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Integrated Department of Immunology, University of Colorado Health Sciences Center, and National Jewish Medical and Research Center, Denver, CO 80206
B cell tolerance can be maintained by functional inactivation, or
anergy, wherein B cell Ag receptors (BCR) remain capable of binding Ag,
but are unable to transduce signals. Although the molecular mechanisms
underlying this unresponsiveness are unknown, some models of B cell
anergy are characterized by disruption of proximal BCR signaling
events, and by destabilization of the BCR complex. Receptor
destabilization is manifest by a reduced ability to coimmunoprecipitate
membrane Ig with the Ig-
/Ig-
signal-transducing complex. To begin
to explore the possibility that anergy is the consequence of receptor
destabilization, we analyzed a panel of B lymphoma transfectants
expressing constant amounts of signal-competent Ag receptors and varied
amounts of a receptor with identical specificity, but bearing mutations
that render it incapable of interacting with Ig-/Ig-. This
analysis revealed that coaggregation of signal-incompetent receptors
prevented Ag-induced Ig- and Syk phosphorylation, mobilization of
Ca2+, and the up-regulation of CD69 mediated by competent
receptors. In contrast, Ag-induced Cbl and Erk phosphorylation were
unaffected. Data indicate that coaggregation of destabilized receptors
(as few as 
15% of total) with signal-competent receptors
significantly affects the ability of competent receptors to transduce
signals. Thus, BCR destabilization may underlie the Ag unresponsiveness
of anergic B cells.
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