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Principal Investigator: Sarita U Patil
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $834,998
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><7S Gamma Globulin><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Adult><Adult Human><Affect><Affinity><After Care><After-Treatment><Aftercare><Allergens><Allergic><Allergic to food><Allergy><Allergy to food><Allergy to peanuts><Anaphylactic Reaction><Anaphylactic Shock><Anaphylaxis><Antibodies><Antibody Affinity><Antibody Binding Sites><Antibody Repertoire><Antibody Therapy><Antigenic Determinants><Antigens><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Base Sequence><Binding><Binding Determinants><Blood Serum><COVID-19 virus><COVID19 virus><Child><Child Youth><Children (0-21)><Clinical><Clinical Treatment Moab><Cloning><CoV-2><CoV2><Collaborations><Communicable Diseases><Cross Sectional Analysis><Cross-Sectional Analyses><Cross-Sectional Studies><Cross-Sectional Survey><DNA Recombination><Data><Development><Disease><Disease Frequency Surveys><Disorder><ELISA><Effector Cell><Enzyme-Linked Immunosorbent Assay><Epitopes><Evolution><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Food Allergy><Food Hypersensitivity><Frequencies><Genetic Recombination><Genetics-Mutagenesis><Germ Lines><Goals><Grippe><Groundnut Hypersensitivity><HIV><Human Immunodeficiency Viruses><Hypersensitivity><IgE><IgG><Immune mediated therapy><Immunodominant Antigenic Determinants><Immunodominant Determinants><Immunodominant Domains><Immunodominant Epitopes><Immunodominant Regions><Immunodominant Sites><Immunoglobulin E><Immunoglobulin G><Immunologically Directed Therapy><Immunotherapy><Incidence><Individual><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Influenza><Interferometry><Intervention><Intervention Strategies><LAV-HTLV-III><Life><Life Experience><Lymphadenopathy-Associated Virus><Modeling><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Monoclonal Antibodies><Mutagenesis><Mutagenesis Molecular Biology><Mutate><Nucleotide Sequence><Nut Allergy><Nut Hypersensitivity><Nuts><Paratopes><Pathway interactions><Patients><Peanut Hypersensitivity><Population><Position><Positioning Attribute><Prevalence><Public Health><Reaction><Recombinant Antibody><Recombination><Reporting><Risk><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Serum><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Single Crystal Diffraction><Single cell seq><Site><Site-Directed Mutagenesis><Site-Specific Mutagenesis><Targeted DNA Modification><Targeted Modification><Testing><Therapeutic antibodies><Tree Nut Allergy><Tree Nut Hypersensitivity><Trees><Virus-HIV><Work><Wuhan coronavirus><X Ray Crystallographies><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray/Neutron Crystallography><Xray Crystallography><adaptive immune response><adulthood><aeroallergens><airborn allergen><airborne allergen><allergic to nuts><allergic to peanuts><allergy to nuts><antibody based therapies><antibody combining site><antibody treatment><antibody-based therapeutics><antibody-based treatment><antigen antibody affinity><clinical relevance><clinically relevant><cohort><conformation><conformational><conformational state><conformationally><conformations><coronavirus disease 2019 virus><coronavirus disease-19 virus><developmental><enzyme linked immunoassay><flow cytophotometry><food allergen><hCoV19><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><insight><interventional strategy><kids><mAbs><monoclonal Abs><nCoV2><neutralizing antibody><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><next generation><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><nucleic acid sequence><oral immunotherapy><pathway><peanut allergy><post treatment><single cell next generation sequencing><single cell sequencing><youngster>