Convergent allergen-specific antibodies in food allergy - 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.
