Human lupus anti-DNA autoantibodies undergo essentially primary V kappa gene rearrangements.
We have recently characterized the heavy chain variable region (VH) genes expressed by a panel of human anti-DNA antibodies derived from four patients with systemic lupus erythematosus and expressing an idiotypic marker representative of a subset of pathogenic autoantibodies. Here, we have cloned and sequenced the kappa chain variable region genes (V kappa) of the clones whose VH genes had been previously analysed. All the V kappa genes utilized map to the 280 kb portion of the 3' end of the locus, suggesting that they represent essentially the products of primary rearrangements. This proximal clustering of the V kappa genes used contrasts with the broad distribution of immunization-induced human antibody V kappa genes over 1400 kb of the locus. In addition, lupus autoantibodies show no tendency to express the downstream junctional (J kappa) exons--another indication of infrequent secondary variable gene assembly. Since successive rearrangements may extinguish high-affinity recognition of self antigens, we propose that this bias in V kappa and J kappa expression reflects a low rate of secondary light chain rearrangements among lupus autoantibodies. We also postulate that the corrective mechanism capable of editing potentially aggressive, self-reactive antibodies in these patients may be deficient--a deficit that could be genetically determined and/or somatically acquired.
Institut Pasteur, Paris, France.
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C
Bensimon
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P
Chastagner
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M
Zouali
D000595:Amino Acid Sequence; D000974:Antibodies, Antinuclear / Q000235:genetics*; D000916:Antibody Diversity / Q000235:genetics; D001402:B-Lymphocytes; D001483:Base Sequence; D002461:Cell Line, Transformed; D003001:Cloning, Molecular; D004247:DNA / Q000032:analysis; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain / Q000235:genetics*; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D008177:Lupus Vulgaris / Q000276:immunology*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D017422:Sequence Analysis, DNA
D000974:Antibodies, Antinuclear; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D004247:DNA