the immunopeptidome. When we calculated the HLA allotype-specific proteasomal cleavage probabilities for MHC class I ligands, the peptides presented by HLA-A*30:01 showed characteristics hinting at a reduced C-terminal proteasomal cleavage probability independently of the type of proteasome. This was confirmed by HLA-A*30:01 ligands from the immune epitope database, which also showed this effect. Furthermore, two additional HLA allotypes, namely, HLA-A*03:01 and HLA-A*11:01, presented peptides with a markedly reduced C-terminal proteasomal cleavage probability. The peptides eluted from all three HLA allotypes shared a peptide binding motif with a C-terminal lysine residue, suggesting that this lysine residue impairs proteasome-dependent HLA ligand production and might, in turn, favor peptide generation by other cellular proteases.

Metformin Impedes Oxidation of LDL In Vitro.

Metformin is the most commonly prescribed glucose-lowering drug for the treatment of type 2 diabetes. The aim of this study was to investigate whether metformin is capable of impeding the oxidation of LDL, a crucial step in the development of endothelial dysfunction and atherosclerosis. LDL was oxidized by addition of CuCl2 in the presence of increasing concentrations of metformin. The extent of LDL oxidation was assessed by measuring lipid hydroperoxide and malondialdehyde concentrations, relative electrophoretic mobilities, and oxidation-specific immune epitopes. Cytotoxicity of oxLDL in the vascular endothelial cell line EA.hy926 was assessed using the alamarBlue viability test. Quantum chemical calculations were performed to determine free energies of reactions between metformin and radicals typical for lipid oxidation. Metformin concentration-dependently impeded the formation of lipid hydroperoxides, malondialdehyde, and oxidation-specific immune epitopes when oxidation of LDL was initiated by addition of Cu2+. The cytotoxicity of oxLDL was reduced when it was obtained under increasing concentrations of metformin. The quantum chemical calculations revealed that only the reaction of metformin with hydroxyl radicals is exergonic, whereas the reactions with hydroperoxyl radicals or superoxide radical anions are endergonic. Metformin, beside its glucose-lowering effect, might be a suitable agent to impede the development of atherosclerosis and associated CVD. This is due to its capability to impede LDL oxidation, most likely by scavenging hydroxyl radicals.

Immunoinformatics-based multi-epitope vaccine design for the re-emerging monkeypox virus

BackgroundOn May 7, 2022, WHO reported a new monkeypox case. By May 2023 over 80,000 cases had been reported worldwide outside previously endemic nations. (This primarily affected the men who have sex with men (MSM) community in rich nations). The present research aims to develop a multi-epitope vaccine for the monkeypox virus (MPXV) using structural and cell surface proteins. MethodsThe first part of the research involved retrieving protein sequences. The Immune Epitope Database (IEDB) was then used to analyze the B and T lymphocyte epitopes. After analyzing the sensitizing properties, toxicity, antigenicity, and molecular binding, appropriate linkers were utilizedto connect selected epitopes to adjuvants, and the structure of the vaccine was formulated. Algorithms from the field of immunoinformatics predicted the secondary and tertiary structures of vaccines. The physical, chemical, and structural properties were refined and validated to achieve maximum stability. Molecular docking and molecular dynamic simulations were subsequently employed to assess the vaccine’s efficacy. Afterward, the ability of the vaccine to interact with toll-like receptors 3 and 4 (TLR3 and TLR4) was evaluated. Finally, the optimized sequence was then introduced into the Escherichia coli (E. coli) PET30A + vector. ResultsAn immunoinformatics evaluation suggested that such a vaccine might be safe revealed that this vaccine is safe, hydrophilic, temperature- and condition-stable, and can stimulate innate immunity by binding to TLR3 and TLR4. ConclusionOur findings suggest that the first step in MPXV pathogenesis is structural and cell surface epitopes. In this study, the most effective and promising epitopes were selected and designed throughprecision servers. Furthermore,through the utilization of multi-epitope structures and a combination of two established adjuvants, this research has the potential to be a landmarkin developing an antiviralvaccine against MPXV. However, additional in vitro and in vivo tests are required to confirm these results.

