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BackgroundFollowing the launch of the global COVID-19 vaccination campaign, there have been increased reports of autoimmune diseases developing de novo following vaccination. These cases include rheumatoid arthritis, autoimmune hepatitis, immune thrombotic thrombocytopenia, and connective tissue diseases. Nevertheless, COVID-19 vaccines are considered safe for patients with autoimmune diseases and are strongly recommended.ObjectivesThe aim of this in silico analysis is to investigate the presence of protein epitopes encoded by the BNT-162b2 mRNA vaccine, one of the most commonly administered COVID-19 vaccines, that could elicit an aberrant adaptive immune response in predisposed individuals.MethodsThe FASTA sequence of the protein encoded by the BNT-162b2 vaccine was retrieved from http://genome.ucsc.edu and used as a key input to the Immune Epitope Database and Analysis Resource (www.iedb.org). Linear peptides with 90% BLAST homology were selected, and T-cell, B-cell, and MHC ligand assays without MHC restriction were searched and evaluated. HLA-disease associations were screened on the HLA-SPREAD platform (https://hla-spread.igib.res.in) by selecting only positive markers.ResultsA total of 183 epitopes were found, corresponding to 178 SARS-CoV-2 and 5 SARS-CoV spike epitopes, respectively. Results were obtained from 22 T-cell assays, 398 B-cell assays, and 2 MHC ligand assays. Complementary receptors included 1080 T-cell receptors and 0 B-cell receptors.Specifically, the IEDB_epitope:1329790 (NATNVVIKVCEFQFCNDPFLGVYY) was shown to bind to HLA-DRB1*15:02 and HLA-DRB1*15:03 alleles, whereas the IEDB_epitope:1392457 (TKCTLKSFTVEKGIYQTSNFRVQPT) was reported to bind to HLA-DRB1*07:01, HLA-DRB1*03:01, HLA-DRB3*01:01, and HLA-DRB4*01:01 alleles. The HLA alleles detected were found to be positively associated with various immunological disorders (Table 1).Table 1.MHC-restricted epitopes of the BNT-162b2 vaccine and potentially associated immunological conditionsEpitopeAssayMHC moleculeAssociated disease (population)NATNVVIKVCEFQFCNDPFLGVYY + OX(C10)cellular MHC/mass spectrometry ligand presentationHLA-DRB1*15:02Takayasu arteritis (Japanese) Arthritis (Taiwanese) Scleroderma (Japanese) Colitis (Japanese)HLA-DRB1*15:03Systemic lupus erythematosus (Mexican American)TKCTLKSFTVEKGIYQTSNFRVQPT + SCM(K2)as aboveHLA-DRB1*07:01Allergy, hypersensitivity (Caucasian)HLA-DRB1*03:01Type 1 diabetes (African) Sarcoidosis, good prognosis (Finnish)HLA-DRB3*01:01Graves' disease (Caucasian) Thymoma (Caucasian) Sarcoidosis (Scandinavian) Autoimmune hepatitis (Caucasian)HLA-DRB4*01:01Vitiligo (Saudi Arabian)ConclusionSimilar to the SARS-CoV-2 spike protein, the protein product of the BNT-162b2 mRNA vaccine contains immunogenic epitopes that may trigger autoimmune phenomena in predisposed individuals. Genotyping for HLA alleles may help identify at-risk individuals. However, further research is needed to elucidate the underlying mechanisms and potential clinical implications.References[1]Vita R, Mahajan S, Overton JA et al. The Immune Epitope Database (IEDB): 2018 update. Nucleic Acids Res. 2019 Jan 8;47(D1):D339-D343. doi: 10.1093/nar/gky1006.[2]Dholakia D, Kalra A, Misir BR et al. HLA-SPREAD: a natural language processing based resource for curating HLA association from PubMed s. BMC Genomics 23, 10 (2022). https://doi.org/10.1186/s12864-021-08239-0[3]Parker R, Partridge T, Wormald C et al. Mapping the SARS-CoV-2 spike glycoprotein-derived peptidome presented by HLA class II on dendritic cells. Cell Rep. 2021 May 25;35(8):109179. doi: 10.1016/j.celrep.2021.109179.[4]Knierman MD, Lannan MB, Spindler LJ et al. The Human Leukocyte Antigen Class II Immunopeptidome of the SARS-CoV-2 Spike Glycoprotein. Cell Rep. 2020 Dec 1;33(9):108454. doi: 10.1016/j.celrep.2020.108454.