ANTI-LAMININ REACTIVITY AND GLOMERULAR IMMUNE DEPOSITION BY IN-VITRO RECOMBINANT ANTIBODIES

Growing evidence suggests that recombinatorial events prior to antigen contact can generate pathogenic autoantibodies in the nonautoimmune i ndividual, thus providing potential disease mediators if conditions ar ise that permit bypass of tolerance and activation of autoreactive lym phocytes. To examine the disease potential of selected germline antibo dy genes, Ig were created de novo by in vitro recombination of Ig H an d L chains. H chain loss variant (i.e., L-chain only) cell lines were transfected with a DNA construct encoding the variable region and regu latory sequences (LamH) of a nephrotropic murine lupus anti-laminin Ig , and the resultant Ig were examined for in vitro antigen reactivity a nd in vivo glomerular immune deposition. The results indicate that two light chains, LamL (Vk8, Jk5) and 238L (Vk4, Jk5), expressing unrelat ed germline V-1 genes, combine with LamH to generate Ig that bind base ment membrane laminin in vitro, diverge in their capacity to bind ssDN A, and produce two distinct patterns of glomerular immune deposits in vivo: dense mesangial matrix (LamH/LamL) and dramatic linear glomerula r basement membrane (LamH/238L) deposits. The Ig genes used by both La mH and 238L are present in nonautoimmune mice as well as in lupus-pron e strains. We conclude that certain unmutated Ig genes can contribute to multiple distinct disease associated specificities, including bindi ng to intrinsic kidney antigens, and that mutation is not essential to generate these Ig. Collectively, these observations suggest that path ogenic autoantibodies can be generated in the normal preimmune reperto ire by random recombinatorial and somatic events in the absence of mut ation.