Alteration of B-cell Antigen Receptor Signaling by CD19 Co-ligation.

Abstract

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 muF(ab)2 fragments, unable to induce a proliferative response. Detailed analysis of the early signaling events showed that compared with muF(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.

Complement Component C3d-Antigen Complexes Can Either Augment or Inhibit B Lymphocyte Activation and Humoral Immunity in Mice Depending on the Degree of CD21/CD19 Complex Engagement

“…The CD19/ CD21 complex is generally envisioned to serve as a costimulatory receptor where Ag-C3d complexes cross-link the CD19/CD21 and BCR complexes (5,(27)(28)(29)53). However, the current study demonstrates that SA-C3dg ligation of the CD19/CD21 complex can independently augment BCR-induced [Ca 2ϩ ] i responses when the two signals are given simultaneously (Fig.…”

“…CD21 is a component of a multimeric complex on B cells (24,25) that includes CD19, a molecule that generates transmembrane signals during B cell activation (26). Co-cross-linking of the CD19/CD21 complex with the BCR complex using either C3d-tagged Ags or CD19 mAbs can augment BCR-induced [Ca 2ϩ ] i responses and lower B cell activation thresholds (5,(27)(28)(29). SAC3dg tetramers, formed by SA binding four monobiotinylated C3dg molecules, also augments B cell [Ca 2ϩ ] i responses and specifically binds CD21 on wild-type, but not CD21 Ϫ/Ϫ , B cells (13,30).…”

A novel subset of memory B cells is enriched in autoreactivity and correlates with adverse outcomes in SLE

“…Thus, a smaller proportion of CD19 was phosphorylated in CD19 hi B cells compared to CD19 lo cells. Because CD19 phosphorylation amplifies Syk activation [37], we were surprised to find that despite a lower frequency of CD19 phosphorylation, nearly all CD19 hi B cells displayed significantly elevated levels of phosphorylated Syk (pSyk) in contrast to the CD19 lo B cells from the same patient and to healthy control B cells (Fig. 3B-D).…”

Ca2+ signaling in antigen receptor‐activated B lymphocytes

“…A direct B‐cell regulator of PI3K is the BCR coreceptor CD19, which upon tyrosine phosphorylation by Lyn binds the enzyme by virtue of the SH2 domain in p85. Coligation of CD19 and the BCR strongly augments the Ca 2+ response and lowers the antigen threshold for B‐cell activation (92, 93). Hence, CD19 acts as a transmembrane adapter protein for recruitment of the enzyme that itself is a key to generate membrane‐docking sites for protein recruitment.…”