TY - JOUR
T1 - Lupus susceptibility genes may breach tolerance to DNA by impairing receptor editing of nuclear antigen-reactive B cells
AU - Liu, Yang
AU - Li, Liunan
AU - Kumar, Kirthi Raman
AU - Xie, Chun
AU - Lightfoot, Skip
AU - Zhou, Xin J.
AU - Kearney, John F.
AU - Weigert, Martin
AU - Mohan, Chandra
PY - 2007/7/15
Y1 - 2007/7/15
N2 - An NZM2410-derived lupus susceptibility locus on murine chromosome 4, Sle2z, has previously been noted to engender generalized B cell hyperactivity. To study how Sle2z 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 Sle2z. 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.Sle2z.56R spleens were largely composed of the transgenic H chain paired with a spectrum of L chains, predominantly recombined to Jk1 or Jk2. In addition, Sle2z-bearing B cells adopted divergent phenotypes depending on their Ag specificity. Whereas Sle2z-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 Sle1z, 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.
AB - An NZM2410-derived lupus susceptibility locus on murine chromosome 4, Sle2z, has previously been noted to engender generalized B cell hyperactivity. To study how Sle2z 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 Sle2z. 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.Sle2z.56R spleens were largely composed of the transgenic H chain paired with a spectrum of L chains, predominantly recombined to Jk1 or Jk2. In addition, Sle2z-bearing B cells adopted divergent phenotypes depending on their Ag specificity. Whereas Sle2z-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 Sle1z, 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.
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U2 - 10.4049/jimmunol.179.2.1340
DO - 10.4049/jimmunol.179.2.1340
M3 - Article
C2 - 17617627
AN - SCOPUS:34548786270
SN - 0022-1767
VL - 179
SP - 1340
EP - 1352
JO - Journal of Immunology
JF - Journal of Immunology
IS - 2
ER -