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1.
Mucosal Immunol ; 14(5): 1144-1159, 2021 09.
Article in English | MEDLINE | ID: covidwho-1550272

ABSTRACT

Increased IgE is a typical feature of allergic rhinitis. Local class-switch recombination has been intimated but B cell precursors and mechanisms remain elusive. Here we describe the dynamics underlying the generation of IgE-antibody secreting cells (ASC) in human nasal polyps (NP), mucosal tissues rich in ASC without germinal centers (GC). Using VH next generation sequencing, we identified an extrafollicular (EF) mucosal IgD+ naïve-like intermediate B cell population with high connectivity to the mucosal IgE ASC. Mucosal IgD+ B cells, express germline epsilon transcripts and predominantly co-express IgM. However, a small but significant fraction co-express IgG or IgA instead which also show connectivity to ASC IgE. Phenotypically, NP IgD+ B cells display an activated profile and molecular evidence of BCR engagement. Transcriptionally, mucosal IgD+ B cells reveal an intermediate profile between naïve B cells and ASC. Single cell IgE ASC analysis demonstrates lower mutational frequencies relative to IgG, IgA, and IgD ASC consistent with IgE ASC derivation from mucosal IgD+ B cell with low mutational load. In conclusion, we describe a novel mechanism of GC-independent, extrafollicular IgE ASC formation at the nasal mucosa whereby activated IgD+ naïve B cells locally undergo direct and indirect (through IgG and IgA), IgE class switch.


Subject(s)
Antibody Formation/immunology , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , Immunoglobulin D/immunology , Immunoglobulin E/immunology , Nasal Mucosa/immunology , Nasal Mucosa/metabolism , Adult , Antibody Formation/genetics , Antibody-Producing Cells/immunology , Antibody-Producing Cells/metabolism , Computational Biology , Gene Expression Profiling , Germinal Center/immunology , High-Throughput Nucleotide Sequencing , Humans , Hypersensitivity/etiology , Hypersensitivity/metabolism , Immunoglobulin Class Switching/genetics , Immunoglobulin Class Switching/immunology , Immunoglobulin Isotypes/genetics , Immunoglobulin Isotypes/immunology , Immunophenotyping , Nasal Polyps/etiology , Nasal Polyps/metabolism , Nasal Polyps/pathology , Pollen/immunology , Seasons , Somatic Hypermutation, Immunoglobulin
2.
Nat Commun ; 12(1): 6222, 2021 10 28.
Article in English | MEDLINE | ID: covidwho-1493103

ABSTRACT

The importance of breastmilk in postnatal life lies in the strong association between breastfeeding and the reduction in the risk of infection and infection-related infant mortality. However, data regarding the induction and dynamics of breastmilk antibodies following administration of the Pfizer-BioNTech BNT162b2 COVID-19 mRNA vaccine is scarce, as pregnant and lactating women were not included in the initial vaccine clinical trials. Here, we investigate the dynamics of the vaccine-specific antibody response in breastmilk and serum in a prospective cohort of ten lactating women who received two doses of the mRNA vaccine. We show that the antibody response is rapid and highly synchronized between breastmilk and serum, reaching stabilization 14 days after the second dose. The response in breastmilk includes both IgG and IgA with neutralization capacity.


Subject(s)
Breast Feeding , COVID-19 Vaccines/genetics , RNA, Messenger/blood , Adult , Animals , Antibody Formation/genetics , Antibody Formation/physiology , Female , Humans , Milk/chemistry , RNA, Messenger/analysis , Vaccines, Synthetic/therapeutic use
3.
Immunity ; 54(6): 1290-1303.e7, 2021 06 08.
Article in English | MEDLINE | ID: covidwho-1237724

