Lupus susceptibility genes may breach tolerance to DNA by impairing receptor editing of nuclear antigen-reactive B cells.
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.
Liu
Yang
Y
Department of Internal Medicine and Center for Immunology, University of Texas Southwestern Medical School, Dallas, TX 75390, USA.
Li
Liunan
L
Kumar
Kirthi Raman
KR
Xie
Chun
C
Lightfoot
Skip
S
Zhou
Xin J
XJ
Kearney
John F
JF
Weigert
Martin
M
Mohan
Chandra
C
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood / Q000276:immunology*; D034961:Antigens, Nuclear / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D004247:DNA / Q000276:immunology*; D005455:Fluorescent Antibody Technique; D050438:Genes, Immunoglobulin Heavy Chain / Q000276:immunology; D020022:Genetic Predisposition to Disease; D007108:Immune Tolerance; D016130:Immunophenotyping; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019076:Transgenes
D000974:Antibodies, Antinuclear; D034961:Antigens, Nuclear; D004247:DNA