NEPHRITOGENIC ANTIBODIES IN MRL/LPR LUPUS MICE - MOLECULAR CHARACTERISTICS IN PATHOLOGICAL AND GENETIC-ASPECTS

MRL/lpr mice spontaneously develop a lethal glomerulonephritis (GN). We found that IgG3 production in this strain of mice has a critical role on the development of GN; 1) IgG3 levels mere high in kidney-extracted IgG and in circulating IgG immune complexes (IC), 2) serum IgG3 was selectively reduced by cyclosporin A. treatment, associated with amelioration of GN, and 3) the mRNA levels of IgG3 correlated well with the severity of GN among the MRL/lpr X (MRL/lprxCSH/lpr) B, backcross mice with the rearranged genetic profile. Besed on these results, me have successfully established five hybridoma clones which produce nephritogenic IgG;3 antibodies from an unmanipulated MRL/lpf mouse. When they were injected to normal mice, four of the five clones generated cell-proliferative GN associated with the marked cellular infiltrates, while that remaining clone induced wire loop-like lesions. This result suggests that particular antibodies generated in MRL/lpr mice have a different pathogenic potency. The V-region sequence study of these nephritogenic antibodies revealed that the two types of the glomerular lesions were mediated by a different B cell precursor. In conclusion, GN in MRL/lpr lupus mice is thought to be generated by the expansion of clonally different B cells producing nephritogenic antibodies with a different pathogenic potency.