Constitutive expression of bcl-2 in B cells causes a lethal form of lupuslike autoimmune disease after induction of neonatal tolerance to H-2b alloantigens.
The bcl-2 protooncogene has been shown to provide a survival signal to self-reactive B cells, but it fails to override their developmental arrest after encounter with antigen. Furthermore, constitutive expression of bcl-2 in B cells does not promote the development of autoimmune disease in most strains of mice, indicating that signals other than those conferred by bcl-2 are required for long-term survival and differentiation of self-reactive B cells in vivo. To further examine the factors that are required for the pathogenesis of autoimmune disease, we have assessed the effect of bcl-2 overexpression on the development of host-versus-graft disease, a self-limited model of systemic autoimmune disease. In this model, injection of spleen cells from (C57BL/6 x BALB/c)F1 hybrid mice into BALB/c newborn parental mice induces immunological tolerance to donor tissues and activation of autoreactive F1 donor B cells through interactions provided by allogeneic host CD4+ T cells. BALB/c newborns injected with spleen cells from (C57BL/6 x BALB/c)F1 mice expressing a bcl-2 transgene in B cells developed high levels of anti-single-stranded DNA and a wide range of pathogenic autoantibodies that were not or barely detectable in mice injected with nontransgenic spleen cells. In mice injected with transgenic B cells, the levels of pathogenic autoantibodies remained high during the course of the study and were associated with long-term persistence of donor B cells, development of a severe autoimmune disease, and accelerated mortality. These results demonstrate that bcl-2 can provide survival signals for the maintenance and differentiation of autoreactive B cells, and suggest that both increased B cell survival and T cell help play critical roles in the development of certain forms of systemic autoimmune disease.
López-Hoyos
M
M
Department of Immunology, Hospital Universitarìo M. Valdecilla, Santander, Spain.
Carrió
R
R
Merino
R
R
Buelta
L
L
Izui
S
S
Núñez
G
G
Merino
J
J
D000375:Aging / Q000276:immunology*; D000818:Animals; D000831:Animals, Newborn; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology*; D003433:Crosses, Genetic; D003643:Death; D019204:GTP-Binding Proteins / Q000096:biosynthesis; D006183:H-2 Antigens / Q000276:immunology*; D006579:Heterozygote; D007108:Immune Tolerance; D007519:Isoantigens / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D019253:Proto-Oncogene Proteins c-bcl-2; D011519:Proto-Oncogenes; D013154:Spleen / Q000276:immunology / Q000473:pathology
D006183:H-2 Antigens; D007519:Isoantigens; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019204:GTP-Binding Proteins