Attenuated but immunostimulatory Mycobacterium tuberculosis variant bovis strain Ravenel shows variation in T cell epitopes

Tuberculosis, caused by Mycobacterium tuberculosis complex (MTBC) organisms, affects a range of humans and animals globally. Mycobacterial pathogenesis involves manipulation of the host immune system, partially through antigen presentation. Epitope sequences across the MTBC are evolutionarily hyperconserved, suggesting their recognition is advantageous for the bacterium. Mycobacterium tuberculosis var. bovis (MBO) strain Ravenel is an isolate known to provoke a robust immune response in cattle, but typically fails to produce lesions and persist. Unlike attenuated MBO BCG strains that lack the critical RD1 genomic region, Ravenel is classic-type MBO structurally, suggesting genetic variation is responsible for defective pathogenesis. This work explores variation in epitope sequences in MBO Ravenel by whole genome sequencing, and contrasts such variation against a fully virulent clinical isolate, MBO strain 10-7428. Validated MTBC epitopes (n = 4818) from the Immune Epitope Database were compared to their sequences in MBO Ravenel and MBO 10-7428. Ravenel yielded 3 modified T cell epitopes, in genes rpfB, argC, and rpoA. These modifications were predicted to have little effect on protein stability. In contrast, T cells epitopes in 10-7428 were all WT. Considering T cell epitope hyperconservation across MTBC variants, these altered MBO Ravenel epitopes support their potential contribution to overall strain attenuation. The affected genes may provide clues on basic pathogenesis, and if so, be feasible targets for reverse vaccinology.

Immunization with lytic polysaccharide monooxygenase CbpD induces protective immunity against Pseudomonas aeruginosa pneumonia

Pseudomonas aeruginosa (PA) CbpD belongs to the lytic polysaccharide monooxygenases (LPMOs), a family of enzymes that cleave chitin or related polysaccharides. Here, we demonstrate a virulence role of CbpD in PA pneumonia linked to impairment of host complement function and opsonophagocytic clearance. Following intratracheal challenge, a PA ΔCbpD mutant was more easily cleared and produced less mortality than the wild-type parent strain. The x-ray crystal structure of the CbpD LPMO domain was solved to subatomic resolution (0.75Å) and its two additional domains modeled by small-angle X-ray scattering and Alphafold2 machine-learning algorithms, allowing structure-based immune epitope mapping. Immunization of naive mice with recombinant CbpD generated high IgG antibody titers that promoted human neutrophil opsonophagocytic killing, neutralized enzymatic activity, and protected against lethal PA pneumonia and sepsis. IgG antibodies generated against full-length CbpD or its noncatalytic M2+CBM73 domains were opsonic and protective, even in previously PA-exposed mice, while antibodies targeting the AA10 domain were not. Preexisting antibodies in PA-colonized cystic fibrosis patients primarily target the CbpD AA10 catalytic domain. Further exploration of LPMO family proteins, present across many clinically important and antibiotic-resistant human pathogens, may yield novel and effective vaccine antigens.

Are the integrin binding motifs within SARS CoV-2 spike protein and MHC class II alleles playing the key role in COVID-19?

The previous studies on the RGD motif (aa403-405) within the SARS CoV-2 spike (S) protein receptor binding domain (RBD) suggest that the RGD motif binding integrin(s) may play an important role in infection of the host cells. We also discussed the possible role of two other integrin binding motifs that are present in S protein: LDI (aa585-587) and ECD (661-663), the motifs used by some other viruses in the course of infection. The MultiFOLD models for protein structure analysis have shown that the ECD motif is clearly accessible in the S protein, whereas the RGD and LDI motifs are partially accessible. Furthermore, the amino acids that are present in Epstein-Barr virus protein (EBV) gp42 playing very important role in binding to the HLA-DRB1 molecule and in the subsequent immune response evasion, are also present in the S protein heptad repeat-2. Our MultiFOLD model analyses have shown that these amino acids are clearly accessible on the surface in each S protein chain as monomers and in the homotrimer complex and bind to HLA-DRB1 β chain. Therefore, they may have the identical role in SARS CoV-2 immune evasion as in EBV infection. The prediction analyses of the MHC class II binding peptides within the S protein have shown that the RGD motif is present in the core 9-mer peptide IRGDEVRQI within the two HLA-DRB1*03:01 and HLA-DRB3*01.01 strong binding 15-mer peptides suggesting that RGD motif may be the potential immune epitope. Accordingly, infected HLA-DRB1*03:01 or HLA-DRB3*01.01 positive individuals may develop high affinity anti-RGD motif antibodies that react with the RGD motif in the host proteins, like fibrinogen, thrombin or von Willebrand factor, affecting haemostasis or participating in autoimmune disorders.

