ImmunogeneticsPub Date : 2025-02-05DOI: 10.1007/s00251-025-01371-1
Cassandra R Woolley, Julia H Chariker, Eric C Rouchka, Easton E Ford, Elizabeth Hudson, Kamille M Rasche, Caleb S Whitley, Zachary Vanwinkle, Carolyn R Casella, Melissa L Smith, Thomas C Mitchell
{"title":"Full-length mRNA sequencing resolves novel variation in 5' UTR length for genes expressed during human CD4 T-cell activation.","authors":"Cassandra R Woolley, Julia H Chariker, Eric C Rouchka, Easton E Ford, Elizabeth Hudson, Kamille M Rasche, Caleb S Whitley, Zachary Vanwinkle, Carolyn R Casella, Melissa L Smith, Thomas C Mitchell","doi":"10.1007/s00251-025-01371-1","DOIUrl":"10.1007/s00251-025-01371-1","url":null,"abstract":"<p><p>Isoform sequencing (Iso-Seq) uses long-read technology to produce highly accurate full-length reads of mRNA transcripts. Visualization of individual mRNA molecules can reveal new details of transcript variation within understudied portions of mRNA, such as the 5' untranslated region (UTR). Differential 5' UTRs may contain motifs, upstream open reading frames (uORFs), and secondary structures that can serve to regulate translation or further indicate changes in promoter usage, where transcriptional control may impact protein expression levels. To begin to explore isoform variation during T-cell activation, we generated the first Iso-Seq reference transcriptome of activated human CD4 T cells. Within this dataset, we discovered many novel splice- and end-variant transcripts. Remarkably, one in every eight genes expressed in our dataset was found to have a notable proportion of transcripts with 5' UTR lengthened by over 100 bp compared to the longest corresponding UTR within the Gencode dataset. Among these end-variant transcripts, two novel isoforms were identified for CXCR5, a chemokine receptor associated with T follicular helper cell (Tfh) function and differentiation. When investigated in a model cell system, these lengthened UTR conferred reduced transcript stability and, for one of these isoforms, short uORFs introduced by the added length altered protein expression kinetics. This study highlights instances in which current reference databases are incomplete relative to the information obtained by long-read sequencing of intact mRNA. Iso-Seq is thus a promising approach to better understanding the plasticity of promoter usage, alternative splicing, and UTR sequences that influence RNA stability and translation efficiency.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":"77 1","pages":"14"},"PeriodicalIF":2.9,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunogeneticsPub Date : 2025-01-31DOI: 10.1007/s00251-025-01370-2
Laura Cardoso Corrêa-Dias, Ágata Lopes-Ribeiro, Geovane Marques-Ferreira, Letícia Gomes-de-Pontes, Thaiza Aline Pereira-Santos, Erik Vinicius de Sousa Reis, Thaís de Fátima Silva Moraes, Olindo Assis Martins-Filho, Edel Figueiredo Barbosa-Stancioli, Flávio Guimarães da Fonseca, Jordana Grazziela Coelho-Dos-Reis
{"title":"HCV immunodominant peptide mapping reveals unique HLA-A*02-restricted signatures: insights for CD8<sup>+</sup> T-cell-based vaccines and immunotherapies.","authors":"Laura Cardoso Corrêa-Dias, Ágata Lopes-Ribeiro, Geovane Marques-Ferreira, Letícia Gomes-de-Pontes, Thaiza Aline Pereira-Santos, Erik Vinicius de Sousa Reis, Thaís de Fátima Silva Moraes, Olindo Assis Martins-Filho, Edel Figueiredo Barbosa-Stancioli, Flávio Guimarães da Fonseca, Jordana Grazziela Coelho-Dos-Reis","doi":"10.1007/s00251-025-01370-2","DOIUrl":"https://doi.org/10.1007/s00251-025-01370-2","url":null,"abstract":"<p><p>Several barriers for the development of an HCV vaccine still exist, including the genetic diversity of the virus, and the shortage of assessable models for in vitro and in vivo assays. Therefore, in this study, HCV epitope mapping was performed for 59 polyprotein sequences from 7 HCV genotypes. Around 2,880 peptides were considered epitopes for CD8<sup>+</sup> T cells. The peptide induction of cytokines from Th1 and/or Th2 axes of the cellular immune response was assessed, indicating a tendency for Th2 axis. In vitro evaluation was performed using peptide microarray and a recombinant HLA-A*02:01 molecule. A total of 615 peptides of high reactivity to HLA-A*02:01 were identified, with predominance of leucine and tryptophan residues, highlighting their importance for TCR-epitope binding and CD8<sup>+</sup> T activation. Finally, HCV-derived peptide patterns restricted to HLA-A2*02:01 observed in this study provide important information for the development of a multi-epitope-based pan-genotypic vaccine against the virus.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":"77 1","pages":"13"},"PeriodicalIF":2.9,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunogeneticsPub Date : 2025-01-17DOI: 10.1007/s00251-024-01369-1
