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Cell Rep ; 35(6): 109109, 2021 05 11.
Article in English | MEDLINE | ID: covidwho-1201425


It is unclear whether individuals with enormous diversity in B cell receptor repertoires are consistently able to mount effective antibody responses against SARS-CoV-2. We analyzed antibody responses in a cohort of 55 convalescent patients and isolated 54 potent neutralizing monoclonal antibodies (mAbs). While most of the mAbs target the angiotensin-converting enzyme 2 (ACE2) binding surface on the receptor binding domain (RBD) of SARS-CoV-2 spike protein, mAb 47D1 binds only to one side of the receptor binding surface on the RBD. Neutralization by 47D1 is achieved independent of interfering RBD-ACE2 binding. A crystal structure of the mAb-RBD complex shows that the IF motif at the tip of 47D1 CDR H2 interacts with a hydrophobic pocket in the RBD. Diverse immunoglobulin gene usage and convergent epitope targeting characterize neutralizing antibody responses to SARS-CoV-2, suggesting that vaccines that effectively present the receptor binding site on the RBD will likely elicit neutralizing antibody responses in a large fraction of the population.

Antibodies, Neutralizing/genetics , COVID-19/genetics , Immunoglobulins/genetics , Adult , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Binding Sites/immunology , COVID-19/immunology , COVID-19/therapy , Epitopes/genetics , Epitopes/immunology , Female , Genes, Immunoglobulin/genetics , Genetic Variation/genetics , Humans , Immunization, Passive/methods , Immunoglobulins/immunology , Male , Middle Aged , Peptidyl-Dipeptidase A/metabolism , Protein Binding/immunology , Protein Domains/genetics , Receptors, Virus/immunology , Receptors, Virus/metabolism , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity
Science ; 372(6543): 738-741, 2021 05 14.
Article in English | MEDLINE | ID: covidwho-1180894


Vaccination and infection promote the formation, tissue distribution, and clonal evolution of B cells, which encode humoral immune memory. We evaluated pediatric and adult blood and deceased adult organ donor tissues to determine convergent antigen-specific antibody genes of similar sequences shared between individuals. B cell memory varied for different pathogens. Polysaccharide antigen-specific clones were not exclusive to the spleen. Adults had higher clone frequencies and greater class switching in lymphoid tissues than blood, while pediatric blood had abundant class-switched convergent clones. Consistent with reported serology, prepandemic children had class-switched convergent clones to severe acute respiratory syndrome coronavirus 2 with weak cross-reactivity to other coronaviruses, while adult blood or tissues showed few such clones. These results highlight the prominence of early childhood B cell clonal expansions and cross-reactivity for future responses to novel pathogens.

Antibodies, Viral/immunology , B-Lymphocytes/immunology , Coronavirus/immunology , Immunologic Memory , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Aging , Child, Preschool , Cross Reactions , Ebolavirus/immunology , Female , Fetal Blood/immunology , Genes, Immunoglobulin , Humans , Immunoglobulin Class Switching , Immunoglobulin D/genetics , Immunoglobulin D/immunology , Immunoglobulin Heavy Chains/immunology , Immunoglobulin M/genetics , Immunoglobulin M/immunology , Infant , Lymph Nodes/immunology , Male , Middle Aged , Receptors, Antigen, B-Cell/immunology , Somatic Hypermutation, Immunoglobulin , Spleen/immunology , Young Adult
Trends Immunol ; 41(7): 586-600, 2020 07.
Article in English | MEDLINE | ID: covidwho-824927


Activation-Induced cytidine Deaminase (AID) initiates affinity maturation and isotype switching by deaminating deoxycytidines within immunoglobulin genes, leading to somatic hypermutation (SHM) and class switch recombination (CSR). AID thus potentiates the humoral response to clear pathogens. Marking the 20th anniversary of the discovery of AID, we review the current understanding of AID function. We discuss AID biochemistry and how error-free forms of DNA repair are co-opted to prioritize mutagenesis over accuracy during antibody diversification. We discuss the regulation of DNA double-strand break (DSB) repair pathways during CSR. We describe genomic targeting of AID as a multilayered process involving chromatin architecture, cis- and trans-acting factors, and determining mutagenesis - distinct from AID occupancy at loci that are spared from mutation.

Antibody Diversity , Cytidine Deaminase , Antibody Diversity/genetics , Cytidine Deaminase/metabolism , Genes, Immunoglobulin , Humans , Immunoglobulin Class Switching/genetics , Mutation