CHARACTERIZATION OF A GERMLINE VK GENE ENCODING CATIONIC ANTI-DNA ANTIBODY AND ROLE OF RECEPTOR EDITING FOR DEVELOPMENT OF THE AUTOANTIBODYIN PATIENTS WITH SYSTEMIC LUPUS-ERYTHEMATOSUS

We found previously that cationic anti-DNA autoantibodies (autoAbs) ha ve nephritogenic potential and usage of a specific germline Vk gene, A 30, has major influences on cationic charge of the autoAb in human lup us nephritis. In the present study, we have characterized A30 germline Vk gene using cosmid cloning technique in patients with SLE. A30 gene locus locates in less than 250 kb from the Ck region, and the cationi c anti-DNA mRNA used the upstream Jk2 gene, indicating that cationic a nti-DNA mRNA is a product of primary gene rearrangement. By using PCR technique, we found that A30 gene locus in the genome was defective in eight out of nine SLE patients without nephritis. In contrast, all ni ne patients with lupus nephritis had intact A30 gene. The presence and absence of A30 gene was associated with the development of lupus neph ritis or not (P < 0.01, by Fisher's exact test, two-sided). It was thu s suggested that absence of functional A30 gene may rescue from develo ping lupus nephritis in the patients. A30 is reported to be a potentia lly functional but rarely expressed Vk gene in humans. It is possible that normal B cells edit primarily rearranged A30 gene with autoreacti ve potentials by receptor editing mechanism for changing the affinity of the B cell Ag receptor to avoid self-reactivity, whereas SLE B cell s may have a defect in this mechanism. Indeed, we found that normal B cells edit A30-Jk2 gene in their genome possibly by inversion mechanis m, whereas SLE B cells contain rearranged A30-Jb2-Ck gene in the genom e and express A30-associated mRNA, suggesting that receptor editing me chanism is also defective in patients with SLE. Our study suggests tha t polymorphism of Ig Vk locus, and failure of receptor editing may con tribute to the development of pathogenic anti-DNA responses in humans.