SARS-CoV-2 Gut-Targeted Epitopes: Sequence Similarity and Cross-Reactivity Join Together for Molecular Mimicry.

The gastrointestinal tract can be heavily infected by SARS-CoV-2. Being an auto-immunogenic virus, SARS-CoV-2 represents an environmental factor that might play a role in gut-associated autoimmune diseases. However, molecular mimicry between the virus and the intestinal epitopes is under-investigated. The present study aims to elucidate sequence similarity between viral antigens and human enteric sequences, based on known cross-reactivity. SARS-CoV-2 epitopes that cross-react with human gut antigens were explored, and sequence alignment was performed against self-antigens implicated in enteric autoimmune conditions. Experimental SARS-CoV-2 epitopes were aggregated from the Immune Epitope Database (IEDB), while enteric antigens were obtained from the UniProt Knowledgebase. A Pairwise Local Alignment tool, EMBOSS Matcher, was employed for the similarity search. Sequence similarity and targeted cross-reactivity were depicted between 10 pairs of immunoreactive epitopes. Similar pairs were found in four viral proteins and seven enteric antigens related to ulcerative colitis, primary biliary cholangitis, celiac disease, and autoimmune hepatitis. Antibodies made against the viral proteins that were cross-reactive with human gut antigens are involved in several essential cellular functions. The relationship and contribution of those intestinal cross-reactive epitopes to SARS-CoV-2 or its potential contribution to gut auto-immuno-genesis are discussed.

Identification of a GII.6 norovirus blockade antibody epitope

Noroviruses (NoVs) are the leading agent that causes acute viral gastroenteritis worldwide. Sporadic cases of GII.6 NoV have been reported primarily in addition to occasional outbreaks. Using the major capsid protein VP1 of GII.6 NoV derived from three distinct clusters, we demonstrated three blockade monoclonal antibodies (mAbs, 1F7, 1F11, and 2B6) generated previously exhibited cluster-specific binding effects. Combining sequence alignment and blocking immune epitopes, we sequentially designed a total of 18 mutant proteins containing one, two, or three mutations, or swapped regions. Indirect enzyme-linked immunosorbent assay (ELISA) demonstrated that the three blocking mAbs lost or showed significantly reduced binding for H383Y, D387N, V390D, and T391D mutant proteins. Combining data from mutant proteins with swapping regions and point mutations, the binding region of the three mAbs was mapped to residues 380–395. Sequence alignment of this region showed within-cluster conservation and between-cluster variations, further strengthening the idea of blockade epitope-mediated evolution of NoV.

Molecular Mimicry and HLA Polymorphisms May Drive Autoimmunity in Recipients of the BNT-162b2 mRNA Vaccine: A Computational Analysis.

After the start of the worldwide COVID-19 vaccination campaign, there were increased reports of autoimmune diseases occurring de novo after vaccination. This in silico analysis aimed to investigate the presence of protein epitopes encoded by the BNT-162b2 mRNA vaccine, one of the most widely administered COVID-19 vaccines, which could induce autoimmunity in predisposed individuals. The FASTA sequence of the protein encoded by the BNT-162b2 vaccine served as the key input to the Immune Epitope Database and Analysis Resource. Linear peptides with 90% BLAST homology were selected, and T-cell, B-cell, and MHC-ligand assays without MHC restriction were searched and analyzed. HLA disease associations were screened on the HLA-SPREAD platform by selecting only positive markers. By 7 May 2023, a total of 5693 epitopes corresponding to 21 viral but also human proteins were found. The latter included CHL1, ENTPD1, MEAF6, SLC35G2, and ZFHX2. Importantly, some autoepitopes may be presented by HLA alleles positively associated with various immunological diseases. The protein product of the BNT-162b2 mRNA vaccine contains immunogenic epitopes that may trigger autoimmune phenomena in predisposed individuals through a molecular mimicry mechanism. Genotyping for HLA alleles may help identify individuals at risk. However, further wet-lab studies are needed to confirm this hypothesis.

