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Monocyte and lymphocyte membrane markers: Ontogeny and clinical significance
Published in Gabriel Virella, Medical Immunology, 2019
Scott Sugden, Damien Montamat-Sicotte, Karen K. Yam, Joseph Murphy, Bader Yassine Diab, Virginia Litwin
The productively rearranged β chain will be present in the cytoplasm for several days prior to TCRα gene rearrangement. During that period, the β chain will associate with a protective polypeptide, known as the pre-Tα. When the β chain/pre-Tα associates with CD3 molecules and is transported to the cell membrane, the pre-TCR is formed. CD3 is a complex of five unique subunits designated γ, δ, ε, ζ, and η (note that the γ and δ chains of the CD3 unit are distinct from the γδ chains of the TCR1). The CD3γδε trimolecular complex is synthesized first and remains intracytoplasmic, where it becomes associated with pre-Tα molecules. Soon thereafter, the CD3ζ chains are synthesized and become associated to the CD3 complex. Once the ζ chain has been added to the CD3 molecule, the whole CD3-pre-Tα complex is transported from the Golgi apparatus to the cell membrane. A critical characteristic of the ζ chain is its long intracytoplasmic tail, which has affinity for the ζ-associated protein kinase (ZAP70). The association of ZAP70 to the ζ chain is critical for further differentiation of the T cell. The congenital absence of ZAP70 is associated with a block at the DN stage of T cell development.
Gene Expression Profiling to Detect New Treatment Targets in Leukemia and Lymphoma: A Future Perspective
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Torsten Haferlach, Wolfgang Kern, Alexander Kohlmann
One highlight to establish the use of gene expression profiling to define new targets in leukemia was the detection of ZAP70 to be expressed in a large proportion of chronic lymphocytic leukemia (CLL) (14). As the expression of ZAP70 was high in IgVH-unmutated cases of CLL, this gene was further correlated to distinction within CLL cases with respect to prognosis. This finding also led to the investigation of the ZAP70 antigen expression by antibodies in CLL using multiparameter immunophenotyping (44). Recently, it was demonstrated that ZAP70 can also be successfully screened by a quantitative RT-PCR method (45). After definition of CLL signature genes, the protein products of these genes may represent such new targets for monoclonal antibodies or for vaccine approaches. Another aspect detected in this investigation was the fact that B-cell activation genes were upregulated in Ig-unmutated patients. Thus, pathways downstream of the B-cell receptor may contribute to aggressive clinical cases. It may be beneficial to target these signaling pathways.
Case 10
Published in Atul B. Mehta, Keith Gomez, Clinical Haematology, 2017
Flow cytometry will demonstrate that the cells in classic CLL are positive for the T-cell marker cluster of differentiation 5 (CD5) and the mature B-cell markers CD19, 20 and 23. FMC7 is negative on classic CLL but typically positive when the condition has transformed; CD5 may also become negative. In classic CLL, expression of the protein kinase ZAP-70 and of CD38 are both more common in cases which are germ line (unmutated) at the immunoglobulin heavy chain (IgH) locus and all these features are associated with a worse prognosis. Chromosome and fluorescence in situ hybridization (FISH) analysis will give useful prognostic information – for example, deletion of p53 is often seen in advanced CLL whereas 13q deletions are associated with a good prognosis.
Platelets after burn injury – hemostasis and beyond
Published in Platelets, 2022
B. Z. Johnson, A. W. Stevenson, L. W. Barrett, M. W Fear, F. M. Wood, M. D. Linden
CD4 + T-regulatory cells (Tregs) play a crucial role in controlling inflammatory responses, limiting the extent of tissue damage. A mouse model of 25% TBSA (severe) injury with or without depletion of Tregs or platelets has been used to investigate in vivo platelet–Treg interactions [100]. The authors noted a “biologically significant” increase in zeta-chain-associated protein kinase 70 (ZAP-70) and protein kinase C-theta (PKC-θ) in lymph node Tregs 2 h following burn injury, which was decreased in the platelet-depleted model. Increased activation was not seen in splenic Tregs, however in the platelet-depleted model ZAP-70 and PKC-θ expression was again lower. ZAP-70 is necessary for T-cell receptor (TCR) signaling, and therefore required for functional T-cell responses. Conversely, evidence suggests PKC-θ is dispensable for Treg function, and potentially negatively regulates suppressive capacity; however, it seems to play a role in Treg differentiation and development [101].
