ZAP-70

Zeta-chain associated protein kinase 70 kDa (ZAP-70) deficiency is one of the rare immunodeficiency disorders due to autosomal recessive homozygous or compound heterozygous loss-of-function mutations in the ZAP-70 GENE In the literature, patients with ZAP-70 deficiency have been reported with a broad spectrum of clinical manifestations including recurrent respiratory infections (81.8%), cutaneous involvement (57.9%), lymphoproliferation (32.4%), autoimmunity (19.4%), enteropathy (18.4%) and increased risk of malignancies (8...

UBASH3A and UBASH3B are protein families of atypical protein tyrosine phosphatases that function as regulators of various cellular processes during mammalian development. As UBASH3A has only mild phosphatase activity, its regulatory effects are based on the phosphatase-independent mechanisms. On the contrary, UBASH3B has strong phosphatase activity, and the suppression of its receptor signalling is mediated by Syk and Zap-70 kinases. The regulatory functions of UBASH3A and UBASH3B are particularly evident in the lymphoid tissues and kidney development...

Zeta-chain associated protein kinase 70 kDa (ZAP70) combined immunodeficiency (CID) is an autosomal recessive severe immunodeficiency that is characterized by abnormal T-cell receptor signaling. Children with the disorder typically present during the first year of life with diarrhea, failure to thrive, and recurrent bacterial, viral, or opportunistic infections. To date, the only potential cure is hematopoietic stem cell transplant (HSCT). The majority of described mutations causing disease occur in the homozygous state, though heterozygotes are reported without a clear understanding as to how the individual mutations interact to cause disease...

Expression of ZAP-70 in a subset of CLL patients positively correlates with the absence of IGHV mutations and is indicative of a more active disease and shorter treatment free survival. We recently demonstrated that ZAP-70 regulates the constitutive expression of CCL3 and CCL4, activation of AKT and expression of MYC in the absence of an overt BCR signal, bona fide functions of BCR activation. We here provide evidence that these features relate to the presence of a constitutive tonic BCR signal, exclusively found in IGHV unmutated CLL and dependent on the ZAP-70 mediated activation of AKT and its downstream target GSK3b...

CD4+ T-cell counts are increased and activated in patients with chronic heart failure (CHF), whereas regulatory T-cell (Treg) expansion is inhibited, probably due to aberrant T-cell receptor (TCR) signaling. TCR signaling is affected by protein tyrosine phosphatase nonreceptor type 22 (PTPN22) in autoimmune disorders, but whether PTPN22 influences TCR signaling in CHF remains unclear. This observational case-control study included 45 patients with CHF [18 patients with ischemic heart failure versus 27 patients with nonischemic heart failure (NIHF)] and 16 non-CHF controls...

CONTEXT: ZAP-70 (zeta-chain-associated protein of 70 kDa), serving as a critical regulator for T cell antigen receptor signaling, represents an attractive therapeutic target for autoimmunity disease. How the mechanistical mechanism of ZAP-70 to a human autoimmune syndrome-associated R192W mutation remains unclear. The results indicated that the R192W mutation of ZAP-70 clearly affected the conformational flexibility of the N-terminal ITAM-Y2P. Structural analysis unveiled that the R192W mutation of ZAP-70 caused the exposure of the N-terminal ITAM-Y2P to the solvent...

Nitrogen from ammonia is one of the most common pollutants toxics to aquatic species in aquatic environment. The intestinal mucosa is one of the key mucosal defenses of aquatic species, and the accumulation of ammonia nitrogen in water environment will cause irreversible damage to intestinal function. In this study, histology, immunohistochemistry, ultrastructural pathology, enzyme activity analysis and qRT-PCR were performed to reveal the toxic effect of ammonia nitrogen stress on the intestine of Pelteobagrus fulvidraco ...

Specific antigen recognition is one of the immune system's features that allows it to mount intense yet controlled responses to an infinity of potential threats. T cells play a relevant role in the host defense and the clearance of pathogens by means of the specific recognition of peptide antigens presented by antigen-presenting cells (APCs), and, to do so, they are equipped with a clonally distributed antigen receptor called the T-cell receptor (TCR). Upon the specific engagement of the TCR, multiple intracellular signals are triggered, which lead to the activation, proliferation and differentiation of T lymphocytes into effector cells...

Immunologists have activated T cells in vitro using various stimulation methods, including phorbol myristate acetate (PMA)/ionomycin and αCD3/αCD28 agonistic antibodies. PMA stimulates protein kinase C, activating nuclear factor-κB, and ionomycin increases intracellular calcium levels, resulting in activation of nuclear factor of activated T cell. In contrast, αCD3/αCD28 agonistic antibodies activate T cells through ZAP-70, which phosphorylates linker for activation of T cell and SH2-domain-containing leukocyte protein of 76 kD...

The immune synapse, a highly organized structure formed at the interface between T lymphocytes and antigen-presenting cells (APCs), is essential for T cell activation and the adaptive immune response. It has been shown that this interface shares similarities with the primary cilium, a sensory organelle in eukaryotic cells, although the roles of ciliary proteins on the immune synapse remain elusive. Here, we find that inositol polyphosphate-5-phosphatase E (INPP5E), a cilium-enriched protein responsible for regulating phosphoinositide localization, is enriched at the immune synapse in Jurkat T-cells during superantigen-mediated conjugation or antibody-mediated crosslinking of TCR complexes, and forms a complex with CD3ζ, ZAP-70, and Lck...

