5. Normal mature B-cell activation and signaling mechanisms

Antigen binding to mIg induces the BCR aggregation, which leads to the rapid transmembrane disulfide-linked heterodimer phosphoprotein Igα (CD79a)/Igβ (CD79b) ITAM phosphorylation through recruitment of Syk and SFKs (Fyn, Lyn). This process begins with the formation of a "signalosome" [57]. The signalosome activation leads to three main pathways [58], including Btk, PLC-γ2, and PI3K. BCR can transactivate the B-cell co-receptor CD19, which forms, on B-cell surface, a tetrameric co-receptor complex with CD21 and CD81 (target of anti-proliferative antibody 1 (TAPA-1), a tetraspanin family member tetraspanin 1 (Tspan1, NET-1), and Leu13 (CD225)) [59]. CD19 can also be BCR-independently activated but lacks intrinsic or associated tyrosine kinase activity [60]. As CD19 has a long cytoplasmic domain, it binds and amplifies the function of the SFKs and recruits a heterodimer p85/p110 class IA PI3K concurrently, which phosphorylates a membrane phospholipid, PIP2, leading to the production of a second messenger PIP3 [61], as well as promoting Btk and Akt, and a serine/threonine, kinase phosphorylation in B-cell [62] (Figure 7).

#### Figure 8.

Main types of diseases related to B-cell abnormalities. AID, activation-induced cytidine deaminase; Btk, Bruton's tyrosine kinase; HIGM1, X-linked hyper-IgM syndrome type 1; CD40L, CD40 ligand (CD154); CSR, class switch recombination; GCs, germinal centers; Ig H, immunoglobulin heavy chain; BAFF, B-cell activating factor also known as B-lymphocyte stimulator (BLyS) or tumor necrosis factor (TNF) ligand superfamily member 13B (TNF-like molecule BAFF); BCL-2, B-cell lymphoma 2; EBV, Epstein–barr virus; CVID, common variable immunodeficiency; IVIg, intravenous immunoglobulin; SCID, severe combined immunodeficiency; SHM, somatic hypermutation; SLOs, secondary lymphoid organs; TACI, transmembrane activator and calcium modulator and cytophilin ligand interactor; XLA, X-linked agammaglobulinemia (Bruton's agammaglobulinemia); HIGM2, hyper-IgM syndrome type 2 (autosomal recessive).
