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 were 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/lpr x C3H/lpr) F1 backcross mice with the rearranged genetic profile. Based on these results, we have successfully established five hybridoma clones which produce nephritogenic IgG3 antibodies from an unmanipulated MRL/lpr mouse. When they were injected to normal mice, four of the five clones generated cell-proliferative GN associated with the marked cellular infiltrates, while the 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.
Itoh
J
J
Department of Pathology, Tohoku University School of Medicine, Sendai, Japan.
Takahashi
S
S
Ono
M
M
Yamamoto
T
T
Nose
M
M
Kyogoku
M
M
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000276:immunology*; D001483:Base Sequence; D005921:Glomerulonephritis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D008181:Lupus Nephritis / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains / Q000276:immunology*; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000378:metabolism
D000906:Antibodies; D007074:Immunoglobulin G; D012333:RNA, Messenger