Ligation of retinoic acid receptor alpha (RARα) by RA promotes varied transcriptional programs associated with immune activation and tolerance, but genetic deletion approaches suggest the impact of RARα on TCR signaling. Here, we examined whether RARα would exert roles beyond transcriptional regulation. Specific deletion of the nuclear isoform of RARα revealed an RARα isoform in the cytoplasm of T cells. Extranuclear RARα was rapidly phosphorylated upon TCR stimulation and recruited to the TCR signalosome...

Psoriasis is a chronic inflammatory skin disease closely related with T cells, and its management remains a challenge. Novel targets and associated drugs are urgently needed. Zeta-chain-associated protein kinase 70 kDa (ZAP-70) has been recognized as a potential target for treating autoimmune diseases due to its crucial role in T cell receptor signaling. In our previous work, we identified a potent and selective covalent ZAP-70 inhibitor with anti-inflammatory activity in vitro . Herein, we report the structural optimization of covalent ZAP-70 inhibitors...

Zeta chain-associated protein kinase 70 (ZAP-70) is a non-receptor tyrosine kinase that interacts with the activated T-cell receptor to transduce downstream signals, and thus plays an important role in the adaptive immune system. The biphosphorylated immunotyrosine-based activation motifs (ITAM-Y2P) binds to the N-SH2 and C-SH2 domains of ZAP-70 to promote the activation of ZAP-70. The present study explores molecular mechanisms of allosteric inactivation of ZAP-70 induced by the hot spot W165C mutation through atomically detailed molecular dynamics simulation approaches...

Chronic lymphocytic leukemia (CLL) is a malignant blood disorder in which there is an excess of white blood cells (lymphocytes) in blood and lymphoid tissues. CLL patients experience different clinical behaviors with diversity in disease course and outcome. Accordingly, prognostic markers are crucial for employing appropriate therapy protocols. CD163 (cluster of differentiation 163) is a monocyte/macrophage receptor. Soluble CD163 (sCD163) is an emerging prognostic player in the field of hematopoietic neoplasms...

Introduction: Sjögren's syndrome (SS) is a chronic autoimmune disorder characterized by exocrine gland dysfunction, leading to loss of salivary function. Histological analysis of salivary glands from SS patients reveals a high infiltration of immune cells, particularly activated CD4+ T cells. Thus, interventions targeting abnormal activation of CD4+ T cells may provide promising therapeutic strategies for SS. Here, we demonstrate that Hect, uba, and wwe domain containing 1 (HUWE1), a member of the eukaryotic Hect E3 ubiquitin ligase family, plays a critical role in CD4+ T-cell activation and SS pathophysiology...

INTRODUCTION: ZAP-70, a protein tyrosine kinase recruited to the T cell receptor (TCR), initiates a TCR signaling cascade upon antigen stimulation. Mutations in the ZAP70 gene cause a combined immunodeficiency characterized by low or absent CD8+ T cells and nonfunctional CD4+ T cells. Most deleterious missense ZAP70 mutations in patients are located in the kinase domain but the impact of mutations in the SH2 domains, regulating ZAP-70 recruitment to the TCR, are not well understood. METHODS: Genetic analyses were performed on four patients with CD8 lymphopenia and a high resolution melting screening for ZAP70 mutations was developed...

The two members of the UBASH3/STS/TULA protein family have been shown to critically regulate key biological functions, including immunity and hemostasis, in mammalian biological systems. Negative regulation of signaling through immune receptor tyrosine-based activation motif (ITAM)- and hemITAM-bearing receptors mediated by Syk-family protein tyrosine kinases appears to be a major molecular mechanism of the down-regulatory effect of TULA-family proteins, which possess protein tyrosine phosphatase (PTP) activity...

Zeta(ζ)-Chain Associated Protein Kinase 70 kDa (ZAP-70) deficiency is a rare autosomal recessive primary immunodeficiency disease. Little is known about this disease. In this study, we report two patients to extend the range of clinical phenotypes and immunophenotypes associated with ZAP-70 mutations. We describe the clinical, genetic, and immunological phenotypes of two patients with ZAP-70 deficiency in China, and the data are also compared with the literature. Case 1 presented with leaky severe combined immunodeficiency with low to the absence of CD8 + T cells, while case 2 suffered from a recurrent respiratory infection and had a past medical history of non-EBV-associated Hodgkin's lymphoma...

BACKGROUND: Chronic lymphocytic leukemia (CLL) is prognosticated using the Rai and the Binet's staging. In the past few years, new parameters have been considered for prognostication. One such marker that has been a subject of speculation and found useful by some western studies is zeta-associated protein 70 (ZAP-70). AIM: To investigate the prevalence of ZAP-70 and find out its association with other prognostic markers like Rai and Binet's stage and CD38 in Indian CLL patients...

INTRODUCTION: Both microenvironmental signals from surrounding cells and changes in the genome of leukemic cells play essential role in the development of chronic lymphocytic leukemia. Nurse like cells (NLCs) are one of the important elements of the microenvironment of CLL cells. The key role in the interactions of leukemic cells with NLCs is played by chemokines, which may interfere with the programmed cell death process in the leukemic lymphocytes. The aim of our study was analysis of selected microenvironmental factors having potential impact on the leukemic cells survival, as well as their association with clinical, cytogenetic and molecular parameters...