Lupus susceptibility genes may breach tolerance to DNA by impairing receptor editing of nuclear antigen-reactive B cells.

Academic Article

Abstract

  • An NZM2410-derived lupus susceptibility locus on murine chromosome 4, Sle2(z), has previously been noted to engender generalized B cell hyperactivity. To study how Sle2(z) impacts B cell tolerance, two Ig H chain site-directed transgenes, 3H9 and 56R, with specificity for DNA were backcrossed onto the C57BL/6 background with or without Sle2(z). Interestingly, the presence of the NZM2410 "z" allele of Sle2 on the C57BL/6 background profoundly breached B cell tolerance to DNA, apparently by thwarting receptor editing. Whereas mAbs isolated from the spleens of B6.56R control mice demonstrated significant usage of the endogenous (i.e., nontargeted) H chain locus and evidence of vigorous L chain editing; Abs isolated from B6.Sle2(z).56R spleens were largely composed of the transgenic H chain paired with a spectrum of L chains, predominantly recombined to J(k)1 or J(k)2. In addition, Sle2(z)-bearing B cells adopted divergent phenotypes depending on their Ag specificity. Whereas Sle2(z)-bearing anti-DNA transgenic B cells were skewed toward marginal zone B cells and preplasmablasts, B cells from the same mice that did not express the transgene were skewed toward the B1a phenotype. This work illustrates that genetic loci that confer lupus susceptibility may influence B cell differentiation depending on their Ag specificity and potentially contribute to antinuclear autoantibody formation by infringing upon B cell receptor editing. Taken together with a recent report on Sle1(z), these studies suggest that dysregulated receptor-editing of nuclear Ag-reactive B cells may be a major mechanism through which antinuclear Abs arise in lupus.
  • Published In

    Keywords

  • Animals, Antibodies, Antinuclear, Antigens, Nuclear, B-Lymphocytes, Cell Differentiation, DNA, Fluorescent Antibody Technique, Genes, Immunoglobulin Heavy Chain, Genetic Predisposition to Disease, Immune Tolerance, Immunophenotyping, Lupus Erythematosus, Systemic, Mice, Mice, Inbred C57BL, Mice, Transgenic, Transgenes
  • Author List

  • Liu Y; Li L; Kumar KR; Xie C; Lightfoot S; Zhou XJ; Kearney JF; Weigert M; Mohan C
  • Start Page

  • 1340
  • End Page

  • 1352
  • Volume

  • 179
  • Issue

  • 2