6.2 B cell receptor structure and signaling

B cell receptors are crucial for immune response. They consist of membrane-bound immunoglobulins and signaling components that recognize antigens and trigger activation. Understanding their structure and function is key to grasping how B cells defend against pathogens.

When B cell receptors bind antigens, they kick off complex signaling cascades. These involve kinase activation, second messenger generation, and transcription factor activation. Co-receptors fine-tune the response, either enhancing or dampening signaling to control B cell activation.

B Cell Receptor Structure

Structure of B cell receptor complex

• Membrane-bound immunoglobulin (mIg) consists of two heavy chains and two light chains forming antigen-binding sites in variable regions
• Signaling components include Igα (CD79a) and Igβ (CD79b) heterodimer with cytoplasmic tails containing ITAM motifs crucial for signal transduction
• Accessory molecules CD19, CD21 (complement receptor 2), and CD81 enhance BCR signaling and lower activation threshold

B cell receptor in antigen recognition

• Variable regions of mIg bind specific epitopes enabling clonal selection of B cells with matching receptors
• Antigen binding triggers conformational changes initiating intracellular signaling cascades
• Receptor-mediated endocytosis internalizes bound antigens for processing and presentation on MHC class II molecules

B Cell Receptor Signaling

Signaling cascades of B cell activation

1. Tyrosine kinase activation: Lyn kinase phosphorylates ITAM motifs, recruiting and activating Syk kinase
2. Signaling complex formation: BLNK (SLP-65) acts as scaffold protein recruiting Btk and PLCγ2
3. Second messenger generation: PLCγ2 cleaves PIP2 into IP3 and DAG, IP3 triggers calcium release from endoplasmic reticulum
4. Transcription factor activation: NF-κB pathway activated by PKC, NFAT activated through calcium-calcineurin pathway, ERK/MAPK pathway activated
5. Cellular responses: Proliferation, differentiation, cytokine production, and antibody class switching initiated

Co-receptors in B cell signaling

• CD19-CD21-CD81 complex lowers activation threshold and enhances BCR signaling through PI3K pathway
• CD45 dephosphorylates inhibitory tyrosine residues on Src-family kinases promoting BCR signaling initiation
• CD22 negatively regulates BCR signaling by recruiting SHP-1 phosphatase to dampen activation
• FcγRIIB inhibits signaling by recruiting SHIP phosphatase to counteract PI3K signaling
• CD40 provides co-stimulatory signals enhancing B cell survival, proliferation, and isotype switching upon binding CD40L
• Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns synergizing with BCR signaling to enhance B cell activation