The sequences encoded by immunoglobulin diversity (D H ) gene segments play key roles in controlling B-cell development, antigen-binding site diversity, and antibody production

Academic Article


  • Although at first glance the diversity of the immunoglobulin repertoire appears random, there are a number of mechanisms that act to constrain diversity. For example, key mechanisms controlling the diversity of the third complementarity determining region of the immunoglobulin heavy chain (CDR-H3) include natural selection of germline diversity (D H ) gene segment sequence and somatic selection upon passage through successive B-cell developmental checkpoints. To test the role of D H gene segment sequence, we generated a panel of mice limited to the use of a single germline or frameshifted D H gene segment. Specific individual amino acids within core D H gene segment sequence heavily influenced the absolute numbers of developing and mature B-cell subsets, antibody production, epitope recognition, protection against pathogen challenge, and susceptibility to the production of autoreactive antibodies. At the tip of the antigen-binding loop (PDB position 101) in CDR-H3, both natural (germline) and somatic selection favored tyrosine while disfavoring the presence of hydrophobic amino acids. Enrichment for arginine in CDR-H3 appeared to broaden recognition of epitopes of varying hydrophobicity, but led to diminished binding intensity and an increased likelihood of generating potentially pathogenic dsDNA-binding autoreactive antibodies. The phenotype of altering the sequence of the D H was recessive for T-independent antibody production, but dominant for T-cell-dependent responses. Our work suggests that the antibody repertoire is structured, with the sequence of individual D H selected by evolution to preferentially generate an apparently preferred category of antigen-binding sites. The result of this structured approach appears to be a repertoire that has been adapted, or optimized, to produce protective antibodies for a wide range of pathogen epitopes while reducing the likelihood of generating autoreactive specificities.
  • Published In

    Digital Object Identifier (doi)

    Pubmed Id

  • 3712069
  • Author List

  • Khass M; Vale AM; Burrows PD; Schroeder HW
  • Start Page

  • 106
  • End Page

  • 119
  • Volume

  • 284
  • Issue

  • 1