Usage of a novel class of germ-line Ig variable region gene for cationic anti-DNA autoantibodies in human lupus nephritis and its role for the development of the disease.

It has been shown that cationic anti-DNA autoantibodies have nephritogenic potential in murine models of lupus nephritis. We have recently reported the close relationship between the presence of cationic anti-DNA Abs and the development of lupus nephritis in humans. To investigate underlining mechanisms responsible for the production of pathogenic autoantibodies, we have isolated a cDNA clone (SC17) encoding cationic anti-DNA Ab of human systemic lupus erythematosus with severe nephritis that was present at the onset of disease but disappeared after disease remission with corticosteroids. We have also cloned a counterpart Ig VL germ-line gene (SG3) from purified neutrophils of the patient and found the presence of replacement mutations only in the CDR of SC17. Surprisingly, predicted isoelectric point (pI) of deduced protein encoded by SG3 was the most cationic one among those encoded by previously reported human V kappa germ-line genes in the DNA database. These results raise the possibility that the use of specific germ-line genes may confer a cationic charge on the anti-DNA Ab, whereas somatic mutations induce affinity maturation of anti-DNA Ab in human lupus nephritis. Anti-DNA Ab-secreting B cells, but not DNA nonbinding B cells of the same patient, constitutively expressed SC17 mRNA. This mRNA is also expressed by B cells from a vast majority of patients at the onset of disease or exacerbation of lupus nephritis. However, the mRNA is absent in B cells from patients with lupus nephritis during disease remission, systemic lupus erythematosus patients without renal involvements, and normal individuals. It is suggested that the SC17 mRNA expression of B cells is rather restricted to systemic lupus erythematosus patients with active renal involvements.