Peptide Mapping with LC-HRMS and In Silico Tools for Evaluation of Potential Allergenicity of Commercially Available Whey Protein Hydrolysates

Hypoallergenic formulas containing hydrolyzed protein are intended for use by infants to prevent cow’s milk protein allergy. The degree of hydrolysis of epitopic areas determines the residual allergenicity of whey protein hydrolysates (WPHs). However, only amino-acid-based infant formulas (IFs) are considered entirely nonallergenic. The aim of this study was to investigate four commercially available WPHs with different degree of hydrolysis (H1–H4) for potential allergenicity, by applying LC-HRMS analysis of peptides, and using in silico tools to search for the immunoglobulin (IgE)-binding allergenic epitopes from the Immune Epitope Database. Additionally, the molecular weight distribution of proteins and peptides in the WPHs was measured by SE-UPLC. Based on the peptide coverage and peptide-length distribution profiles, the WPHs showed different extents of hydrolysis: extensively (H1 and H2), partially (H3), and slightly hydrolyzed (H4). Altogether, numerous peptides related to 46 specific IgE-binding epitopes from β-lactoglobulin and α-lactalbumin were found in all the WPHs, regardless of their extent of hydrolysis. Sequence-based identification of the specific peptide composition, with an application of in silico tools, is a reliable approach for discovering the potential allergenicity of protein hydrolysates for IFs.

Quantum vaccinomics platforms to advance in vaccinology.

The opinion flows from Introduction to the immunological quantum that requires a historical perspective, to Quantum vaccine algorithms supported by a bibliometric analysis, to Quantum vaccinomics describing from our perspective the different vaccinomics and quantum vaccinomics algorithms. Finally, in the Discussion and conclusions we propose novel platforms and algorithms developed to further advance on quantum vaccinomics. In the paper we refer to protective epitopes or immunological quantum for the design of candidate vaccine antigens, which may elicit a protective response through both cellular and antibody mediated mechanisms of the host immune system. Vaccines are key interventions for the prevention and control of infectious diseases affecting humans and animals worldwide. Biophysics led to quantum biology and quantum immunology reflecting quantum dynamics within living systems and their evolution. In analogy to quantum of light, immune protective epitopes were proposed as the immunological quantum. Multiple quantum vaccine algorithms were developed based on omics and other technologies. Quantum vaccinomics is the methodological approach with different platforms used for the identification and combination of immunological quantum for vaccine development. Current quantum vaccinomics platforms include in vitro, in music and in silico algorithms and top trends in biotechnology for the identification, characterization and combination of candidate protective epitopes. These platforms have been applied to different infectious diseases and in the future should target prevalent and emerging infectious diseases with novel algorithms.

Supplementing the Carbohydrate Structure Database with glycoepitopes.

Carbohydrate structures in the Carbohydrate Structure Database have been referenced to glycoepitopes from the Immune Epitope Database allowing users to explore the glycan structures and contained epitopes. Starting with an epitope, one can figure out the glycans from other organisms that share the same structural determinant, and retrieve the associated taxonomical, medical, and other data. This database mapping demonstrates the advantages of the integration of immunological and glycomic databases.

Structure and Role of O-Linked Glycans in Viral Envelope Proteins.

N- and O-glycans are both important constituents of viral envelope glycoproteins. O-linked glycosylation can be initiated by any of 20 different human polypeptide O-acetylgalactosaminyl transferases, resulting in an important functional O-glycan heterogeneity. O-glycans are organized as solitary glycans or in clusters of multiple glycans forming mucin-like domains. They are functional both in the viral life cycle and in viral colonization of their host. Negatively charged O-glycans are crucial for the interactions between glycosaminoglycan-binding viruses and their host. A novel mechanism, based on controlled electrostatic repulsion, explains how such viruses solve the conflict between optimized viral attachment to target cells and efficient egress of progeny virus. Conserved solitary O-glycans appear important for viral uptake in target cells by contributing to viral envelope fusion. Dual roles of viral O-glycans in the host B cell immune response, either epitope blocking or epitope promoting, may be exploitable for vaccine development. Finally, specific virus-induced O-glycans may be involved in viremic spread.

