Molecular biology of anti-DNA autoantibodies with nephritogenic potential in human lupus nephritis

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Extensive studies in murine models of lupus nephritis have shown that cationic anti-DNA autoantibodies have nephritogenic potential. We have first investigated whether cationic anti-DNA antibodies of lgG class are also produced in vivo in patients with active lupus nephritis. The highly cationic anti-DNA of lgG class were prominent in the sera of patients with active lupus nephritis. Decreased proteinuria after successful treatment with prednisolone was associated with disappearance of the cationic anti-DNA in their circulation. The cationic anti-DNA did bind to heparan sulfate, which is a major glycosaminoglycan in glomerular basement membrane, much better than did neutral anti-DNA.The results indicate that the cationic anti-DNA autoantibodies may play a certain role in the development of lupus nephritis.We next turned our attention to the investigation of underlying mechanisms responsible for the production of pathogenic autoantibodies. We have isolated lg VL genes(SC17) encoding cat … More ionic anti-DNA of human SLE with severe nephritis, which were present at the disease onset but disappeared after disease remission with corticosteroids. We have also cloned a counterpart lg VL germline gene(SG3) from neutrophils of the patient and found the presence of replacement mutations only in the complementarity-determining regions. Surprisingly, predicted isoelectric point of deduced protein encoded by SG3 was the most cationic one among those encoded by previously reported human Vkappa germline genes in the DNA database. Additionally, the SG3 gene existed in almost all of the SLE patients, wherease approximately a half of normal individuals lacked the SG3 gene, when their genomic DNA of the neutrophils were studied by PCR-single strand conformation polymorphism-Southern blotting based techniques. These results raise the possibility that the usage of specific germline gene may confer cationic charge on the anti-DNA, while somatic mutations induce affinity maturation of anti-DNA in human lupus nephritis and that the presence of such germline gene in the genome is associated with the development of the disease. Less