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
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
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.