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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

Lopez-Hoyos, Marcos
Carrio, R.
Merino, Ramon
Buelta, Luis
Nunez, G.
Merino, Jesus
Published in Journal of Experimental Medicine. 1996, vol. 183, no. 6, p. 2523-2531
Abstract 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.
Keywords Aging/ immunologyAnimalsAnimals, NewbornAutoimmune Diseases/immunology/pathologyB-Lymphocytes/ immunologyCrosses, GeneticDeathGTP-Binding Proteins/biosynthesisH-2 Antigens/ immunologyHeterozygoteImmune ToleranceIsoantigens/ immunologyLupus Erythematosus, Systemic/ immunology/pathologyLymph Nodes/immunologyMiceMice, Inbred BALB CMice, Inbred C57BLMice, TransgenicProto-Oncogene Proteins/ biosynthesisProto-Oncogene Proteins c-bcl-2Proto-OncogenesSpleen/immunology/pathology
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PMID: 8676073
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