ABSTRACT

Dissecting the evolution of memory B cells (MBCs) against SARS-CoV-2 is critical for understanding antibody recall upon secondary exposure. Here, we used single-cell sequencing to profile SARS-CoV-2-reactive B cells in 38 COVID-19 patients. Using oligo-tagged antigen baits, we isolated B cells specific to the SARS-CoV-2 spike, nucleoprotein (NP), open reading frame 8 (ORF8), and endemic human coronavirus (HCoV) spike proteins. SARS-CoV-2 spike-specific cells were enriched in the memory compartment of acutely infected and convalescent patients several months post symptom onset. With severe acute infection, substantial populations of endemic HCoV-reactive antibody-secreting cells were identified and possessed highly mutated variable genes, signifying preexisting immunity. Finally, MBCs exhibited pronounced maturation to NP and ORF8 over time, especially in older patients. Monoclonal antibodies against these targets were non-neutralizing and non-protective in vivo. These findings reveal antibody adaptation to non-neutralizing intracellular antigens during infection, emphasizing the importance of vaccination for inducing neutralizing spike-specific MBCs.


Subject(s)
Antibodies, Viral/immunology , Antibody Formation/immunology , B-Lymphocytes/immunology , COVID-19/immunology , Host-Pathogen Interactions/immunology , Immunodominant Epitopes/immunology , SARS-CoV-2/immunology , Antibodies, Neutralizing/immunology , Antibody Formation/genetics , B-Lymphocytes/metabolism , Computational Biology/methods , Cross Reactions/immunology , Epitope Mapping , Female , Gene Expression Profiling , High-Throughput Nucleotide Sequencing , Host-Pathogen Interactions/genetics , Humans , Immunodominant Epitopes/genetics , Immunologic Memory , Male , Neutralization Tests , Single-Cell Analysis/methods , Spike Glycoprotein, Coronavirus/immunology , Transcriptome
4.
Genome Med ; 12(1): 93, 2020 10 27.
Article in English | MEDLINE | ID: covidwho-897564

ABSTRACT

BACKGROUND: Humans and viruses have co-evolved for millennia resulting in a complex host genetic architecture. Understanding the genetic mechanisms of immune response to viral infection provides insight into disease etiology and therapeutic opportunities. METHODS: We conducted a comprehensive study including genome-wide and transcriptome-wide association analyses to identify genetic loci associated with immunoglobulin G antibody response to 28 antigens for 16 viruses using serological data from 7924 European ancestry participants in the UK Biobank cohort. RESULTS: Signals in human leukocyte antigen (HLA) class II region dominated the landscape of viral antibody response, with 40 independent loci and 14 independent classical alleles, 7 of which exhibited pleiotropic effects across viral families. We identified specific amino acid (AA) residues that are associated with seroreactivity, the strongest associations presented in a range of AA positions within DRß1 at positions 11, 13, 71, and 74 for Epstein-Barr virus (EBV), Varicella zoster virus (VZV), human herpesvirus 7, (HHV7), and Merkel cell polyomavirus (MCV). Genome-wide association analyses discovered 7 novel genetic loci outside the HLA associated with viral antibody response (P < 5.0 × 10-8), including FUT2 (19q13.33) for human polyomavirus BK (BKV), STING1 (5q31.2) for MCV, and CXCR5 (11q23.3) and TBKBP1 (17q21.32) for HHV7. Transcriptome-wide association analyses identified 114 genes associated with response to viral infection, 12 outside of the HLA region, including ECSCR: P = 5.0 × 10-15 (MCV), NTN5: P = 1.1 × 10-9 (BKV), and P2RY13: P = 1.1 × 10-8 EBV nuclear antigen. We also demonstrated pleiotropy between viral response genes and complex diseases, from autoimmune disorders to cancer to neurodegenerative and psychiatric conditions. CONCLUSIONS: Our study confirms the importance of the HLA region in host response to viral infection and elucidates novel genetic determinants beyond the HLA that contribute to host-virus interaction.


Subject(s)
Disease Susceptibility , Genetic Predisposition to Disease , Host-Pathogen Interactions/genetics , Virus Diseases/etiology , Antibody Formation/genetics , Disease Susceptibility/immunology , Gene Expression Profiling , Genome-Wide Association Study , HLA Antigens/genetics , HLA Antigens/immunology , Humans , Immunity , Immunoglobulin G/immunology , Quantitative Trait, Heritable
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