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Basics of Allergy
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Rafeul Alam, Dipa K Sheth, Magdalena M Gorska
Mature DC present antigenic epitopes to a specific T cell through the formation of the ‘immunological synapse’ (Dustin 2002). TCR and co-stimulatory molecules (e.g., CD4/CD8, CD28) engage with their counter ligands on APCs in the immunological synapse. The TCR is associated with the CD3 complex (composed of a, b, g, d, e and two z subunits). Proper assembly of this receptor complex is important for TCR signaling. The lack of the CD3g subunit causes severe immunodeficiency whereas that of the CD3e subunit induces a milder form of immunodeficiency. The binding of the TCR to the peptide-MHC complex results in the activation of CD4- and CD3-associated tyrosine kinases—Lck: lymphocyte specific kinase and Src: Rouse sarcoma. These kinases phosphorylate CD3-associated z chains at ITAM (immunoreceptor tyrosine-based activation motif) sites, which allow docking of multiple signaling molecules and transduction of signals through downstream pathways (Hermiston et al. 2002).
Immune Reconstitution after Hematopoietic Stem Cell Transplantation
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Andreas Thiel, Tobias Alexander, Christian A. Schmidt, Falk Hiepe, Renate Arnold, Andreas Radbruch, Larissa Verda, Richard K. Burt
Numerous membrane protein kinases are crucial for TCR signaling. After T cell activation, tyrosine kinases such as Lck (lymphocyte specific tyrosine kinase), fyn (a novel kinase with homology to viral oncogenes V-Fgr and V-yes, and is thus termed fyn for Fgr yes novel protein), and Zap-70 (zeta chain associated protein-70) phosphorylate the immunoreceptor tyrosine based activation motifs (ITAM) on the γ, δ, ε, ζ CD3 chains initiating signal transduction (Fig. 1).8-9,104 Aged T cells have been reported to have altered distribution of kinases such as pp56lck and protein kinase C (PKC) compared to T cells from young individuals.105 Whether these changes are due to differences in protein kinases between memory cells and naïve T cells, or are related to T cell longevity independent of phenotype, remains unclear.9,106-108
Immunoglobulins: Metabolism and biological properties
Published in Gabriel Virella, Medical Immunology, 2019
A significant property of Fcγ receptors is their ability to deliver activating signals to the cells where they are inserted. Activation is mediated by immunoreceptor tyrosine-based activation motifs (ITAMs) located either in the α-polypeptide chain (FcγRIIa) or in one or both of the associated chains (γ and β). The activation of ITAMs requires cross-linking of Fc receptors by Ag-Ab complexes containing at least two antibody molecules.
CLEC5a-directed bispecific antibody for effective cellular phagocytosis
Published in mAbs, 2022
Vivekananda Kedage, Diego Ellerman, Mingjian Fei, Wei-Ching Liang, Gu Zhang, Eric Cheng, Juan Zhang, Yongmei Chen, Haochu Huang, Wyne P. Lee, Yan Wu, Minhong Yan
CLEC5A (C-type Lectin Domain Containing 5A, also known as myeloid DAP12-associating lectin (MDL-1)) is a type II transmembrane protein that is expressed by monocytes, macrophages and neutrophils.7,8 It is associated with the immunoreceptor tyrosine-based activation motif (ITAM)- or YINM motif-containing adaptor proteins DAP12 and DAP10, respectively.9,10 CLEC5A has not been demonstrated to induce phagocytosis, but other receptors, such as TREM2, that are associated with ITAM-containing proteins like DAP12 have been shown to induce phagocytosis.11 Therefore, we hypothesized that CLEC5A could be harnessed to enhance phagocytosis through a bispecific antibody approach. Here, we show that CLEC5A agonized by bispecific antibodies can mediate phagocytosis in vitro as effectively as FcγRs. Moreover, we show that CLEC5A-directed bispecific antibodies were effective in inhibiting tumor growth in mouse tumor models.
The ubiquitous role of spleen tyrosine kinase (Syk) in gut diseases: From mucosal immunity to targeted therapy
Published in International Reviews of Immunology, 2022
Wenbin Gong, Peizhao Liu, Tao Zheng, Xiuwen Wu, Yun Zhao, Jianan Ren
The Syk protein comprises a pair of Src homology 2 (SH2) domains at the N terminus and a C-terminal kinase domain (Figure 1A). The SH2 domains are joined by interdomain A and separated by a longer interdomain B from the catalytic domain [1,6]. In resting condition, Syk shows a closed structure of self-suppression, with interdomain A and interdomain B binding to the kinase domain to form a linker-kinase sandwich to prevent interaction with the potential substrates (Figure 1B) [7]. Activation of Syk leads to an open conformational change, which makes the exposed catalytic kinase domain interact with downstream targets. Due to the catalytic activity and the ability to bind other proteins via SH2 domains, Syk has the properties of both kinase and adaptor protein. The essential step for Syk activation is its binding through SH2 domains to the signaling proteins containing phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) in the cytoplasmic regions [6]. Upon ligand binding, Syk is recruited to the dually phosphorylated ITAMs of the transmembrane adaptor molecule or the receptor chain itself, and then activated to modulate downstream signaling (Figure 1C) [6,7].
Targeting platelet inhibition receptors for novel therapies: PECAM-1 and G6b-B
Published in Platelets, 2021
Eva M Soriano Jerez, Jonathan M Gibbins, Craig E Hughes
The immunoreceptor tyrosine-based inhibition motif (ITIM) comprises a conserved sequence of amino acids that were initially identified in the cytoplasmic tails of selected receptors on the surface of immune cells [1]. The ITIM consensus sequence (L/I/V/S)xYxx(L/V) (single letter abbreviation where x can denote any amino acid) [1,2] is commonly found in pairs separated by 15 to 30 amino acid residues. ITIMs were named due to their role opposing the activity of immunoreceptor tyrosine-based activation motif (ITAM) bearing receptors in immune cell function [3,4]. The ITAM consensus sequence (YxxL/Ix6-12YxxL/I) is distinct from the ITIM most notably for being a dual tyrosine containing sequence [5,6]. However, in more recent years, a related motif, the hemITAM, has also been described (consensus sequence DEDGYxxL) [7].