develop a severe, progressive lymphoproliferative 
disorder, which results in death after 2-6 months. 
Early morbidity and mortality have made this disease 
difficult to study. However, Dr. Nussenzweig and 
his colleagues have made substantial progress in 
characterizing the pathology, and current efforts are 
focused on molecular etiology. 
Gross examination shows enlarged spleens, 
lymph nodes, and lymphatic channels early in the 
disease. Moribund animals display a variety of phe- 
notypes, including total body edema, enlarged kid- 
neys and liver, and a number of different types of 
infections. Microscopic analysis reveals loss of ar- 
chitecture in lymph nodes and spleen, with a pre- 
dominance of hystiocytoid cells. All other organs 
contain perivascular lymphoid infiltration, which 
only invades the parenchyma of the kidneys, liver, 
and lungs late in the disease. 
Immunologic characterization shows increased 
numbers of lymphocytes in all classes, with a dis- 
proportionate increase in T cells of both CD4 
and CDS subclasses. Lymphocytes removed from 
spleens and lymph nodes proliferate spontaneously 
at a 20-fold greater rate than lymphocytes from 
wild-type litter mates. However, the proliferating 
cells are neither clonal (by Southern blotting analy- 
sis) nor malignant, since they do not form tumors in 
nude mice and do not grow continuously in vitro. 
Despite the abundance of lymphocytes, immune re- 
sponses appear to be blunted severely in the RAG 
transgenic mice. 
A number of molecular defects may explain this 
complex phenotype. One possibility is that deregu- 
lated expression of the RAG genes in mature T cells 
aborts allelic exclusion and results in continued T 
cell receptor (TCR) gene rearrangements. In this 
model, continued rearrangements would lead to 
formation of self-reactive T cell clones and a disease 
that is mediated by an autoimmune mechanism. A 
second hypothesis is that deregulated expression of 
RAG results in aberrant chromosomal translocations 
and abnormal expression of genes that regulate lym- 
phocyte proliferation. 
However, the phenotype may be entirely indepen- 
dent of recombination, since the RAG proteins are 
not known to be direct components of the recombi- 
nation machinery. Indeed, the RAG products may 
function as gene activators, and aberrant gene acti- 
vation may be another explanation for the trans- 
genic phenotype. Dr. Nussenzweig and his col- 
leagues are currently focusing on experiments that 
test these hypotheses, which should help to clarify 
the function of the RAG genes and further the un- 
derstanding of allelic exclusion. 
Signal Transduction by IgM 
Membrane immunoglobulin is a key regulator in 
the B cell pathway. Early in B cell differentiation, 
IgM regulates allelic exclusion and B cell develop- 
ment. In mature B cells the same IgM protein func- 
tions as the antigen receptor that is responsible for 
detecting foreign antigens and triggering a cascade 
of events whose end result is specific antibody pro- 
duction. Despite the central role of receptor immu- 
noglobulin, little is known about the mechanism by 
which this receptor produces a signal. 
Two important features of the immunoglobulin 
antigen receptor have hindered understanding of its 
mechanism of signaling. First, its intracytoplasmic 
domain is composed of three amino acids that offer 
no specific clues about the mechanism of receptor 
function. Second, the receptor immunoglobulins 
are associated with several other polypeptides on 
the cell surface to form a multisubunit structure. 
Two of these receptor-associated polypeptides, 
MB-1 and B29, have been implicated in receptor as- 
sembly and cell surface transport. In addition, both 
are rapidly phosphorylated upon receptor cross- 
linking, but the functional role of the IgM- 
associated proteins is poorly defined. 
As an initial step in studying the structural and 
functional requirements for signal transduction by 
immunoglobulin, Dr. Nussenzweig and his col- 
leagues set out to reconstitute the immunoglobulin 
antigen receptor of B lymphocytes in the Jurkat T 
cell line by transfection of cloned components. 
T cell lines were chosen for these experiments for 
several reasons. First, there are no available models 
that faithfully reproduce the process of allelic 
exclusion in vitro. Second, T cells do not nor- 
mally express either immunoglobulin or the IgM- 
associated proteins. Third, T cells are closely related 
to B cells and possess the specialized connections 
that are required for signal transduction by the TCR, 
which is highly homologous to immunoglobulins. 
The reconstitution experiments showed that the 
combination of IgM and B29 was both necessary and 
sufficient to reconstitute antigen-specific signal 
transduction by immunoglobulin in the transfected 
T cells. IgM alone was not an active receptor in T 
cells. Crosslinking of the transfected IgM-B29 com- 
plex with either antireceptor antibodies or antigen 
induced cellular responses, such as calcium flux, 
phosphoinositol turnover, and interleukin-2 (IL-2) 
secretion. MB-1, a second IgM-associated polypep- 
tide, was not required for either transport or signal 
transduction. 
These experiments are the first to establish a re- 
quirement for B29 in immunoglobulin receptor 
350 