Clinical and Mutation Description of the First Iranian Cohort of Infantile Inflammatory Bowel Disease: The Iranian Primary Immunodeficiency Registry (IPIDR)
Published in Immunological Investigations, 2021
Farzaneh Rahmani, Elham Rayzan, Mohammad Reza Rahmani, Sepideh Shahkarami, Samaneh Zoghi, Arezoo Rezaei, Zahra Aryan, Mehri Najafi, Meino Rohlfs, Tim Jeske, Majid Aflatoonian, Zahra Chavoshzadeh, Fatemeh Farahmand, Farzaneh Motamed, Pejman Rohani, Hossein Alimadadi, Alireza Mahdaviani, Mahboubeh Mansouri, Marzieh Tavakol, Mirjam Vanderberg, Daniel Kotlarz, Christoph Klein, Nima Rezaei
The product of ZAP70 gene, ZAP-70, is essential for T cell receptor (TCR) signal transduction and is expressed predominantly on natural killer cells and T cell (Chan et al. 2016). ZAP-70 deficiency is characterized by the absence of CD8 + T cells in the periphery, defective TCR signalling in CD4+ cells, and defective T cell tolerance induction, the latter being cited for autoimmune manifestations in these patients (Liu et al. 2017). Importantly, the presence of IBD in patients with ZAP70 mutation is associated with a leaky SCID phenotype with residual CD4 + T cell activity (Liu et al. 2017). Single nucleotide variants of ZAP70 have been found to affect IBD risk in some populations (Bouzid et al. 2013). Our patient had low CD8+ counts, recurrent thrush and a CD phenotype and unfortunately died due to complications of candidemia at 14 months old.
Cordycepin exhibits a suppressive effect on T cells through inhibiting TCR signaling cascade in CFA-induced inflammation mice model
Published in Immunopharmacology and Immunotoxicology, 2020
Xiaoli Wang, Deshuang Xi, Jian Mo, Ke Wang, Yu Luo, Erbin Xia, Rong Huang, Shunrong Luo, Jiao Wei, Zhenghua Ren, Hui Pang, Rirong Yang
T cell receptor (TCR) signaling cascade is composed by a series of molecules, such as LCK, ZAP70, LAT, and PLCγ1 [9]. When TCR signaling is stimulated, three downstream signaling pathways, including the nuclear factor of activated T cells (NFAT), the mitogen-activated protein kinase (MAPK) kinase, and the nuclear factor-κB (NF-κB) signaling pathways, could be activated, leading to T cell activation, proliferation, and/or cytokines production [9–11]. When TCR signal is triggered, the SRC family kinase (SFK) members LCK (also known as p56-LCK) is firstly recruited to the TCR-CD3 complex to phosphorylate the immunoreceptor tyrosine-based activation motif (ITAM) of TCR associated CD3ζ-chain residues [9–11]. Elevated CD3ζ phosphorylation is functionally connected to the recruitment of ZAP70 (ζ-chain associated protein kinase of 70 kDa), which is also phosphorylated by LCK [9–11]. Then, activated ZAP70 can induce LAT (linker for activation of T cells) phosphorylation. Phosphorylated LAT recruits adaptors or signaling molecules to form a multiprotein complex named LAT signalosome [9–11]. Phospholipase Cγ1 (PLCγ1) is a key member of LAT signalosome. When PLCγ1 is recruited to LAT signalosome and phosphorylated, it mainly activates NFAT and MAPK pathways for T cell activation and proliferation [9–11].