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Front Immunol ; 13: 967972, 2022.
Article in English | MEDLINE | ID: covidwho-2080147


Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a serious pandemic. COVID-19 vaccination is urgent needed for limiting SARS-CoV-2 outbreaks by herd immunity. Simultaneously, post-marketing surveillance to assess vaccine safety is important, and collection of vaccine-related adverse events has been in progress. Vision-threatening ophthalmic adverse events of COVID-19 vaccines are rare but are a matter of concern. We report a 45-year-old Japanese male with positive for HLA-DR4/HLA-DRB1*0405, who developed bilateral panuveitis resembling Vogt-Koyanagi-Harada (VKH) disease after the second dose of Pfizer-BioNTech COVID-19 mRNA (BNT162b2) vaccine. Glucocorticosteroid (GC) therapy combined with cyclosporine A (CsA) readily improved the panuveitis. The immune profile at the time of onset was analyzed using CyTOF technology, which revealed activations of innate immunity mainly consisting of natural killer cells, and acquired immunity predominantly composed of B cells and CD8+ T cells. On the other hand, the immune profile in the remission phase was altered by GC therapy with CsA to a profile composed primarily of CD4+ cells, which was considerably similar to that of the healthy control before the vaccination. Our results indicate that BNT162b2 vaccine may trigger an accidental immune cross-reactivity to melanocyte epitopes in the choroid, resulting in the onset of panuveitis resembling VKH disease.

COVID-19 , Panuveitis , Uveomeningoencephalitic Syndrome , BNT162 Vaccine , CD8-Positive T-Lymphocytes , COVID-19 Vaccines/adverse effects , Cyclosporine/therapeutic use , Epitopes , HLA-DR4 Antigen , Humans , Male , Middle Aged , Panuveitis/diagnosis , Panuveitis/drug therapy , Panuveitis/etiology , RNA, Messenger/therapeutic use , SARS-CoV-2 , Uveomeningoencephalitic Syndrome/diagnosis , Uveomeningoencephalitic Syndrome/drug therapy , Uveomeningoencephalitic Syndrome/etiology
Hum Vaccin Immunother ; 18(5): 2048622, 2022 11 30.
Article in English | MEDLINE | ID: covidwho-1900981


We report a Human Immune System (HIS)-humanized mouse model ("DRAGA": HLA-A2.HLA-DR4.Rag1KO.IL-2 RγcKO.NOD) for COVID-19 research. DRAGA mice express transgenically HLA-class I and class-II molecules in the mouse thymus to promote human T cell development and human B cell Ig-class switching. When infused with human hematopoietic stem cells from cord blood reconstitute a functional human immune system, as well as human epi/endothelial cells in lung and upper respiratory airways expressing the human ACE2 receptor for SARS-CoV-2. The DRAGA mice were able to sustain SARS-CoV-2 infection for at least 25 days. Infected mice showed replicating virus in the lungs, deteriorating clinical condition, and human-like lung immunopathology including human lymphocyte infiltrates, microthrombi and pulmonary sequelae. Among the intra-alveolar and peri-bronchiolar lymphocyte infiltrates, human lung-resident (CD103+) CD8+ and CD4+ T cells were sequestered in epithelial (CD326+) lung niches and secreted granzyme B and perforin, suggesting anti-viral cytotoxic activity. Infected mice also mounted human IgG antibody responses to SARS-CoV-2 viral proteins. Hence, HIS-DRAGA mice showed unique advantages as a surrogate in vivo human model for studying SARS-CoV-2 immunopathological mechanisms and testing the safety and efficacy of candidate vaccines and therapeutics.

COVID-19 , HLA-DR4 Antigen , Animals , B-Lymphocytes , CD8-Positive T-Lymphocytes , Disease Models, Animal , Endothelial Cells , HLA-A2 Antigen/genetics , Humans , Mice , Mice, Inbred NOD , Mice, Transgenic , SARS-CoV-2
Cell Mol Immunol ; 18(8): 1847-1860, 2021 08.
Article in English | MEDLINE | ID: covidwho-1387308


CD4+ T cells orchestrate adaptive immune responses via binding of antigens to their receptors through specific peptide/MHC-II complexes. To study these responses, it is essential to identify protein-derived MHC-II peptide ligands that constitute epitopes for T cell recognition. However, generating cells expressing single MHC-II alleles and isolating these proteins for use in peptide elution or binding studies is time consuming. Here, we express human MHC alleles (HLA-DR4 and HLA-DQ6) as native, noncovalent αß dimers on yeast cells for direct flow cytometry-based screening of peptide ligands from selected antigens. We demonstrate rapid, accurate identification of DQ6 ligands from pre-pro-hypocretin, a narcolepsy-related immunogenic target. We also identify 20 DR4-binding SARS-CoV-2 spike peptides homologous to SARS-CoV-1 epitopes, and one spike peptide overlapping with the reported SARS-CoV-2 epitope recognized by CD4+ T cells from unexposed individuals carrying DR4 subtypes. Our method is optimized for immediate application upon the emergence of novel pathogens.

CD4-Positive T-Lymphocytes/metabolism , COVID-19/metabolism , Epitopes, T-Lymphocyte/metabolism , HLA-DQ Antigens/metabolism , HLA-DR4 Antigen/metabolism , Saccharomyces cerevisiae/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Two-Hybrid System Techniques , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , COVID-19/genetics , COVID-19/immunology , Epitopes, T-Lymphocyte/genetics , Epitopes, T-Lymphocyte/immunology , Flow Cytometry , HLA-DQ Antigens/genetics , HLA-DQ Antigens/immunology , HLA-DR4 Antigen/genetics , HLA-DR4 Antigen/immunology , Ligands , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology