Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Severe combined immunodeficiencies (SCID) represent an heterogeneous group of diseases characterized by a profound defect in either T cell differentiation or function. The molecular nature of the defect has so far been defined for a small number of SCID, i.e. purin metabolism enzyme deficiencies. Progress has however been made in either gene localization (i.e. X-linked SCID--characterized by an isolated blockade of T-cell differentiation) or in determining mechanisms underlying SCID (i.e. abnormal T cell receptor and immunoglobulin gene rearrangements in alymphocytosis, defective signal transduction in some atypical SCID with non functional T cells or membrane abnormalities such as low expression of the T cell receptor/CD3 complex or defective expression of MHC Class II molecules). Significant improvement in the therapy of SCIDs has been made in the last 10 years leading to cure of at least 3/4 patients with SCID by either HLA identical or non identical bone marrow transplantation. Alternative therapy has been proposed for adenosine deaminase (ADA) deficiency enzyme substitution by polyethylene glycol-ADA. The prospect of gene therapy for this disease and potentially for other types SCIDs is forthcoming.
...
PMID:Severe combined immunodeficiencies. 155

We have studied an 8-yr-old male patient with adenosine deaminase-positive severe combined immunodeficiency disease with a normal number of peripheral CD3+, T cell receptor-alpha beta+ T cells. The majority of these T cells expressed the CD8 molecule and were oligoclonal in nature as proven by Southern blot analysis of the T cell receptor genes. T cells failed to proliferate in vitro either upon stimulation with T cell mitogens or when stimulated with a combination of the phorbol ester phorbol myristate acetate and the Ca-ionophore ionomycin. High doses of recombinant IL-2, when added to in vitro cultures, were able to restore proliferation induced by phorbol myristate acetate and ionomycin but the response to concanavalin A remained severely defective. However, activation of the patient's T cells with phytohemagglutinin or concanavalin A induced an increase of free cytoplasmic Ca++, which was 2- to 5-fold higher than in normal CD8+ T cells. Furthermore, phorbol myristate acetate or phytohemagglutinin induced the translocation of protein kinase C from cytosol to plasma membrane. Analysis of membrane phospholipid composition of the patient's T cells disclosed that the ratio of phosphatidylcholine to phosphatidylserine was 5-fold higher than in normal T cells. The abnormal Ca++ response after activation with T cell mitogens as well as the high phosphatidylcholine/phosphatidylserine ratio may be causally linked to the defective in vitro T cell proliferation. Because the capacity of T lymphocytes to produce or respond to IL-2 may vary, the oligoclonality of the T cells of the patient should be considered as well in the explanation of defective cell proliferation.
...
PMID:Abnormal signal transduction in a patient with severe combined immunodeficiency disease. 190 23

We performed limiting dilution culture of T cells from a patient affected by primary immunodeficiency as a result of complete lack of adenosine deaminase (ADA) activity and also affected by insulin-dependent diabetes mellitus (type I diabetes). Despite the occurrence of immunodeficiency, we were able to raise and grow T cell clones derived from this patient in long-term culture. These T cells displayed ADA enzymatic activity and produced interleukin-2 after engagement of their T cell receptor (TCR)/CD3 complex. We analyzed the TCR repertoire of such clones by nucleotide sequencing of TCR beta chains. The results show that the T cell clones express different V beta but similar J regions. However, the CDR3 regions which are implicated in antigen recognition were found to be heterogeneous.
...
PMID:Long-term culture and T cell receptor analysis of T cell clones isolated from a patient with adenosine deaminase deficiency and type I diabetes. 795 66

CD26 and ecto-adenosine deaminase (ADA) are found associated on the plasma membrane of T lymphocytes and each possess distinct catalytic activities. CD26 has a proteolytic activity identical to dipeptidylpeptidase IV (DPPIV; E.C. 3.4.14.5), and ecto-ADA (E.C. 3.5.4.4) degrades extracellular adenosine. The cell surface expression of CD26 and ecto-adenosine deaminase (ecto-ADA) is regulated on stimulated T lymphocytes, and ADA binding to CD26 produces a synergistic costimulatory response with T cell receptor activation. This study addresses the potential regulation by allosteric interactions of the catalytic activities of CD26 associated with ecto-ADA, which could define the mechanism of the synergism observed in T cell signaling. Cell lines genetically deficient in ADA, ligands for ADA such as adenosine, and a specific inhibitor of ADA, deoxycoformycin, were used to define the effect of ADA activity on CD26 DPPIV activity and affinity for dipeptide substrate. Conversely, a recombinant Chinese hamster ovary cell line expressing human CD26 with or without a mutation in the DPPIV catalytic domain, and the boronic acid inhibitor Val-boroPro, were used to determine the effect of DPPIV activity on ecto-ADA activity and association with CD26. These studies found no significant allosteric interaction between the catalytic activities of CD26 and ecto-ADA when associated. Therefore, signaling events in T cells involving costimulation with CD26 and ecto-ADA and the synergism observed upon ADA binding to CD26 occur independently of the catalytic activities of these cell surface molecules.
...
PMID:Effect of deoxycoformycin and Val-boroPro on the associated catalytic activities of lymphocyte CD26 and ecto-adenosine deaminase. 898 39

