B Cell Receptor Signaling in Human Systemic Lupus Erythematosus

Aimee E. Pugh-Bernard; John C. Cambier

Disclosures

Curr Opin Rheumatol. 2006;18(5):451-455. 

In This Article

B Cell Signaling in Health

Aggregation of antigen receptors on the surface of a lymphocyte triggers a series of intracellular events that engage and utilize various signaling molecules that connect to diverse yet often interconnected pathways and multiple outcomes, including activation, inhibition or apoptosis. Aggregation of the B cell receptor (BCR), leads to activation of protein tyrosine kinases, such as Lyn, which phosphorylate crucial immunoreceptor tyrosine-based activation motif (ITAM) tyrosine residues on the BCR-associated Igα and Igβ signaling molecules.[17] Phosphorylation of two precisely spaced tyrosine residues within the ITAM allows recruitment and activation of the cytosolic tyrosine kinase Syk,[18,19] which is the gatekeeper for initiation of several different parallel pathways such as protein kinase C, MAPK, or phospholipase Cγ2 (PLCγ2).[20] B cell linker protein (BLNK, also known as SLP-65 and BASH)[21,22,23] plays a critical role as a Syk substrate and nexus for multiple downstream pathways. Upon activation, PLCγ2 cleaves the membrane phosphoinositide, phosphatidyl inositol 4,5-biphosphate (PIP2) generating diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). DAG activates protein kinase C while IP3 binds to specific receptors on the endoplasmic reticulum inducing the release of calcium from intracellular stores.[24] The increase of intracellular calcium results in the regulation of various signal transduction pathways via transcription factor activation and gene expression.[25]

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