Germline-encoded recognition underlies development of convergent antibodies in humans

Introduction/Rationale: The presence of food-specific IgG in response to dietary ingestion has been long-observed. In a subset of individuals, food-specific IgG can class-switch to IgE, potentially causing anaphylaxis. We and others have previously identified highly homologous, or public, peanut-specific antibodies in allergic individuals. We hypothesized that we can use the similar, stereotyped pathways of convergent antibodies to peanut to construct germline-encoded structural models of antibody convergence.

Methods: Using a set of epitope-specific antibodies to peanut cloned from peanut-allergic patients, we probed antibody-antigen interactions using mutagenesis, biolayer interferometry and molecular modeling.

Results: Using this set of convergent antibodies with distinct antibody gene rearrangements and similar complementary determining regions (CDRs), we identified had identical epitope-paratope interactions and highly similar energetics in structural models. Peanut specificity of these antibodies is germline-encoded across commonly used gene rearrangements, occurs irrespective of allelic heterogeneity, and has significant junctional malleability. Using molecular modeling, we identified the paratope residues critical for these convergent binding interactions and probed the entire human antibody repertoire to understand the genetic constraints on this stereotyped recognition of a public epitope on a dominant allergen.

Conclusion: We can utilize molecularly defined germline-encoded recognition of peanut allergen to better understand how the human antibody genome predisposing humans to recognizing peanut proteins.