title: Human B-cell isotype switching origins of IgE.
abstract: BACKGROUND
  B cells expressing IgE contribute to immunity against parasites and venoms and are the source of antigen specificity in allergic patients, yet the developmental pathways producing these B cells in human subjects remain a subject of debate. Much of our knowledge of IgE lineage development derives from model studies in mice rather than from human subjects.
  
  
  OBJECTIVE
  We evaluate models for isotype switching to IgE in human subjects using immunoglobulin heavy chain (IGH) mutational lineage data.
  
  
  METHODS
  We analyzed IGH repertoires in 9 allergic and 24 healthy adults using high-throughput DNA sequencing of 15,843,270 IGH rearrangements to identify clonal lineages of B cells containing members expressing IgE. Somatic mutations in IGH inherited from common ancestors within the clonal lineage are used to infer the relationships between B cells.
  
  
  RESULTS
  Data from 613,641 multi-isotype B-cell clonal lineages, of which 592 include an IgE member, are consistent with indirect switching to IgE from IgG- or IgA-expressing lineage members in human subjects. We also find that these inferred isotype switching frequencies are similar in healthy and allergic subjects.
  
  
  CONCLUSIONS
  We found evidence that secondary isotype switching of mutated IgG1-expressing B cells is the primary source of IgE in human subjects, with lesser contributions from precursors expressing other switched isotypes and rarely IgM or IgD, suggesting that IgE is derived from previously antigen-experienced B cells rather than naive B cells that typically express low-affinity unmutated antibodies. These data provide a basis from which to evaluate allergen-specific human antibody repertoires in healthy and diseased subjects.
authors: Department of Pathology, Transplantation and Infection, Stanford University, Stanford, Calif.
authors: Timothy J
authors: TJ
authors: Looney
authors: Department of Pathology, Transplantation and Infection, Stanford University, Stanford, Calif.
authors: Ji-Yeun
authors: JY
authors: Lee
authors: Department of Pathology, Transplantation and Infection, Stanford University, Stanford, Calif.
authors: Krishna M
authors: KM
authors: Roskin
authors: Department of Pathology, Transplantation and Infection, Stanford University, Stanford, Calif.
authors: Ramona A
authors: RA
authors: Hoh
authors: Department of Pathology, Transplantation and Infection, Stanford University, Stanford, Calif; Department of Biology, Transplantation and Infection, Stanford University, Stanford, Calif.
authors: Jasmine
authors: J
authors: King
authors: Department of Pathology, Transplantation and Infection, Stanford University, Stanford, Calif; Program in Immunology, Transplantation and Infection, Stanford University, Stanford, Calif.
authors: Jacob
authors: J
authors: Glanville
authors: Department of Pathology, Transplantation and Infection, Stanford University, Stanford, Calif; Biomedical Informatics Training Program, Transplantation and Infection, Stanford University, Stanford, Calif.
authors: Yi
authors: Y
authors: Liu
authors: Department of Pathology, Transplantation and Infection, Stanford University, Stanford, Calif.
authors: Tho D
authors: TD
authors: Pham
authors: Department of Pediatrics, Transplantation and Infection, Stanford University, Stanford, Calif.
authors: Cornelia L
authors: CL
authors: Dekker
authors: Department of Microbiology & Immunology, Transplantation and Infection, Stanford University, Stanford, Calif; Howard Hughes Medical Institute, Transplantation and Infection, Stanford University, Stanford, Calif; Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, Calif.
authors: Mark M
authors: MM
authors: Davis
authors: Department of Pathology, Transplantation and Infection, Stanford University, Stanford, Calif. Electronic address: sboyd1@stanford.edu.
authors: Scott D
authors: SD
authors: Boyd
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D001483:Base Sequence; D016022:Case-Control Studies; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000235:genetics* / Q000276:immunology; D007073:Immunoglobulin E / Q000235:genetics* / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007132:Immunoglobulin Isotypes / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D058977:Molecular Sequence Annotation; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D027041:Somatic Hypermutation, Immunoglobulin; D055815:Young Adult
chemical_list: D007143:Immunoglobulin Heavy Chains; D007132:Immunoglobulin Isotypes; D007073:Immunoglobulin E
keywords: B cell; IgE; antibody; direct; high-throughput DNA sequencing; indirect; isotype switching; repertoire