tiation and may result in the rearrangement and ex- 
pression of the K locus. Alternatively, inappropriate 
expression of the IkB-7 message in mature B or 
plasma cells may affect the expression of genes spe- 
cific for the later stages of B cell development. 
To test these hypotheses, Dr. Ghosh and his col- 
leagues will do experiments to alter the level of 
I/cB-7 message in cells, using either antisense RNA 
for reducing levels of expression or strong constitu- 
tive promoter/enhancers for elevating levels of ex- 
pression. These studies will also be extended to ani- 
mals, using transgenic techniques. Transgenic mice 
will be made using promoter/enhancer combina- 
tions that are active throughout B cell development, 
e.g., the immunoglobulin heavy-chain promoter/ 
enhancer, to drive the expression of IKB-7. Such in- 
appropriate expression may lead to a block in the 
differentiation of B cells at a stage where, under nor- 
mal circumstances, IkB-7 expression would be shut 
off, and such blockage may disrupt the normal bal- 
ance between differentiation and proliferation. As a 
consequence one may observe the generation of B 
cell lymphomas similar to that observed in the case 
of dysregulated expression of another putative IkB, 
bcl-3- This is a putative oncogene whose elevated 
expression due to a chromosomal translocation 
leads to development of B cell lymphomas. Al- 
though a recent report indicates that bcl-3 in vitro 
preferentially interacts with the p50 dimer, it is still 
unclear if p50 is the physiological target in vivo. 
Therefore it appears that inappropriate inhibition of 
the function of certain rel transcription factors (the 
target of bcl-3} can cause transformation of pre-B 
cells. Transgenic mice expressing kB-7 will be gen- 
erated, and to determine if B cell differentiation is 
blocked in these mice, the number of peripheral B 
cells expressing surface IgM will be measured using 
FACS (fluorescence-activated cell-sorting) analysis. 
Finally, to determine if the expression of UB-y 
causes neoplasia, pathological analysis of periph- 
eral blood, spleen, and bone marrow will be 
performed. 
Dr. Ghosh is also Assistant Professor of Immu- 
nobiology and of Molecular Biophysics and Bio- 
chemistry at Yale University School of Medicine. 
Articles 
Fujita, T., Nolan, G.P., Ghosh, S., and Baltimore, D. 
1992. Independent modes of transcriptional acti- 
vation by the p50 and p65 subunits of NF-zcB. 
Genes Dev 6:11=>-1S1. 
Liou, H.-C, Nolan, G.P., Ghosh, S., Fujita, T., and 
Baltimore, D. 1992. The NF-kB p50 precursor, 
pi 05, contains an internal kB-like inhibitor that 
preferentially inhibits p50. EMBO f 11:3003- 
3009. 
Raziuddin, Mikovits, J.A., Calvert, 1., Ghosh, S., 
Kung, H.-F., and Ruscetti, F.W. 1991. Negative 
regulation of human immunodeficiency virus 
type 1 expression in monocytes: role of the 65- 
kDa plus 50-kDa NF-kB dimer. Proc Natl Acad Sci 
USA 88:9426-9430. 
SELF-TOLERANCE MECHANISMS IN B LYMPHOCYTES 
Christopher C. Goodnow, B.V.Sc, Ph.D., Assistant Investigator 
Production of autoantibodies is characteristic of 
most autoimmune diseases and is normally avoided 
by censoring of self-reactive cells within both the B 
cell and helper T cell repertoires. Research in Dr. 
Goodnow's laboratory focuses on the B cell reper- 
toire and has three major aims: 1) definition of cel- 
lular and molecular events responsible for censor- 
ing self-reactive B cells in vivo, 2 ) development of 
new mouse models for analyzing B cell tolerance or 
autoimmunity to different types of self antigens, and 
3) determination of the basis for failure of B cell 
tolerance in strains of autoimmune mice. 
Elimination of Self-reactive B Cells 
To visualize the development and fate of self- 
reactive B lymphocytes in vivo, Dr. Goodnow's labo- 
ratory makes use of transgenic mice carrying 
rearranged immunoglobulin (Ig) genes. Because 
the rearranged Ig transgenes prevent endogenous Ig 
gene rearrangement, most of the developing B cells 
in these mice express a single specificity of Ig mole- 
cules as cell surface antigen receptors and as se- 
creted antibodies. Thus mice carrying Ig genes en- 
coding an anti-lysozyme antibody contain a large 
number of hen egg lysozyme (HEL) -specific B cells 
that can be easily followed and analyzed. 
During the past year, members of Dr. Goodnow's 
laboratory have been studying one mechanism of B 
cell censoring that involves physical elimination of 
self-reactive B cells. Elimination of lysozyme- 
specific B cells could be clearly shown to occur in 
offspring from matings between anti-HEL Ig- 
IMMUNOLOGY 331 