Griffin Kutler Dodd, Can Keşmir
{"title":"In silico functional analysis of the human, chimpanzee, and gorilla MHC-A repertoires.","authors":"Griffin Kutler Dodd, Can Keşmir","doi":"10.1007/s00251-024-01369-1","DOIUrl":"10.1007/s00251-024-01369-1","url":null,"abstract":"<p><p>T cells recognize peptides displayed on the surface of cells on MHC molecules. Genetic variation in MHC genes alters their peptide-binding repertoire and thus influences the potential immune response generated against pathogens. Both gorillas and chimpanzees show reduced diversity at their MHC class I A (MHC-A) locus compared to humans, which has been suggested to be the result of a pathogen-mediated selective sweep. More specifically, gorillas lack A3 lineage alleles while chimpanzees seem to have lost the A2 lineage. While previous studies showed this using phylogenetic analysis, here, we take an in silico functional approach and use the peptide-MHC binding prediction software NetMHCpan to examine the peptide-binding repertoires of common human, chimpanzee, and gorilla MHC-A molecules. We find that both gorillas and chimpanzees lack the A02 peptide binding specificity (supertype) despite gorillas being expected to have this specificity since they kept the A2 lineage. Additionally, we show that human MHC molecules with the A02 specificity bind fewer virus-derived peptides than other MHC molecules. We also do not find differential presentation of self-peptides by the A02 supertype, making the purpose of maintaining this specificity in high frequencies in the human population unclear. Taken together, we hypothesize that poor presentation of viral peptides by A02 supertype MHC molecules could have resulted in a selective sweep in chimpanzees and/or gorillas, though we could not identify a specific virus that may have caused this sweep.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":"77 1","pages":"12"},"PeriodicalIF":2.9,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11741996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunogeneticsPub Date : 2025-01-08DOI: 10.1007/s00251-024-01368-2
Cleopatra Petrohilos, Emma Peel, Luke W Silver, Katherine Belov, Carolyn J Hogg
{"title":"AMPed up immunity: 418 whole genomes reveal intraspecific diversity of koala antimicrobial peptides.","authors":"Cleopatra Petrohilos, Emma Peel, Luke W Silver, Katherine Belov, Carolyn J Hogg","doi":"10.1007/s00251-024-01368-2","DOIUrl":"10.1007/s00251-024-01368-2","url":null,"abstract":"<p><p>Characterising functional diversity is a vital element to understanding a species' immune function, yet many immunogenetic studies in non-model organisms tend to focus on only one or two gene families such as the major histocompatibility complex (MHC) or toll-like receptors (TLR). Another interesting component of the eukaryotic innate immune system is the antimicrobial peptides (AMPs). The two major groups of mammalian AMPs are cathelicidins and defensins, with the former having undergone species-specific expansions in marsupials. Here, we utilised data from 418 koala whole genomes to undertake the first comprehensive analysis of AMP diversity across a mammalian wildlife species' range. Overall, allelic diversity was lower than other immune gene families such as MHC, suggesting that AMPs are more conserved, although balancing selection was observed in PhciDEFB12. Some non-synonymous SNPs in the active peptide are predicted to change AMP function through stop gains, change in structure, and increase in peptide charge. Copy number variants (CNVs) were observed in two defensins and one cathelicidin. Interestingly, the most common CNV was the duplication of PhciCATH5, a cathelicidin with activity against chlamydia, which was more common in the southern part of the species range than the north. AMP copy number is correlated with expression levels, so we hypothesise that there is a selective pressure from chlamydia for duplications in PhciCATH5. Future studies should use phenotypic metadata to assess the functional impacts of this gene duplication.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":"77 1","pages":"11"},"PeriodicalIF":2.9,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11711154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunogeneticsPub Date : 2025-01-07DOI: 10.1007/s00251-024-01367-3
Edgar G Gutierrez, Jorge Ortega
