Development of autoimmune disease in SCID mice populated with longTerm “In Vitro” proliferating (NZB × NZW)F1 Pre-B cells

Abstract

Pre-B cell lines proliferating for several months on stromal cells in the presence of interleukin 7 (IL 7) were established from fetal liver of (NZB × NZW)F1 mice. They express the B lineagespecific markers PB76, B220, and VpreB, but do not express surface immunoglobulin (sIg). Upon removal of IL-7 from the culture, they differentiate to sIg+B cells that can then be stimulated by lipopolysaccharide to become IgM-secreting cells. Transfer of these pre-B cell lines into SCID mice leads to hypergammaglobulinemia of IgM (600-900 μg/ml), IgG2a (1-3 μg/ml), and IgG3 (300-500 μg/ml) for the next 3-5 mo. The spleen appears populated with (NZB × NZW)F1 derived pre-B cells, few B cells, and many IgM and/or IgG-producing plasma cells. In contrast, SCID mice populated with pre-B cell lines of normal (C57BL/6 × DBA/2)F1 mouse fetal liver develop normal levels of serum IgM (∼100-300 μg/ml), almost no detectable levels of IgG, and no plasma cell hyperplasia. The (NZB × NZW)F1 pre-13 cell-populated SCID mice contain elevated serum titers of IgG antinuclear autoantibodies, but no retroviral gp70-specific nor erythrocyte-specific autoantibodies. Up to 20% of the SCID mice develop proteinuria as a consequence of IgG deposits in the kidney glomeruli during a 7-mo period of observation. All signs of autoimmune disease seen in these mice are independent of the sex of the SCID host. This experimental system provides a distinction between the disease-determining (NZB × NZW)F1 genes, which are expressed in the B lymphocyte lineage and cause the development of the disease, from those expressed in other cell lineages which only modulate its progression. © 1992, Rockefeller University Press., All rights reserved.