Alterations in B cell development, CDR-H3 repertoire and dsDNA-binding antibody production among C57BL/6 ΔD-iD mice congenic for the lupus susceptibility loci sle1, sle2 or sle3.

Academic Article

Abstract

  • Systemic lupus erythematosus (SLE) is an autoimmune disease that reflects a failure to block the production of self-reactive antibodies, especially those that bind double-stranded DNA (dsDNA). Backcrossing the lupus-prone NZM2410 genome onto C57BL/6 led to the identification of three genomic intervals, termed sle1, sle2 and sle3, which are associated with lupus susceptibility. We previously generated a C57BL/6 strain congenic for an immunoglobulin DH locus (ΔD-iD) that enriches for arginine at dsDNA-binding positions. We individually introduced the ΔD-iD allele into the three sle strains to test whether one or more of these susceptibility loci could affect the developmental fate of B cells bearing arginine-enriched CDR-H3s, the CDR-H3 repertoire created by the DH and the prevalence of dsDNA-binding antibodies. We found that the combination of the ΔD-iD allele and the sle1 locus led to a decrease in mature, recirculating B cell numbers and an increase in marginal zone cell numbers while maintaining a highly charged CDR-H3 repertoire. ΔD-iD and sle2 had no effect on peripheral B cell numbers, but the CDR-H3 repertoire was partially normalized. ΔD-iD and sle3 led to an increase in marginal zone B cell numbers, with some normalization of hydrophobicity. Mice with ΔD-iD combined with either sle1 or sle3 had increased production of dsDNA-binding IgM and IgG by 12 months of age. These findings indicate that the peripheral CDR-H3 repertoire can be categorically manipulated by the effects of nonimmunoglobulin genes.
  • Published In

  • Autoimmunity  Journal
  • Keywords

  • B-cell repertoire, CDR-H3 and diversity gene segments, DH, Sle, Systemic lupus erythematosus, third complementary determining region heavy chain, Alleles, Amino Acid Sequence, Animals, Antibodies, Antinuclear, Antibody Formation, Autoantibodies, B-Lymphocytes, Cell Differentiation, Complementarity Determining Regions, Disease Models, Animal, Disease Susceptibility, Immunoglobulin G, Immunoglobulin M, Lupus Erythematosus, Systemic, Lymphocyte Activation, Lymphocyte Count, Mice, Mice, Congenic, Mice, Inbred C57BL, Mice, Knockout, Quantitative Trait Loci
  • Digital Object Identifier (doi)

    Authorlist

  • Khass M; Schelonka RL; Liu CR; Elgavish A; Morel L; Burrows PD; Schroeder HW
  • Start Page

  • 42
  • End Page

  • 51
  • Volume

  • 50
  • Issue

  • 1