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Volume 271, Number 37, Issue of September 13, 1996 pp. 22326-22330
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Alteration of B-cell Antigen Receptor Signaling by CD19 Co-ligation
A STUDY WITH BISPECIFIC ANTIBODIES

(Received for publication, February 22, 1996, and in revised form, May 30, 1996)

From the Central Laboratory of the Netherlands Red Cross Blood Transfusion Service and Laboratory for Experimental and Clinical Immunology, University of Amsterdam, 1066 CX Amsterdam, The Netherlands

The activation of B-cell antigen receptor-associated protein tyrosine kinases is an early and crucial event in B-cell signaling. Apart from the B-cell antigen receptor (BCR), the B-cell-specific transmembrane glycoprotein CD19 has also been shown to directly activate intracellular signaling cascades. In addition, because CD19 and the BCR are associated on the surface of activated B-cells, it has been proposed that close approximation between these two entities is crucial for optimal B-cell triggering. To test this hypothesis, bispecific antibodies were generated that bind membrane IgM and CD19 simultaneously. Although CD19 bispecific antibodies strongly induced tyrosine phosphorylation, they were, in contrast to µF(ab)₂ fragments, unable to induce a proliferative response. Detailed analysis of the early signaling events showed that compared with µF(ab)₂ fragments CD19 bispecific antibodies potently raised the intracellular [Ca²⁺], which was correlated with an efficient tyrosine phosphorylation of syk. Strikingly, the assembly of Grb2 complexes that may couple the BCR to p21^ras was clearly altered by the CD19 bispecific antibody. In addition to the reported Shc and 145-kDa phosphoproteins, a prominent 90-95-kDa phosphoprotein resembling CD19 was detected in the Grb2 complexes. Thus, studies with CD19 bispecific antibodies show that CD19 co-ligation both quantitatively and qualitatively alters BCR signaling.

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