GLOMERULOPATHY INDUCED BY IGG3 ANTI-TRINITROPHENYL MONOCLONAL CRYOGLOBULINS DERIVED FROM NON-AUTOIMMUNE MICE

We have previously shown that murine IgG3 monoclonal autoantibodies wi th cryoglobulin activity, derived from lupus-prone mice, are able to i nduce glomerular lesions resembling the ''wire-loop'' lesion typically described for human lupus nephritis. In the present study, we have fu rther assessed the nephritogenic potential of four IgG3 anti-hapten, t rinitrophenyl (TNP), monoclonal antibodies (mAb) obtained from non-aut oimmune mice immunized with TNP-conjugated foreign antigens. Our resul ts showed that two of four IgG3 anti-TNP monoclonal cryoglobulins were capable of inducing glomerular lesions, characterized by voluminous i ntracapillary thrombi and mesangial deposition of PAS-positive materia ls, which differed from ''wire-loop'' lesions generated by IgG3 monocl onal cryoglobulins with autoantibody activities. These anti-TNP monocl onal cryoglobulins, however, failed to induce glomerular lesions when mice were kept at 37 degrees C after the mAb administration. This find ing formally proves that the cryoglobulin activity is critically invol ved in the development of glomerular lesions induced by IgG3 anti-TNP mAb. In addition, we have demonstrated a remarkable difference in the nephritogenic activities of two IgG3 anti-TNP mAb, which exhibit a mar ked sequence homology in the variable regions of their heavy and light chains (91.5% and 99.1% at the amino acid level, respectively) and an identical isoelectric point. Our results indicate first, that IgG3 mo noclonal cryoglobulins are able to generate two different kinds of glo merular lesions, and second, that a subtle difference in variable regi on sequences may determine not only the nephritogenic activities, but also the type of glomerular lesions mediated by IgG3 cryoglobulins.