{"title":"Uncovering selection pressures on the IRF gene family in bats' immune system.","authors":"Edgar G Gutierrez, Jorge Ortega","doi":"10.1007/s00251-024-01367-3","DOIUrl":"10.1007/s00251-024-01367-3","url":null,"abstract":"<p><p>Unlike other mammals, bats serve as natural reservoirs for several highly pathogenic viruses without exhibiting symptoms of infection. Recent research has explored the complex mechanisms underlying the balance between bats' antiviral defenses and their pathological responses. However, the evolution of the molecular drivers behind bats' antiviral strategies remains largely unknown. Interferon regulatory factors (IRFs) are essential transcription factors that bind to DNA and regulate the expression of numerous genes involved in antiviral defense, inflammation, immune cell differentiation, apoptosis, and oncogenesis. Our research focused on members of the IRF family, using 17 bat species and four terrestrial mammals available in GenBank. We employed CodeML to detect signs of positive selection through three different models. Statistically significant results were obtained for the IRF-1, IRF-4, IRF-5, IRF-6, and IRF-9 genes, which are known to play pivotal roles in various regulation mechanisms. Specifically, IRF-4 and IRF-5 are key in modulating the inflammatory response, while IRF-1 is essential for antiviral defense in bats, and IRF-9 regulates genes activated by type I interferon. Although the role of IRF-6 in these mechanisms requires further investigation in bats, all these genes show signs of positive selection, suggesting an optimization of the processes they regulate. These findings highlight the adaptive role of IRF elements in enhancing, among other things, the bat immune system, potentially improving their resilience and efficacy. Our study not only provides new genetic insights into bats but also underscores the remarkable molecular evolution within this unique group of mammals.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":"77 1","pages":"10"},"PeriodicalIF":2.9,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunogeneticsPub Date : 2024-12-17DOI: 10.1007/s00251-024-01366-4
Lara Diab, Sahar Al Kattar, Naim Oueini, Jihad Hawi, Antoine Chrabieh, Laura Dosh, Rosalyn Jurjus, Angelo Leone, Abdo Jurjus
{"title":"Syndecan-1: a key player in health and disease.","authors":"Lara Diab, Sahar Al Kattar, Naim Oueini, Jihad Hawi, Antoine Chrabieh, Laura Dosh, Rosalyn Jurjus, Angelo Leone, Abdo Jurjus","doi":"10.1007/s00251-024-01366-4","DOIUrl":"10.1007/s00251-024-01366-4","url":null,"abstract":"<p><p>Syndecan-1 (SDC-1) is a transmembrane protein localized on the basolateral surface of epithelial cells, encompassing a core protein with heparin sulfate and chondroitin sulfate glycosaminoglycan side chains. SDC-1 is involved in a panoply of cellular mechanisms including cell-to-cell adhesion, extracellular matrix interactions, cell cycle modulation, and lipid clearance. Alterations in the expression and function of SDC-1 are implicated in numerous disease entities, making it an attractive diagnostic and therapeutic target. However, despite its broad involvement in several disease processes, the underlying mechanism contributing to its diverse functions, pathogenesis, and therapeutic uses remains underexplored. Therefore, this review examines the role of SDC-1 in health and disease, focusing on liver pathologies, inflammatory diseases, infectious diseases, and cancer, and sheds light on SDC-1-based therapeutic approaches. Moreover, it delves into the mechanisms through which SDC-1 contributes to these diseases, emphasizing cell-type specific mechanisms. By comprehensively summarizing the significance of SDC-1, its association with several diseases, and its underlying mechanisms of action, the findings of this review could inform future research directions toward the development of targeted therapies and early diagnosis for a multitude of disease entities.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":"77 1","pages":"9"},"PeriodicalIF":2.9,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142835493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"VaxOptiML: leveraging machine learning for accurate prediction of MHC-I and II epitopes for optimized cancer immunotherapy.","authors":"Dhanushkumar T, Sunila B G, Sripad Rama Hebbar, Prasanna Kumar Selvam, Karthick Vasudevan","doi":"10.1007/s00251-024-01361-9","DOIUrl":"10.1007/s00251-024-01361-9","url":null,"abstract":"<p><p>Cancer immunotherapy hinges on accurate epitope prediction for advancing vaccine development. VaxOptiML (available at https://vaxoptiml.streamlit.app/ ) is an integrated pipeline designed to enhance epitope prediction and prioritization. This study aims to develop and deploy a robust tool for accurate prediction and prioritization of highly immunogenic and optimized MHC-I and MHC-II T-cell epitopes for cancer vaccine development and immunotherapy. Utilizing a curated dataset of experimentally validated epitopes and employing sophisticated machine learning techniques, VaxOptiML features three models: epitope prediction from target sequences, personalized HLA typing, and prioritization the predicted epitopes based on immunogenicity scores. Our rigorous data extraction, cleaning, and feature extraction processes, coupled with model building, yield exceptional accuracy, sensitivity, specificity, and F1 score, surpassing existing prediction methods. Comprehensive visual representations underscore VaxOptiML's robustness and efficacy in accelerating epitope discovery and vaccine design for cancer immunotherapy. Deployed via Streamlit for public use, VaxOptiML enhances accessibility and usability for researchers and clinicians, demonstrating significant potential in cancer immunotherapy.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":"77 1","pages":"8"},"PeriodicalIF":2.9,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ImmunogeneticsPub Date : 2024-12-04DOI: 10.1007/s00251-024-01363-7
