CONSTITUTIVE EXPRESSION OF BCL-2 IN B-CELLS CAUSES A LETHAL FORM OF LUPUS-LIKE AUTOIMMUNE-DISEASE AFTER INDUCTION OF NEONATAL TOLERANCE TO H-2(B) ALLOANTIGENS

Citation
M. Lopezhoyos et al., CONSTITUTIVE EXPRESSION OF BCL-2 IN B-CELLS CAUSES A LETHAL FORM OF LUPUS-LIKE AUTOIMMUNE-DISEASE AFTER INDUCTION OF NEONATAL TOLERANCE TO H-2(B) ALLOANTIGENS, The Journal of experimental medicine, 183(6), 1996, pp. 2523-2531
Citations number
35
Categorie Soggetti
Immunology,"Medicine, Research & Experimental
ISSN journal
00221007
Volume
183
Issue
6
Year of publication
1996
Pages
2523 - 2531
Database
ISI
SICI code
0022-1007(1996)183:6<2523:CEOBIB>2.0.ZU;2-R
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 a rrest after encounter with antigen. Furthermore, constitutive expressi on of bcl-2 in B cells does not promote the development of autoimmune disease in most strains of mice, indicating that signals other than th ose conferred by bcl-2 are required for long-term survival and differe ntiation of self-reactive B cells in vivo. To further examine the fact ors that are required for the pathogenesis of autoimmune disease, we h ave 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 BAL B/c)F-1 hybrid mice into BALB/c newborn parental mice induces immunolo gical tolerance to donor tissues and activation of autoreactive F-1 do nor B cells through interactions provided by allogeneic host CD4(+) T cells. BALB/c newborns injected with spleen cells from (C57BL/6 X BALB /c)F-1 mice expressing a bcl-2 transgene in B cells developed high lev els of anti-single-stranded DNA and a wide range of pathogenic autoant ibodies that were not or barely detectable in mice injected with nontr ansgenic spleen cells. In mice injected with transgenic B cells, the l evels of pathogenic autoantibodies remained high during the course of the study and were associated with long-term persistence of donor B ce lls, development of a severe autoimmune disease, and accelerated morta lity. These results demonstrate that bcl-2 can provide survival signal s for the maintenance and differentiation of autoreactive B cells, and suggest that both increased B cell survival and T cell help play crit ical roles in the development of certain forms of systemic autoimmune disease.