The efficiency of B cell receptor (BCR) editing is dependent on BCR light chain rearrangement status.
Anti-DNA knock-in mice serve as models for studying B cell tolerance mechanisms to a ubiquitous antigen. We have constructed six strains of double transgenic (C57BL/6xBALB/c)F1 mice, each expressing an unmutated or somatically mutated anti-DNA heavy (H) chain, combined with one of three different light (L) chains, namely V(kappa)1-J(kappa)1, V(kappa)4-J(kappa)4 and V(kappa)8-J(kappa)5. In vitro analysis of the various Ig H/L chain combinations showed that all had a similar specificity for single-stranded DNA and double-stranded DNA, but that antibodies encoded by the mutated H chain had higher affinities for the autoantigen. None of the targeted mouse strains exhibited significant levels of serum anti-DNA activity. However, while B cells from mice carrying the V(kappa)1-J(kappa)1 transgenic L chains were tolerized almost exclusively by L chain receptor editing in an affinity-independent manner, the mice expressing V(kappa)8-J(kappa)5 L chains have utilized affinity-dependent clonal anergy as their sole mechanism of B cell tolerance. V(kappa)4-J(kappa)4 targeted mice exhibited an intermediate phenotype with respect to these two mechanisms of B cell tolerance. Our results suggest that receptor editing is the preferred mechanism of B cell tolerance and that the efficiency of L chain editing is directly related to the number of available J(kappa) segments on the expressed V(kappa) allele.
Yachimovich
Nurit
N
Department of Medicine, Hadassah University Hospital, Faculty of Medicine, Hebrew University, Jerusalem, Israel.
Mostoslavsky
Gustavo
G
Yarkoni
Yuval
Y
Verbovetski
Inna
I
Eilat
Dan
D
D000483:Alleles; D000818:Animals; D000974:Antibodies, Antinuclear / Q000235:genetics* / Q000276:immunology; D000915:Antibody Affinity; D000918:Antibody Specificity; D001324:Autoantigens / Q000276:immunology*; D001854:Bone Marrow Cells / Q000276:immunology; D017635:Clonal Anergy; D003433:Crosses, Genetic; D004247:DNA / Q000276:immunology*; D004277:DNA, Single-Stranded / Q000276:immunology; D005260:Female; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D018390:Gene Targeting; D005803:Genes, Immunoglobulin; D005838:Genotype; D006410:Hematopoiesis; D006825:Hybridomas / Q000276:immunology; D007144:Immunoglobulin J-Chains / Q000235:genetics* / Q000276:immunology; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics* / Q000276:immunology; D007145:Immunoglobulin kappa-Chains / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009101:Multiple Myeloma / Q000473:pathology; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000276:immunology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000276:immunology
D000974:Antibodies, Antinuclear; D001324:Autoantigens; D004277:DNA, Single-Stranded; D007144:Immunoglobulin J-Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D011947:Receptors, Antigen, B-Cell; D004247:DNA