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Background: Recent evidence shows that human cells may produce several noncoding (nc)RNAs in response to viral infections. Among them, a central role has been attributed to long noncoding (lnc)RNAs, more than 200 nucleotides in length, which are also crucially involved in cancer and autoimmunity. LncRNAs epigenetically control the transcription of genes presiding over cell proliferation, differentiation, migration and apoptosis, by directly or indirectly binding cellular or foreign nucleic acids, including viral genomes. Objectives: The objectives of this study were to evaluate in silico the presence of a nucleotide sequence complementarity between the RNA genome of Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) and human ncRNA genes and to analyze any associations between SARS-CoV-2 gene-matching ncRNAs and human diseases. Methods: The FASTA sequence of each of the 11 SARS-CoV-2 isolate Wuhan-Hu-1 genes (ORF1ab, ORF3a, ORF6, ORF7a, ORF7b, ORF8, ORF10, S, E, M, N) was retrieved from NCBI.nlm.nih.gov/gene (reference sequence NC-045512.2). The ensembl.org library for human ncRNA genes was interrogated for any base-pair match and detected human ncRNAs analyzed for their functional activity. Finally, the associations between ncRNAs and human diseases were searched on GWAS databases (https://www.ebi.ac.uk/gwas and https://www.genecards.org). Results: A total of 252 matches between SARS-CoV-2 genes and human ncRNAs were recorded (ORF1ab: 28;ORF3a: 9;ORF6: 50;ORF7a: 31;ORF7b: 16;ORF8: 23;ORF10: 5;S: 24;E: 17;M: 32;N: 17). With the exception of two small nuclear RNAs (RNVU1-4 and RNU4-74P corresponding to ORF6 and ORF10, respectively), all of them were lncRNAs, mostly expressed in testis and central nervous system under physiological conditions. Percentage of alignment ranged from 91.30% to 100%, with a mean nucleotide alignment length of 17.5±2.4. Polymorphic variants of these transcripts have mostly been reported in patients with neuropsychiatric disorders, cancer and dysmetabolism. Of note, we found 13 and 15 complementarities with lncRNAs associated with immune-mediated diseases Table 1. and immunological pathways (IL-2, IL-6, IL-12, IL-12R, IL-13, IL-17, M-CSF, CXCL-10, TRAIL-R2 and IgG glycosylation), respectively. Conclusion: This pivotal study shows that SARS-CoV-2 genes contain complementary sequences to human ncRNAs in turn associated with several diseases, including autoimmunity. The biological effects of this interaction remain to be elucidated.
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Objective: ACE2 is crucially involved in the infection sustained by SARS-CoV-2, as it allows the entry of the virus into target cells while counteracting local inflammation, oxidative stress, and fibrosis. In this narrative review, we aim to discuss the usefulness of ACE2-derived peptides in the infection sustained by SARS-CoV-2. Methods: A total of 49 papers pertinent to the purpose of the review were selected from the PubMed and Google Scholar databases. Clinical trials registered at ClinicalTrials.gov and dealing with the use of ACE2-derived medications in COVID-19 were also searched and discussed. Results: Preclinical and clinical evidence shows that drugs mimicking or potentiating the effects of ACE2 may reduce the viral load and dampen the inflammatory and fibrotic pathways leading to respiratory distress. ACE2-derived therapeutic peptides may have a better pharmacokinetic and pharma-codynamic profile than other ACE2-based medications. They could be easily screened through peptide libraries and chemically modified in order to ameliorate the pharmacological properties. Furthermore, their local administration via an intranasal delivery or inhalation may reduce the risk of systemic side effects, thus conferring a good safety profile. Conclusion: ACE2-derived peptides may play a dual beneficial role in COVID-19, by either preventing virus spread or inhibiting the secretion of pro-inflammatory mediators in airways. Viral, host, and environmental factors may affect the effectiveness of this therapeutic approach to a various extent and represent therefore a matter of investigation for future studies.