tions to help clear these antigens. When activated, 
complement proteins interact with specific recep- 
tors on human cells involved in the immune re- 
sponse. Assistant Investigator V Michael Holers, 
M.D. (Washington University) and his colleagues 
are analyzing the function and regulation of expres- 
sion of these receptors. The group has cloned a 
number of these receptors in both human and 
mouse and is currently using recombinant tech- 
niques to analyze their function. It is knov^^n that 
complement and these receptors play roles in 
chronic inflammatory diseases, such as systemic 
lupus erythematosus and rheumatoid arthritis. Un- 
derstanding the role of these receptors and devel- 
oping abilities to modulate them may provide fur- 
ther methods to treat these diseases. 
Analysis of a primary antihapten immune re- 
sponse has given new^ insight regarding the forma- 
tion and development of memory B cell lineages. 
It has been possible to construct a model outlin- 
ing the development of somatic variants from 
memory B cell lineages. The murine Ly-6 differen- 
tiation antigens are associated vi^ith activated 
T cells. Associate Investigator Alfred L. M. Bothwell, 
Ph.D. (Yale University) and his colleagues have 
generated mutants in one of these proteins and are 
examining the consequences of these mutations 
on T cell activation as well as on the biosynthesis 
of the protein. The promoters of the two best- 
characterized Ly-6 antigens are being studied in 
detail for regulatory elements that effect the tissue- 
specific or induced transcription. A human Ly-6 
homologue, designated CD59, has been cloned. 
One function of CD59 is to inhibit the complement 
system by preventing pore formation through in- 
hibiting oligomerization of complement compo- 
nent C9. It may also have a role in T cell activation 
via CD3. 
Investigator Edward J. Goetzl, M.D. (University of 
California at San Francisco) and his associates have 
characterized chemical signals that mediate human 
immunity and hypersensitivity and have identified 
cellular receptors for some of the signals. One class 
of signals is generated when immune cells cleave 
precursor proteins to liberate peptides resembling 
transmitters of neural impulses. The immune cell 
receptors for such neuropeptide-like signals differ 
in specificity from the nerve cell receptors. Dr. 
Goetzl and his colleagues have isolated the genetic 
message for one such immune cell receptor and are 
working to define its structure to elucidate how it 
differs from the same class of nerve cell receptors at 
the molecular level. 
Assistant Investigator Donald G. Payan, M.D. 
(University of California at San Francisco) and his 
collaborators continue to study the molecular 
mechanisms by which neuropeptides, such as sub- 
stance P, and multifunctional mediators, such as 
histamine, transduce their efforts on specific target 
tissues. Ongoing attempts to isolate the gene for 
the substance P receptor are now focused on using 
the polymerase chain reaction and low-stringency 
hybridization technologies with known tachykinin 
receptor genes. The work on histamine is concen- 
trated on expanding the initial observation that the 
receptor is coupled to two different signaling 
transduction pathways, depending on the state of 
differentiation of the responding cell. In addition, 
collaborative studies have shown that substance P- 
containing nerve fibers are the route by which spe- 
cific viruses infect ocular structures in an animal 
model. 
The laboratory of Assistant Investigator Kenneth 
J. Hardy, M.D., Ph.D. (Baylor College of Medicine) 
has focused its studies on the molecular mech- 
anisms regulating the potent and clinically relevant 
human cytokine, interferon-7 (IFN-7). This potent 
immunomodulator, which is implicated in the 
pathogenesis of rheumatoid arthritis, AIDS, and 
multiple sclerosis, also serves as an excellent 
molecular model of T cell-specific cytokine gene 
regulation. In line with its potential role in autoim- 
mune tissue destruction, IFN-'y was shown to be a 
potent upregulator of its own gene expression by 
certain human blood cells, while being strongly re- 
pressed by other blood cells and their associated 
cytokines. Molecular genetic studies, utilizing trans- 
fection of expression vectors directly into fully 
differentiated human blood cells, have permitted 
detailed elucidation of the genetic regulatory 
elements in the human IFN-7 gene, providing 
functional proof of a T cell-specific, orientation- 
dependent, negative regulatory element. From the 
analyses, a unifying hypothesis was derived that 
corroborates and extends current notions on cyto- 
kine gene regulation. 
Investigator Charles W Parker, M.D. (Washington 
University) and his colleagues are exploring genetic 
influences on immunoglobulin E (IgE) -mediated al- 
lergy. In mice, two independently segregating genes 
have been identified that selectively regulate IgE 
levels. Studies to localize the genes and to elucidate 
their roles are under way. Hormonal effects in the 
autoimmune process are also being examined, with 
emphasis on systemic lupus erythematosus and the 
mouse hybrid models for this disease. 
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