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Mucosal manifestations of immunodeficiencies
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Scott Snapper, Jodie Ouahed, Luigi D. Notarangelo
X-linked agammaglobulinemia (XLA) results from mutations of the Bruton's tyrosine kinase (BTK) gene. BTK is located on the X chromosome and regulates signaling through the pre-B-cell receptor (pre-BCR) and the BCR. BTK deficiency results in a block at the pro-B to pre-B cell stage in B-cell differentiation in the bone marrow. Accordingly, patients with XLA have a severe reduction or absence of circulating B cells, associated with profound deficiency of all immunoglobulin isotypes. A similar phenotype can also be observed in patients with autosomal recessive forms of agammaglobulinemia, due to mutations of the mu (μ) heavy-chain gene; of the Igα, Igβ, and V pre-B components of the pre-BCR; or of the adaptor molecule B-cell linker protein, which is also involved in pre-BCR-mediated signaling.
Transcriptional regulation of B cell class-switch recombination: the role in development of noninfectious complications
Published in Expert Review of Clinical Immunology, 2022
Stelios Vlachiotis, Hassan Abolhassani
Upon receiving stronger BCR signaling, intermediate T cell help (via T follicular helper cells or Tfh) can be achieved due to better affinity maturation. Stronger BCR activity of a GC B cell stimulates B cell linker protein (BLNK) and suppresses phosphatase and tensin homolog (PTEN) that can intensify the phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathways. mTOR can subsequently activate forkhead box O1 (FOXO1) that increases CXCR4 expression mediating migration toward the dark zone of the GC. Improved induction of T cell stimulation can also activate the non-canonical NF-κB pathway molecules that are important for controlling of the cell cycle and epigenetic regulators (mainly with the expression of MYC). However, since this signal is not optimal, it cannot reverse the negative impact of PI3K/AKT/mTOR on BCL-6 expression and BACH2 that again fails to produce plasma cells. In fact, these cells can migrate to the dark zone for another round of somatic hypermutation since they have a high level of FOXO1 and NF-κB signals that activate AID targeting the VDJ regions during rapid B cell proliferation. After generation of a better-fitted antibody with improved avidity, they can return to the LZ and continue the process of CSR via the residual AID expression targeting the S-regions [19,23,24].
Duvelisib for the treatment of chronic lymphocytic leukemia
Published in Expert Opinion on Pharmacotherapy, 2020
Anna Maria Frustaci, Alessandra Tedeschi, Marina Deodato, Giulia Zamprogna, Roberto Cairoli, Marco Montillo
B cells receptor (BCR) signaling pathway is critical for the regulation of B-lymphocytes proliferation, survival and apoptosis and can be activated by both constitutive, antigen-independent and antigen-dependent signals. Through BCR surface immunoglobulins- antigen binding, immunoreceptor tyrosine-based activation mofits (ITAMs) phosphorylation leads to SYC activation and BCR signal transduction operated through the B-cell linker proteins and the downstream signaling BTK and PLCγ2 (phospholipase C gamma 2). PI3 k is recruited by LYN tyrosine kinase-dependent phosphorylation of the cytoplasmatic CD19 domain and its activation, together with BTK, induces several downstream kinases such as protein kinase B (Akt), mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) leading to B-cells apoptosis, transcription, proliferation, and migration [5–7].
Novel insights into the pathogenesis of molecular subtypes of diffuse large B-cell lymphoma and their clinical implications
Published in Expert Review of Clinical Pharmacology, 2019
In C5 (MCD) ABC DLBCLs, genetic alterations of components of the BCR signal cascade can be identified as a source of constitutive NF-кB-signaling (Figure 1). BCRs typically form immobile clusters in ABC lymphomas [29]. The BCR is associated with CD79A and CD79B [30]. Upon antigen stimulation, SRC-family kinases (SFK) phosphorylate the immunoreceptor tyrosine-based activation motifs (ITAM) of CD79A/B and the kinase SYK can be recruited [31,32]. The downstream activation of phosphoinositide 3-kinases (PI3K) will be further described below. Bruton’s tyrosine kinase (BTK), B-cell linker protein and phospholipase Cγ2 (PLCγ2) are located to the plasma membrane [33]. PLCγ2 creates inositol-1,4,5-trisphophate (IP3) and diacylglycerol (DAG) whereas DAG activates protein kinase Cβ (PKCβ) finally leading to the assembly of the so called CBM-complex at the plasma membrane consisting of CARD11, BCL10, and MALT1 [34,35]. The CBM-complex activates the NF-κB pathway via IKK.