Food allergy affects about 10% of the US population, and its incidence continues to grow. More than
40% of individuals with peanut allergies have experienced life-threatening anaphylaxis, which occurs when
allergen binds IgE antibodies to activate allergic effector cells. Immunotherapy for food allergies induces IgG
antibodies that disrupt these IgE-allergen interactions. Therefore, the molecular interactions of high affinity
antibodies with allergen are clinically relevant to food allergy and tolerance. Somatic recombination and
hypermutation have evolved to generate remarkably diverse antibody repertoires. However, we and others
found highly similar antibodies commonly selected out by different individuals during a specific, adaptive
immune response. We propose that understanding this apparent constraint on antibody selection to
immunodominant epitopes of food allergens is essential to understanding the origins of food allergy, the
mechanism of immunotherapy-induced therapeutic antibodies, and new potential avenues of intervention.
Our long-term goal to develop antibody-based therapeutics relies upon understanding antibody
recognition of allergens. We recently identified neutralizing antibodies in patients with durable efficacy after oral
immunotherapy. These antibodies uniquely disrupt IgE-allergen interactions through their epitope-specific
recognition of allergen. During the structural characterization of conformational epitopes of the
immunodominant peanut allergen Ara h 2, we identified that our previously reported highly similar (convergent)
antibodies, bind to the same epitope. Additional Arah2-specific IgG and IgE antibodies with homology to our
convergent antibodies have also been identified in other cohorts. In our preliminary data, we found that
germline reversions of these antibodies can bind to the Ara h 2.
Based on these findings, we hypothesize that frequently occurring convergent antibodies, recognizing
structurally similar epitopes, evolve from several common germline rearrangements and emerge first in early
life. Our approach involves using cloning peanut and tree nut specific antibodies from single antigen-specific B
cells from sensitized and allergic children and adults. We are uniquely positioned to address this topic, through
our application of the allergen-specific B cell multimers, epitope-specific antibody characterization, and
collaborations to develop mutated allergens. We will address our hypothesis in the following specific aims: (1)
Define allergen-specific antibody convergence structurally using monoclonal recombinant antibodies and (2)
Identify prevalence and evolution of convergent allergen-specific antibodies.
We anticipate that the proposed studies will structurally define convergent antibodies and elucidate the
inherent ability of germline antibodies to recognize allergens to provide new insights into how allergen
recognition develops in early life.