INTRINSIC B-CELL DEFECTS IN NZB AND NZW MICE CONTRIBUTE TO SYSTEMIC LUPUS-ERYTHEMATOSUS IN (NZBXNZW)F1 MICE

We have previously shown that long-term in vitro proliferating fetal l iver pre-B cell lines derived from autoimmune-prone (NZB X NZW)F1 (BW) mice, but not normal (B6 X DBA/2)F1 mice, can differentiate in severe combined immunodeficient (SCID) mice to produce elevated levels of se rum immunoglobulin (Ig) M and IgG, and high titers of antinuclear anti bodies. The contribution of parental NZB and NZW strains to B cell abn ormalities of BW hybrid mice was investigated here by preparing pre-B cells and transferring them into immunodeficient SCID- and RAG-2-targe ted mice. We show that transfer of NZB pre-B cells led to a marked IgM hypergammaglobulinemia and to the production of limited amounts of Ig G2a. On the other hand, the transfer of NZW pre-B cell lines led to mo derately elevated IgM levels and marked hypergammaglobulinemia of IgG2 a. High IgM and low IgG anti-DNA titers are found in the recipients of NZB pre-B cells, whereas those receiving NZW pre-B cells contained lo wer levels of IgM and high titers of IgG anti-DNA. In marked contrast, essentially identical titers of antibodies directed against a non-sel f-antigen, DNP, are found in all groups of pre-B cell recipients. Thus , B-lineage cells of both NZB and NZW parental strains manifest abnorm alities associated with the development of this lupus-like disease. Th erefore, the present study strongly suggests a complex inheritance of B cell abnormalities in autoimmune-prone (NZB X NZW)F1 mice and emphas izes the critical importance of intrinsic B cell defects in the develo pment of murine systemic lupus erythematosus.