Development of autoimmune disease in SCID mice populated with long-term "in vitro" proliferating (NZB x NZW)F1 pre-B cells.
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 x NZW)F1 mice. They express the B lineage-specific 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 micrograms/ml), IgG2a (1-3 mg/ml), and IgG3 (300-500 micrograms/ml) for the next 3-5 mo. The spleen appears populated with (NZB x 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 x DBA/2)F1 mouse fetal liver develop normal levels of serum IgM (approximately 100-300 micrograms/ml), almost no detectable levels of IgG, and no plasma cell hyperplasia. The (NZB x NZW)F1 pre-B 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 x 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.
Reininger
L
L
Basel Institute for Immunology, Switzerland.
Radaszkiewicz
T
T
Kosco
M
M
Melchers
F
F
Rolink
A G
AG
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D000914:Antibodies, Viral / Q000032:analysis; D001327:Autoimmune Diseases / Q000209:etiology*; D001402:B-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D004912:Erythrocytes / Q000276:immunology; D005260:Female; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D006942:Hypergammaglobulinemia / Q000209:etiology; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016513:Mice, SCID
D000974:Antibodies, Antinuclear; D000914:Antibodies, Viral; D007074:Immunoglobulin G; D007075:Immunoglobulin M