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B Cell Receptor

By Levi Clancy for Student Reader on

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Cross-linking of a membrane-bound immunoglobulin (mIg) with its complementary antigen initiates a signal transduction cascade that activates the attached B cell.

Membrane-bound immunoglobulins have short cytoplasmic tails, rendering them unable to transduce activating signals on their own. However, each membrane-bound ligand-binding immunoglobulin associates with a single disulfide-linked signal-transducing heterodimer Ig-α/Ig-β to form the B cell receptor. Similarly, the pre-BCR consists of the Ig-α/Ig-β heterodimer associating with the surrogate light chain and µ heavy chains.

Ig-α and Ig-β each contain a cytoplasmic tail with an 18-residue motif known as the immunoreceptor tyrosine-based activation motif (ITAM) which is also present in the T cell receptor (TCR). Also, just like the TCR, the BCR draws protein tyrosine kinases (PTKs) to its cytoplasmic tail upon cross-linking of the mIg by its complementary antigen.

Antigen-antibody crosslinking leads to phosphorylation of the tyrosines within the Ig-α and Ig-β ITAMs.

This phosphorylation is performed by the receptor-associated PTKs Lyn, Blk and Fyn (similar to p56Lck activity on TCRs). This ITAM phosphorylation creates docking sites for the critical proteins Syk (also a PTK, analogous to the TCR's ZAP-70) and B cell linker protein (BLNK). These critical proteins provide docking sites for further proteins. Once BLNK has been phosphorylated by Syk, it recruits Bruton's tyrosine kinase (Btk) and phospholipase Cγ2 (PLCγ2) so Syk can activate Btk, and so that Btk can then phosphorylate PLCγ2. Once PLCγ2 has been phosphorylated, it activates early calcium signaling and the initiation of pathways dependent on protein kinase C (PKC).

The pathways activated by the BCR include small G protein pathways (for growth), PKC-dependent pathways and NF-κB production pathways -- note the similarities to T cell activation.

In addition to the BCR, there are two membrane-bound components which provide stimulation (the B cell coreceptor) or inhibition (CD22).

The B cell co-receptor is a complex of three proteins: CD19, which provides a long cytoplasmic tail with docking sites; CD21 (aka CDR2), which is a receptor for C3d; and CD81. C3d is a byproduct of complement that coats antigens -- while the immunoglobulin binds the antigen, CD21 cross-links with C3d. This forms a BCR-antigen-BCcoR complex, allowing CD19's cytoplasmic tail to interact with Ig-α and Ig-β and undergo phosphorylation.

CD19's phosphorylated cytoplasmic tail then binds signaling molecules, including the protein tyrosine kinase (PTK) Lyn, and hugely amplifies the activating signal. This explains how naïve B cells with low antigen affinity are still able to respond to low concentrations of antigen.

CD22 delivers a negative signal that makes activation of B cells more difficult.

Activation of B cells leads to phosphorylation of the immunoreceptor tyrosine inhibitory motif (ITIM) in the cytoplasmic tail of CD22. Tyrosine phosphatase then binds the CD22 ITIM, stripping phosphates from the ITAMs of neighboring signaling complexes.

Since ITAM phosphorylation is the core of B cell activation, phosphate removal deactivates the cell. CD22 knockout mice develop autoimmune diseases as they age, illuminating the importance of negative regulation.