cells has dramatically altered this view of B cell de- 
velopment. Current hypothetical models suggest 
that xl^LC proteins, encoded by X5/ 14.1 and Vpre-B 
genes, may pair with either t/'HC or /xHC to form 
receptors that signal the progressive differentiation 
of pro-B, pre-B, and immature B cells. However, 
when monoclonal antibodies were prepared and 
used to examine \f/LC protein expression during nor- 
mal and abnormal B cell differentiation, the expres- 
sion pattern was found to be different from that an- 
ticipated by these models. While i^LCs are produced 
during several developmental stages, their cell sur- 
face expression is restricted to a relatively late stage 
in normal pre-B cell differentiation. 
Crosslinkage of the \pLC/fiHC receptors on pre-B 
cells leads to receptor down-modulation and tran- 
sient increase in intracellular calcium levels. How- 
ever, pre-B cell growth and B cell differentiation is 
neither enhanced nor inhibited by anti-i/'LC anti- 
body treatment. The results indicate that xpLC/ixHC 
receptors are not involved in negative selection of 
the B cell repertoire, nor are they informative about 
postulated positive roles in pre-B cell survival and B 
cell differentiation. 
IgM molecules cannot reach the B cell surface by 
themselves, and even if they could, their short intra- 
cytoplasmic tails are inadequate for signal transduc- 
tion. Ig receptors require associated transmembrane 
molecules both to reach the cell surface and to 
transduce signals after crosslinkage by antigens. 
Two covalently linked transmembrane molecules, 
encoded by the mb-1 and B29 genes, have been de- 
fined as integral components of the antigen receptor 
units on B cells. Dr. Cooper's laboratory produced 
monoclonal antibodies against an exposed extracel- 
lular epitope on the 525'-encoded ^ chain. Cyto- 
plasmic expression of /3 chains begins in pro-B 
cells, while surface expression occurs concurrently 
with expression of Ig receptors of all isotypes. Im- 
munochemical analysis reveals molecular heteroge- 
neity of the Ig-associated molecules that varies as a 
function of differentiation stage and Ig isotype. 
The data support the hypothesis that biochemical 
heterogeneity of the surface Ig-associated mole- 
cules may contribute to the variable effects of anti- 
gen receptor crosslinkage on B cells of different mat- 
urational stages. The anti-|S-chain antibodies may 
prove therapeutically useful as universal B cell sup- 
pressants, since they can down-modulate the anti- 
gen receptors on all B cells. 
Defective B Cell Differentiation 
Interruptions in key events occurring in this dif- 
ferentiation pathway may result in antibody defi- 
ciencies. X-linked agammaglobulinemia (XLA), the 
prototypic antibody deficiency, is characterized by 
recurrent bacterial infections due to a severe deficit 
in B cells and their mature antibody-producing prog- 
eny. The gene responsible for this inherent B cell 
defect is located in the Xq2 1.2-22 region. While all 
stages in B cell differentiation can be found in XLA 
bone marrow, the bottleneck appears to involve the 
pre-B cells, relatively few of which enter the cell 
cycle. As clonal expansion normally is prominent in 
this differentiation compartment, identification of 
the XLA gene may be the key to understanding the 
molecular basis for this growth spurt. 
IgA deficiency (IgA-D) and common variable im- 
munodeficiency (CVID), long considered to be 
unrelated and very heterogenous disorders, instead 
may represent polar ends of a continuous clinical 
spectrum. An arrest in differentiation of immature B 
cells is seen in both IgA-D and CVID, the chief dis- 
tinction being in the Ig isotypes involved in the fail- 
ure to undergo plasma cell maturation. Genetic pre- 
disposition is evidenced by variation in incidence of 
IgA-D from 1/500 to 1/18,500 in Caucasians and 
Asians, respectively, and by families in which sev- 
eral members with either CVID or IgA-D are seen in 
successive generations. Location of the underlying 
susceptibility gene(s) in the major histocompatibil- 
ity complex (MHC) region of chromosome 6 is sug- 
gested by the frequent occurrence of certain MHC 
haplotypes in both CVID and IgA-D patients, and 
their rarity in populations in which these immuno- 
deficiencies are uncommon. 
While the highly polymorphic MHC genes tend to 
be inherited as a block, making precise mapping of 
the postulated susceptibility gene difficult, an MHC 
class 111 subregion that normally contains the C4A 
gene is the most frequently conserved portion of the 
disease-associated haplotypes. The C4A gene is of- 
ten deleted in these haplotypes. It is known that the 
C4A complement protein preferentially binds to 
antigen-antibody complexes and indirectly en- 
hances antigen triggering of B cells in antibody re- 
sponses featuring isotype switching. Current efforts 
in Dr. Cooper's laboratory and that of Dr. John Vo- 
lanakis focus on structural and functional evaluation 
of the C4A alleles in CVID and IgA-D patients. (The 
project described above was supported by a grant 
from the National Institute of Allergy and Infectious 
Diseases, National Institutes of Health.) 
Dr. Cooper is also Professor of Medicine, Pediat- 
rics, and Microbiology at the University of Ala- 
bama at Birmingham. 
IMMUNOLOGY 319 
