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Scientific article
English

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

Published inThe Journal of experimental medicine, vol. 183, no. 6, p. 2523-2531
Publication date1996
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/ immunology
  • Animals
  • Animals, Newborn
  • Autoimmune Diseases/immunology/pathology
  • B-Lymphocytes/ immunology
  • Crosses, Genetic
  • Death
  • GTP-Binding Proteins/biosynthesis
  • H-2 Antigens/ immunology
  • Heterozygote
  • Immune Tolerance
  • Isoantigens/ immunology
  • Lupus Erythematosus, Systemic/ immunology/pathology
  • Lymph Nodes/immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Proto-Oncogene Proteins/ biosynthesis
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogenes
  • Spleen/immunology/pathology
Affiliation Not a UNIGE publication
Citation (ISO format)
LOPEZ-HOYOS, Marcos et al. 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. In: The Journal of experimental medicine, 1996, vol. 183, n° 6, p. 2523–2531. doi: 10.1084/jem.183.6.2523
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ISSN of the journal0022-1007
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