Article ; Online: Genetic and structural basis of the human anti-α-galactosyl antibody response.
Proceedings of the National Academy of Sciences of the United States of America
2022 Volume 119, Issue 28, Page(s) e2123212119
Abstract: Humans lack the capacity to produce the Galα1-3Galβ1-4GlcNAc (α-gal) glycan, and produce anti-α-gal antibodies upon exposure to the carbohydrate on a diverse set of immunogens, including commensal gut bacteria, malaria parasites, cetuximab, and tick ... ...
Abstract | Humans lack the capacity to produce the Galα1-3Galβ1-4GlcNAc (α-gal) glycan, and produce anti-α-gal antibodies upon exposure to the carbohydrate on a diverse set of immunogens, including commensal gut bacteria, malaria parasites, cetuximab, and tick proteins. Here we use X-ray crystallographic analysis of antibodies from α-gal knockout mice and humans in complex with the glycan to reveal a common binding motif, centered on a germline-encoded tryptophan residue at Kabat position 33 (W33) of the complementarity-determining region of the variable heavy chain (CDRH1). Immunoglobulin sequencing of anti-α-gal B cells in healthy humans and tick-induced mammalian meat anaphylaxis patients revealed preferential use of heavy chain germline IGHV3-7, encoding W33, among an otherwise highly polyclonal antibody response. Antigen binding was critically dependent on the presence of the germline-encoded W33 residue for all of the analyzed antibodies; moreover, introduction of the W33 motif into naive IGHV3-23 antibody phage libraries enabled the rapid selection of α-gal binders. Our results outline structural and genetic factors that shape the human anti-α-galactosyl antibody response, and provide a framework for future therapeutics development. |
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MeSH term(s) | Anaphylaxis/immunology ; Animals ; Antibodies/chemistry ; Antibodies/genetics ; Antibody Formation/genetics ; Antigen-Antibody Complex/chemistry ; Crystallography, X-Ray ; Food Hypersensitivity/immunology ; Humans ; Immunoglobulin Heavy Chains/chemistry ; Immunoglobulin Heavy Chains/genetics ; Immunoglobulin Variable Region/chemistry ; Immunoglobulin Variable Region/immunology ; Mice ; Mice, Knockout ; Peptide Library ; Protein Conformation ; Tick-Borne Diseases/immunology ; Trisaccharides/genetics ; Trisaccharides/immunology |
Chemical Substances | Antibodies ; Antigen-Antibody Complex ; Immunoglobulin Heavy Chains ; Immunoglobulin Variable Region ; Peptide Library ; Trisaccharides ; alpha-galactosyl epitope |
Language | English |
Publishing date | 2022-07-08 |
Publishing country | United States |
Document type | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 209104-5 |
ISSN | 1091-6490 ; 0027-8424 |
ISSN (online) | 1091-6490 |
ISSN | 0027-8424 |
DOI | 10.1073/pnas.2123212119 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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