Lupus-like nephrotropic autoantibodies in non-autoimmune mice harboring an anti-basement membrane/anti-DNA Ig heavy chain transgene

Autoantibodies target a diverse group of tissue antigens in human and experimental autoimmune nephritis. The proximal events that generate and regulate these various pathogenic Ab remain obscure. To examine the origins and fate in normal mice of autoantibodies reactive with renal basement membrane antigen, we established mice transgenic for an IgM H chain encoding an unmutated nephrotropic V region, termed LamH, derived from an MRL/lpr mouse and directed against basement membrane laminin. We previously demonstrated that in vitro transfectants combining LamH-Cμ with unmutated L chains generate distinct nephrotropic autoantibodies. Herein we report in vivo reconstruction of diverse pathogenic autoreactivity by association of LamH-Cμ with endogenous L chains. Progeny of one founder, termed M7, express a distinct phenotype characterized by minimal B cell mIgM and spontaneous production of LamH-Cμ autoreactivity. Similar Ab were not recovered from two phenotypically distinct transgenic lines expressing abundant transgene mIgM. The results suggest that lupus-like autoantibodies are readily generated in the normal genetic background by random recombinatorial events in the absence of mutation and that these Ab may contribute to disease if normal regulation is disturbed.