regulation during T cell proliferation. They have es- 
tablished a role for the Ets gene family in the tran- 
scriptional regulation of T cell activation. Studies 
concerning the physiologic role of the helper T 
cell-specific receptor CD28 have continued to de- 
fine its role in regulating immune responses and 
lymphokine production. 
The B cell pathway of differentiation in humans is 
a focus of study in the laboratory of Investigator Max 
D. Cooper, M.D. (University of Alabama). Antibod- 
ies specific for surrogate light chains and surface 
immunoglobulin-associated molecules are em- 
ployed in studies of antigen receptor expression 
during B cell development and maturation. This in- 
formation on normal development is used to ex- 
plore the defects in this differentiation pathway that 
result in the inherited antibody deficiency diseases 
of X-linked agammaglobulinemia, common variable 
immunodeficiency, and IgA deficiency, the last of 
which occurs at a frequency of approximately 1 in 
600 North Americans and Europeans. 
Autoimmune diseases such as diabetes mellitus, 
systemic lupus erythematosus, and myasthenia gra- 
vis represent a broad class of disorders caused by 
immunological attack against normal body compo- 
nents. Assistant Investigator Christopher C. Good- 
now, B.V.Sc, Ph.D. (Stanford University) and his 
colleagues are studying the mechanisms that nor- 
mally prevent antibodies from being made to nor- 
mal self components. Antibodies are made by B 
cells, and during the past year this laboratory has 
identified key early events that normally lead self- 
reactive B cells to be either eliminated or inacti- 
vated. These advances open up the possibility of 
understanding the process of self-tolerance in mo- 
lecular terms and identify steps where the process 
may break down in autoimmune disease. 
The goals of the laboratory of Investigator Richard 
A. Flavell, Ph.D. (Yale University) are to understand 
the mechanisms of immune tolerance in which an 
organism eliminates the ability of lymphocytes to 
react with its own tissues and instead restricts their 
immune recognition to foreign antigens. Transgenic 
mice have been used to assess the factors that upset 
normal tolerance mechanisms leading to autoim- 
mune disease. Transgenic production of cytokines 
or co-stimulatory receptors in tissue cells appear to 
play a role in the induction of an autoimmune state, 
suggesting that recruitment of cells in an inflamma- 
tory response, coupled with their activation, is a key 
parameter in the induction of autoimmunity. The 
laboratory has also developed a recombinant vac- 
cine for Lyme disease. This vaccine in now being 
prepared for clinical testing in human patients, and 
the group has shown that humans appear to be capa- 
ble of raising protective antibodies against key com- 
ponents of this vaccine. Moreover, it appears to be 
efficacious in laboratory experiments where infec- 
tion is mediated through deer ticks collected in the 
wild, suggesting that this vaccine may be eff'ective 
in a natural setting. In other work it was found that 
the Lyme disease organism appears to use several 
strategies to evade immune surveillance, one of 
which appears to be mutation of its outer surface 
proteins. 
Assistant Investigator Donald G. Payan, M.D. (Uni- 
versity of California, San Francisco) and his col- 
leagues are elucidating the mechanisms by which 
certain neuropeptides released into important im- 
munologic microenvironments modulate the re- 
sponses of distinct leukocyte subpopulations during 
inflammation. The studies being undertaken ex- 
plore novel immunologic properties conferred to 
lymphocytes that express neuropeptide receptors. 
Additional investigations are aimed at characteriz- 
ing the protease inhibitor domains of the agrin mole- 
cule. Studies on the developing rat demonstrate 
agrin expression in unique tissues that are undergo- 
ing active remodeling, and consequently, agrin may 
play an important role in neural development. 
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