B cell receptor (BCR) signaling is essential for B cell survival and development as well as antibody production under physiological and pathological conditions. Antigen-driven priming signaling is important for the initiation of B cell activation and differentiation into antibody-secreting cells. On the other hand, tonic BCR signaling is required for B cell survival and development whereas chronic signaling is essential for the proliferation of B cell lymphoma cells.
Stimulation of the BCR by antigen engagement initiates receptor clustering leading to phosphorylation of CD79 and CD19 by tyrosine protein kinase Lyn (LYN). The Protein kinase Syk (SYK) binds to phospho-tyrosine residues within the CD79 ITAM domain and is activated. Adaptor proteins such as BLNK, BCAP (PIK3AP1), LAB (LAT2), and GRB2 associate with phospho-tyrosines outside the ITAM on CD79. BLNK and BCAP are also phosphorylated by SYK. Phosphoryated BCAP and CD19 attract the regulatory subunit p85 which results in the activation of catalytic p110 PI3Kδ (PIK3CD). Conversion of phosphatidylinositol 4,5-bisphosphate (PIP2) to Phosphatidylinositol (3,4,5)-trisphosphate (PIP3) by the activated kinase then attracts PH domain containing proteins such as AKT, BTK, PLCγ2 (PLCG2), and Vav (VAV1) to the plasma membrane. Phoshporylated BLNK act as a scaffold for membrane-associated kinases BTK and PLCγ2 (PLCG2), thus facilitating their activation. This catalyzes activation of downstream NF-κB and JNK signaling through the CBM signalosome and activation of ERK signaling. In addition, Vav (VAV1) activation leads to p38 signaling and cytoskeletal rearrangement and Akt signaling leading to activation of mTORC1 and inhibition of FoxO.
BCR antigen engagement also leads the activation to Ca2+ dependent pathways. Activated phospholipase C-γ (PLCG2) hydrolyzes phosphatidylinositol 4,5-bisphosphate (IP2) to the second messenger 1,4,5-trisphosphate (IP3). This leads to Inositol 1,4,5-trisphosphate receptor (IP3R) mediated release of Ca2+ from the endoplasmic reticulum (ER). Upon depletion of the ER Ca2+ store additional Ca2+ enters the cell through the CRAC Channel (ORAI1), further increasing the concentration of cytoplasmic Ca2+ which is bound by Calmodulin (CaM). Ca2+ dependent signaling causes dephosphorylation nuclear factor of activated T cells (NFAT) by Calcineurin and subsequently translocation into the nucleus and activation of NFAT promotors.
In the course of the COVID-19 pandemic and the search for therapeutic approaches, the BCR signaling pathway is increasingly being scrutinized. Epitopes of BCR as well as TCR change in the course of a COVID-19 infection and remain persistent even after the infection had subsided. Several loci are unique to COVID-19 infection indicating their SARS-CoV-2 specificity. Further understanding of B cell mechanisms has potential clinical utility in COVID-19 immunotherapies.
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