Pathway: Antigen activates B Cell Receptor (BCR) leading to generation of second messengers
Reactions in pathway: Antigen activates B Cell Receptor (BCR) leading to generation of second messengers :
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers
Mature B cells express IgM and IgD immunoglobulins which are complexed with Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) to form the B cell receptor (BCR) (Fu et al. 1974, Fu et al. 1975, Kunkel et al. 1975, Van Noesal et al. 1992, Sanchez et al. 1993, reviewed in Brezski and Monroe 2008). Binding of antigen to the immunoglobulin activates phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the cytoplasmic tails of Ig-alpha and Ig-beta by Src family tyrosine kinases, including LYN, FYN, and BLK (Nel et al. 1984, Yamanashi et al. 1991, Flaswinkel and Reth 1994, Saouaf et al. 1994, Hata et al. 1994, Saouaf et al. 1995, reviewed in Gauld and Cambier 2004, reviewed in Harwood and Batista 2010). The protein kinase SYK may also be involved in phosphorylating the ITAMs.
The protein kinase SYK binds the phosphorylated immunoreceptor tyrosine-activated motifs (ITAMs) on the cytoplasmic tails of Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) (Wienands et al. 1995, Rowley et al. 1995, Tsang et al. 2008). The binding causes the activation and autophosphorylation of SYK (Law et al. 1994, Irish et al. 2006, Baldock et al. 2008, Tsang et al. 2008, reviewed in Bradshaw 2010).
Activated SYK and other kinases phosphorylate BLNK (SLP-65, BASH) and BCAP. LYN and FYN phosphorylate CD19. Phosphorylated BLNK, BCAP, and CD19 serve as scaffolds which recruit effectors to the plasma membrane and assemble large complexes, the signalosomes. BCAP and CD19 recruit phosphoinositol 3-kinase (PI3K). BLNK recruits phospholipase C gamma (predominantly PLC-gamma2 in B cells, Coggeshall et al. 1992), NCK, BAM32, BTK, VAV1, and SHC. The effectors are phosphorylated by SYK and other kinases.
Phosphorylated BCAP recruits PI3K, which is phosphorylated by a SYK-dependent mechanism (Kuwahara et al. 1996) and produces phosphatidylinositol-3,4,5-trisphosphate (PIP3). Phosphorylated CD19 likewise recruits PIP3K. PIP3 recruits BAM32 (Marshall et al. 2000) and BTK (de Weers et al. 1994, Baba et al. 2001) to the plasma membrane via their PH domains. PIP3 also recruits and activates PLC-gamma1 and PLC-gamma2 (Bae et al. 1998). BTK binds phosphorylated BLNK via its SH2 domain (Baba et al. 2001). BTK phosphorylates PLC-gamma2 (Rodriguez et al. 2001), which activates phospholipase activity (Carter et al. 1991, Roifman and Wang 1992, Kim et al. 2004, Sekiya et al. 2004). Phosphorylated BLNK recruits PLC-gamma, VAV, GRB2, and NCK (Fu and Chan 1997, Fu et al. 1998, Chiu et al. 2002).
PLC-gamma hydrolyzes phosphatidylinositol-4,5-bisphosphate to yield inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (Carter et al. 1991, Kim et al. 2004). IP3 binds receptors on the endoplasmic reticulum and causes release of Ca2+ ions from the ER into the cytosol. The depletion of calcium from the ER in turn activates STIM1 to interact with ORAI and TRPC1 channels (and possibly other TRP channels) in the plasma membrane, resulting in an influx of extracellular calcium ions (Mori et al. 2002, Muik et al. 2008, Luik et al. 2008, Park et al. 2009).
The protein kinase SYK binds the phosphorylated immunoreceptor tyrosine-activated motifs (ITAMs) on the cytoplasmic tails of Ig-alpha (CD79A, MB-1) and Ig-beta (CD79B, B29) (Wienands et al. 1995, Rowley et al. 1995, Tsang et al. 2008). The binding causes the activation and autophosphorylation of SYK (Law et al. 1994, Irish et al. 2006, Baldock et al. 2008, Tsang et al. 2008, reviewed in Bradshaw 2010).
Activated SYK and other kinases phosphorylate BLNK (SLP-65, BASH) and BCAP. LYN and FYN phosphorylate CD19. Phosphorylated BLNK, BCAP, and CD19 serve as scaffolds which recruit effectors to the plasma membrane and assemble large complexes, the signalosomes. BCAP and CD19 recruit phosphoinositol 3-kinase (PI3K). BLNK recruits phospholipase C gamma (predominantly PLC-gamma2 in B cells, Coggeshall et al. 1992), NCK, BAM32, BTK, VAV1, and SHC. The effectors are phosphorylated by SYK and other kinases.
Phosphorylated BCAP recruits PI3K, which is phosphorylated by a SYK-dependent mechanism (Kuwahara et al. 1996) and produces phosphatidylinositol-3,4,5-trisphosphate (PIP3). Phosphorylated CD19 likewise recruits PIP3K. PIP3 recruits BAM32 (Marshall et al. 2000) and BTK (de Weers et al. 1994, Baba et al. 2001) to the plasma membrane via their PH domains. PIP3 also recruits and activates PLC-gamma1 and PLC-gamma2 (Bae et al. 1998). BTK binds phosphorylated BLNK via its SH2 domain (Baba et al. 2001). BTK phosphorylates PLC-gamma2 (Rodriguez et al. 2001), which activates phospholipase activity (Carter et al. 1991, Roifman and Wang 1992, Kim et al. 2004, Sekiya et al. 2004). Phosphorylated BLNK recruits PLC-gamma, VAV, GRB2, and NCK (Fu and Chan 1997, Fu et al. 1998, Chiu et al. 2002).
PLC-gamma hydrolyzes phosphatidylinositol-4,5-bisphosphate to yield inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (Carter et al. 1991, Kim et al. 2004). IP3 binds receptors on the endoplasmic reticulum and causes release of Ca2+ ions from the ER into the cytosol. The depletion of calcium from the ER in turn activates STIM1 to interact with ORAI and TRPC1 channels (and possibly other TRP channels) in the plasma membrane, resulting in an influx of extracellular calcium ions (Mori et al. 2002, Muik et al. 2008, Luik et al. 2008, Park et al. 2009).
Adaptive immunity refers to antigen-specific immune response efficiently involved in clearing the pathogens. The adaptive immune system is comprised of B and T lymphocytes that express receptors with remarkable diversity tailored to recognize aspects of particular pathogens or antigens. During infection, dendritic cells (DC) which act as sentinels in the peripheral tissues recognize and pick up the pathogen in the form of antigenic determinants and then process these antigens and present them to T cells. These T cells of appropriate specificity respond to the antigen, and either kill the pathogen directly or secrete cytokines that will stimulate B lymphocyte response. B cells provide humoral immunity by secreting antibodies specific for the pathogen or antigen.
Humans are exposed to millions of potential pathogens daily, through contact, ingestion, and inhalation. Our ability to avoid infection depends on the adaptive immune system and during the first critical hours and days of exposure to a new pathogen, our innate immune system.