Design and validation of a novel multi-epitopes vaccine against hantavirus

Hantavirus is a member of the order Bunyavirales and an emerging global pathogen. Hantavirus infections have affected millions of people globally based on available epidemiological data and research studies. Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS) are the two main human diseases associated with hantavirus infections. Hence, efforts are required to develop a potent vaccine against the pathogen. The only vaccine that is in use for hantavirus is an inactivated virus vaccine, “Hantavax”, but it failed to produce neutralizing antibodies. Vaccine development is of much importance in dealing with the surge of hantavirus globally. In this study, hantavirus five proteins (N protein, G1 and G2, L protein, and non-structural proteins) were used in NetCTL 1.2 program to predict T-cell epitopes. To predict major histocompatibility complex (MHC) binding alleles, an immune epitope database (IEDB) was used. All predicted epitopes were then investigated for different immunoinformatics analyses such as antigenicity and toxicity analyses. The good water-soluble, non-toxic, probable antigenic, and DRB*0101 binder was selected. A multi-epitopes-based vaccine designing was then done where linkers were used to connect the shortlisted epitopes. In addition, an adjuvant molecule was supplementary to the multi-epitopes peptide to improve the vaccine’s immunogenic potential. The final vaccine construct’s three-dimensional structure was modeled by ab initio method. The vaccine molecule was then evaluated for its binding potential with TLR-3 immune receptor, which is key for its recognition and processing by the host immune system. Docking studies were performed using HADDOCK software. The best-docked complex was selected and visualized for intermolecular binding and interactions using UCSF Chimera 1.16 software. The findings revealed that the designed vaccine might be a potential vaccine against hantavirus and can be used in experimental animal model testings. Communicated by Ramaswamy H. Sarma

IEPAPI: a method for immune epitope prediction by incorporating antigen presentation and immunogenicity.

CD8+ T cells can recognize peptides presented by class I human leukocyte antigen (HLA-I) of nucleated cells. Exploring this immune mechanism is essential for identifying T-cell vaccine targets in cancer immunotherapy. Over the past decade, the wealth of data generated by experiments has spawned many computational approaches for predicting HLA-I binding, antigen presentation and T-cell immune responses. Nevertheless, existing HLA-I binding and antigen presentation prediction approaches suffer from low precision due to the absence of T-cell receptor (TCR) recognition. Direct modeling of T-cell immune responses is less effective as TCR recognition's mechanism still remains underexplored. Therefore, directly applying these existing methods to screen cancer neoantigens is still challenging. Here, we propose a novel immune epitope prediction method termed IEPAPI by effectively incorporating antigen presentation and immunogenicity. First, IEPAPI employs a transformer-based feature extraction block to acquire representations of peptides and HLA-I proteins. Second, IEPAPI integrates the prediction of antigen presentation prediction into the input of immunogenicity prediction branch to simulate the connection between the biological processes in the T-cell immune response. Quantitative comparison results on an independent antigen presentation test dataset exhibit that IEPAPI outperformed the current state-of-the-art approaches NetMHCpan4.1 and mhcflurry2.0 on 100 (25/25) and 76% (19/25) of the HLA subtypes, respectively. Furthermore, IEPAPI demonstrates the best precision on two independent neoantigen datasets when compared with existing approaches, suggesting that IEPAPI provides a vital tool for T-cell vaccine design.

Incorporating the Molecular Mimicry of Environmental Antigens into the Causality of Autoimmune Hepatitis.

Molecular mimicry between foreign and self-antigens has been implicated as a cause of autoimmune hepatitis in experimental models and cross-reacting antibodies in patients. This review describes the experimental and clinical evidence for molecular mimicry as a cause of autoimmune hepatitis, indicates the limitations and uncertainties of this premise, and encourages investigations that assess diverse environmental antigens as sources of disease-relevant molecular mimics. Pertinent articles were identified in PubMed using multiple search phrases. Several pathogens have linear or conformational epitopes that mimic the self-antigens of autoimmune hepatitis. The occurrence of an acute immune-mediated hepatitis after vaccination for severe acute respiratory syndrome (SARS)-associated coronavirus 2 (SARS-CoV-2) has suggested that vaccine-induced peptides may mimic disease-relevant tissue antigens. The intestinal microbiome is an under-evaluated source of gut-derived antigens that could also engage in molecular mimicry. Chaperone molecules may enhance the pathogenicity of molecular mimics, and they warrant investigation. Molecular mimics of immune dominant epitopes within cytochrome P450 IID6, the autoantigen most closely associated with autoimmune hepatitis, should be sought in diverse environmental antigens and assessed for pathogenicity. Avoidance strategies, dietary adjustments, vaccine improvement, and targeted manipulation of the intestinal microbiota may emerge as therapeutic possibilities. In conclusion, molecular mimicry may be a missing causality of autoimmune hepatitis. Molecular mimics of key immune dominant epitopes of disease-specific antigens must be sought in diverse environmental antigens. The ubiquity of molecular mimicry compels rigorous assessments of peptide mimics for immunogenicity and pathogenicity in experimental models. Molecular mimicry may complement epigenetic modifications as causative mechanisms of autoimmune hepatitis.