Genetic and structural basis of the human anti-alpha-galactosyl antibody response
Humans lack the capacity to produce the Galalpha1-3Galbeta1-4GlcNAc (alpha-gal) glycan, and produce anti-alpha-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 alpha-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-alpha-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 alpha-gal binders. Our results outline structural and genetic factors that shape the human anti-alpha-galactosyl antibody response, and provide a framework for future therapeutics development.
|ISBN||1091-6490 (Electronic) 0027-8424 (Linking)|
|Authors||Langley, D. B.; Schofield, P.; Nevoltris, D.; Jackson, J.; Jackson, K. J. L.; Peters, T. J.; Burk, M.; Matthews, J. M.; Basten, A.; Goodnow, C. C.; van Nunen, S.; Reed, J. H.; Christ, D.|
|Publisher Name||PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/35867757|