Mechanisms of Immunological Self-Tolerance and Autoimmunity 
and breakage of tolerance depends, however, on 
a balance between stimuli that promote antibody 
formation and stimuli that reinforce tolerance. 
One line of research in our laboratory involves 
developing transgenic mouse models for study- 
ing how the interplay between these factors 
shapes the development and remission of autoim- 
mune disease in vivo. This research is funded by 
the National Institutes of Health. 
Identifying the molecular events that prevent 
tolerant cells from mounting an antibody re- 
sponse, or lead to the death of the autoreactive 
cells, will be crucial for fully understanding how 
self-tolerance is induced and maintained. Our ap- 
proach to this problem is severalfold. First, we 
are continuing to delineate the precise condi- 
tions under which tolerance rather than activa- 
tion is induced in B cells in vivo. Second, we 
have developed tissue culture systems that repro- 
duce the cellular responses observed in the 
whole animal, allowing much closer scrutiny of 
the sequence of events accompanying tolerance 
induction. In autoreactive B cells that are unable 
to mount an antibody response, this is due to in- 
terference with the cell's capacity to replicate 
and to differentiate into an antibody-secreting 
cell. For B cells that are triggered to die, the pri- 
mary event appears to be an arrest of cell develop- 
ment at an immature, short-lived stage of develop- 
ment. Third, we are using a combination of 
biochemical, molecular, and genetic strategies to 
search for the key differences in biochemical sig- 
naling cascades or changes in gene expression 
that underlie these events. 
Self-reactive B lymphocytes sorted from the bone marrow and visual- 
ized by electron microscopy. The antigen receptors on these cells have 
already been triggered, and as a result the cells are destined to die 
within a few days in vivo. At this stage, however, the process is revers- 
ible and the cells show none of the ultrastructural changes that precede 
programmed cell death. 
Research of Suzanne Hartley and Christopher Goodnow. 
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