Timothy J Looney1, Ji-Yeun Lee1, Krishna M Roskin1, Ramona A Hoh1, Jasmine King2, Jacob Glanville3, Yi Liu4, Tho D Pham1, Cornelia L Dekker5, Mark M Davis6, Scott D Boyd7. 1. Department of Pathology, Transplantation and Infection, Stanford University, Stanford, Calif. 2. Department of Pathology, Transplantation and Infection, Stanford University, Stanford, Calif; Department of Biology, Transplantation and Infection, Stanford University, Stanford, Calif. 3. Department of Pathology, Transplantation and Infection, Stanford University, Stanford, Calif; Program in Immunology, Transplantation and Infection, Stanford University, Stanford, Calif. 4. Department of Pathology, Transplantation and Infection, Stanford University, Stanford, Calif; Biomedical Informatics Training Program, Transplantation and Infection, Stanford University, Stanford, Calif. 5. Department of Pediatrics, Transplantation and Infection, Stanford University, Stanford, Calif. 6. 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. 7. Department of Pathology, Transplantation and Infection, Stanford University, Stanford, Calif. Electronic address: sboyd1@stanford.edu.
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.
BACKGROUND: B cells expressing IgE contribute to immunity against parasites and venoms and are the source of antigen specificity in allergicpatients, 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: Agustin Erazo; Nino Kutchukhidze; Monica Leung; Ana P Guarnieri Christ; Joseph F Urban; Maria A Curotto de Lafaille; Juan J Lafaille Journal: Immunity Date: 2007-02-08 Impact factor: 31.745
Authors: Monica G Lawrence; Thamiris V Palacios-Kibler; Lisa J Workman; Alexander J Schuyler; John W Steinke; Spencer C Payne; Emily C McGowan; James Patrie; Ramsay L Fuleihan; Kathleen E Sullivan; Patricia L Lugar; Camellia L Hernandez; Douglas E Beakes; James W Verbsky; Thomas A E Platts-Mills; Charlotte Cunningham-Rundles; John M Routes; Larry Borish Journal: J Clin Immunol Date: 2018-02-17 Impact factor: 8.317