Development of the Immune System 
bution patterns shown previously for their avian 
and mammalian counterparts. Cloning of the frog 
TCR genes is one current focus, and the thymus 
dependence and functional capabilities of the 
two sublineages are being explored. The goals of 
th^se studies are to understand the evolutionary 
strategy for generating T cells that can discrimi- 
nate between self and nonself and to gain fresh 
clues for some of the unresolved mysteries of the 
human immune system. 
B Cell Development 
Bone marrow stromal cells can influence the 
growth and development of B cell precursors, ei- 
ther by direct cell contact or via soluble products 
like interleukin-7 (IL-7). We are examining cell 
surface molecules through which pre-B cells 
may receive these environmental cues. One such 
candidate molecule is an ectoenzyme named 
aminopeptidase A (APA), the increased expres- 
sion of which is induced by exposure to IL-7. We 
are testing the hypothesis that IL-7 is either a li- 
gand or a catalytic substrate for APA. We are using 
a mouse gene probe to identify the human gene 
for APA for sequence analysis, with the goal of 
understanding its expression as a function of nor- 
mal and leukemic pre-B cell differentiation. 
Before pre-B cells rearrange their light-chain 
genes to become B cells, they express a complex 
receptor that is composed of surrogate light- 
chain proteins (VpreB and X5), m heavy chains, and 
two small transmembrane proteins called a and 
/3. We have produced monoclonal antibodies 
against exposed configurations of these protein 
receptor units in order to explore the nature of 
the receptor ligand(s) and the signals transduced 
to the pre-B cell. One of these antibodies, which 
is specific for the /3-chain of the Ig receptor unit, 
may prove to be a universal B cell suppressant 
because it down-modulates the antibody recep- 
tors on all B cells. 
Immunodeficiency Diseases 
The pathogenesis of three primary immunodefi- 
ciency diseases is being investigated. X-Iinked 
agammaglobulinemia features an arrest in pre-B 
cell differentiation, the precise nature of which is 
under study in affected boys. Other studies ad- 
dress the hypothesis that selective IgA deficiency 
(IgA-D) and common variable immunodeficiency 
(CVID) may represent polar ends of a clinical 
spectrum reflecting a single underlying gene de- 
fect. The cellular defect in both deficiencies con- 
sists of arrested B cell differentiation. Both dis- 
orders frequently occur in members of the same 
family, and the same MHC class III haplotypes are 
associated with IgA-D and CVID. Current studies 
focus on the C4A complement gene. 
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