Alaine A Marsden, Martin Corcoran, Gunilla Karlsson Hedestam, Nigel Garrett, Salim S Abdool Karim, Penny L Moore, Dale Kitchin, Lynn Morris, Cathrine Scheepers
{"title":"Novel polymorphic and copy number diversity in the antibody IGH locus of South African individuals.","authors":"Alaine A Marsden, Martin Corcoran, Gunilla Karlsson Hedestam, Nigel Garrett, Salim S Abdool Karim, Penny L Moore, Dale Kitchin, Lynn Morris, Cathrine Scheepers","doi":"10.1007/s00251-024-01363-7","DOIUrl":"10.1007/s00251-024-01363-7","url":null,"abstract":"<p><p>The heavy chain of an antibody is crucial for mediating antigen binding. IGHV genes, which partially encode the heavy chain of antibodies, exhibit vast genetic diversity largely through polymorphism and copy number variation (CNV). These genetic variations impact population-level expression levels. In this study, we analyzed expressed antibody transcriptomes and matched germline IGHV genes from donors from KwaZulu-Natal, South Africa. Amplicon NGS targeting germline IGHV sequences was performed on genomic DNA from 70 participants, eight of whom had matched datasets of expressed antibody transcriptomes. Germline IGHV sequencing identified 161 unique IGHV alleles, of which 32 were novel. A further 21 novel IGHV alleles were detected in the expressed transcriptomes of these donors. We also examined the datasets for CNV, uncovering gene duplications of 10 IGHV genes from germline sequencing and 33 genes in the expressed transcriptomes. Many of the IGHV gene duplications have not been described in other populations. This study expands our understanding of genetic differences in distinct populations and suggests the potential impact of genetic diversity on immune responses.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":"77 1","pages":"6"},"PeriodicalIF":2.9,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11615098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142768595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Evolutionary diversity of CXCL16-CXCR6: Convergent substitutions and recurrent gene loss in sauropsids.","authors":"Buddhabhushan Girish Salve, Sandhya Sharma, Nagarjun Vijay","doi":"10.1007/s00251-024-01357-5","DOIUrl":"10.1007/s00251-024-01357-5","url":null,"abstract":"<p><p>The CXCL16-CXCR6 axis is crucial for regulating the persistence of CD8 tissue-resident memory T cells (T<sub>RM</sub>). CXCR6 deficiency lowers T<sub>RM</sub> cell numbers in the lungs and depletes ILC3s in the lamina propria, impairing mucosal defence. This axis is linked to diseases like HIV/SIV, cancer, and COVID-19. Together, these highlight that the CXCL16-CXCR6 axis is pivotal in host immunity. Previous studies of the CXCL16-CXCR6 axis found genetic variation among species but were limited to primates and rodents. To understand the evolution and diversity of CXCL16-CXCR6 across vertebrates, we compared approximately 400 1-to-1 CXCR6 orthologs spanning diverse vertebrates. The unique DRF motif of CXCR6 facilitates leukocyte adhesion by interacting with cell surface-expressed CXCL16 and plays a key role in G-protein selectivity during receptor signalling; however, our findings show that this motif is not universal. The DRF motif is restricted to mammals, turtles, and frogs, while the DRY motif, typical in other CKRs, is found in snakes and lizards. Most birds exhibit the DRL motif. These substitutions at the DRF motif affect the receptor-G<sub>i/o</sub> protein interaction. We establish recurrent CXCR6 gene loss in 10 out of 36 bird orders, including Galliformes and Passeriformes, Crocodilia, and Elapidae, attributed to segmental deletions and/or frame-disrupting changes. Notably, single-cell RNA sequencing of the lung shows a drop in T<sub>RM</sub> cells in species with CXCR6 loss, suggesting a possible link. The concurrent loss of ITGAE, CXCL16, and CXCR6 in chickens may have altered CD8 T<sub>RM</sub> cell abundance, with implications for immunity against viral diseases and vaccines inducing CD8 T<sub>RM</sub> cells.</p>","PeriodicalId":13446,"journal":{"name":"Immunogenetics","volume":"76 5-6","pages":"397-415"},"PeriodicalIF":2.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}