Accumulation of extracellular and intracellular adenosine (Ado) under hypoxic conditions or in the absence of adenosine deaminase results in lymphocyte depletion and in severe combined immunodeficiency, which are currently explained by direct intracellular lymphotoxicity of Ado metabolites. In support of the alternative, "signaling" mechanism, we show that extracellular Ado (extAdo) suppresses all tested T cell receptor (TCR)-triggered effector functions of T lymphocytes including the TCR-triggered FasL mRNA up-regulation in cytotoxic T lymphocytes. Strong evidence against the intracellular lymphotoxicity of Ado (and in support of the signaling model) is provided by abrogation of TCR-triggered growth inhibition in Ado-exposed T cells. The brief exposure to Ado was sufficient to observe inhibition of TCR-triggered effector functions. The "memory" of T cells to exposure to extAdo is best explained by sustained increases in cAMP. Selective agonist (CGS21680) and antagonist (ZM241385) of A2A adenosine receptor were used in functional assays and cDNA probes for different sybtypes of adenosine receptors were used in Northern blot studies. A2A receptors are identified as the predominantly expressed subtype of Gs-coupled Ado receptors in T cells. The demonstration of cross-talk between the A2A receptors and TCR in both directions support the possible role of A2A receptors in mechanisms of extAdo-mediated immunosuppression in vivo under adenosine deaminase deficiency and hypoxic conditions in, e.g., solid tumors.
...
PMID:Memory of extracellular adenosine A2A purinergic receptor-mediated signaling in murine T cells. 932 20

T cells are important effector cells in natural antiviral and anticancer immunity. It is important to reveal the cellular and molecular requirements for T cell differentiation and effector functions. We explored the idea that the final outcome of antigen receptor-driven immune processes is at least partially determined by physiologically abundant small signaling molecules in extracellular environment of lymphocytes in different tissues. Extracellular purines (ATP and adenosine) and their (purinergic) receptors were studied as an example of such molecules. Studies of functional effects of extracellular ATP and adenosine in immunoregulation have evolved in studies of individual molecules of purinergic receptors and of phosphorylation of extracellular domains of functionally important proteins. ATP-gated membrane pore, p2x 7(formerly p2z receptor) and A2a adenosine receptors are found to be predominantly expressed in T cells. The Gs-protein coupled A2a receptors activate cAMP-dependent protein kinase which was shown to have dual role in regulation of T cells functions. The results of our recent studies of adenosine receptors indicate that A2a receptors on T cell surface may play immunosuppressive role in conditions which lead to accumulation of extracellular adenosine. These conditions include pharmacological intervention with widely used anti-inflammatory drugs (methotrexate and sulfasalazine) and extracellular environment near large solid tumors. Hypoxic conditions in such tumors are known to cause accumulation of extracellular adenosine, which, in turn, as we have shown, could inhibit incoming antitumor cytotoxic T-lymphocytes from destroying the tumor. Normal development and functions of immune cells require adenosine deaminase (ADA) activity. Absence or low levels of ADA in humans result in severe combined immunodeficiency (SCID), which is characterized by hypoplastic thymus, T lymphocyte depletion, and autoimmunity. ADA SCID is currently explained only by intracellular lymphotoxicity of accumulated adenosine. We propose that T cell depletion, immunodeficiency, and autoimmunity could also be due to extracellular adenosine-induced signaling, which inhibits the antigen receptor (TCR) signaling and therefore affects the TCR-driven positive and negative selection of thymocytes. This, in turn, may lead to changes in antigen receptor repertoires and to immunodeficiency, Such properties of adenosine receptors suggest an expanded understanding of pathogenesis of ADA SCID as being due to two independent (intracellular and extracellular) mechanisms of adenosine action. It was conclusively demonstrated that functionally important T cell surface proteins including T cell receptor- are constitutively Ser/Thr phosphorylated on their ectodomains. We identified the major ecto-protein kinase activity in T-lymphocytes as casein kinase II-like (CKII-like) protein kinase. Consensus phosphorylation sites for serine and threonine protein kinases were found to be strongly evolutionary conserved in both alfa and beta TCR chains constant region. We have shown that ecto- or releasable by T-cells protein phosphatase has properties of PP1 and PP2a class protein phosphatase. Such covalent modifications of ectodomains may change T cells cognate interactions by e.g. affecting TCR-multimolecular complex formation and antigen binding affinity. It is suggested that TCR ectodomain phosphorylation could serve as a potential mechanism for regulation of TCR-mediated T-lymphocytes response.
...
PMID:Extracellular purines and their receptors in immunoregulation. Review of recent advances. 980 87

CD26 is a T cell activation antigen that contains dipeptidyl peptidase IV activity and is known to bind adenosine deaminase. The mechanism by which CD26 costimulation potentiates T cell receptor-mediated T cell activation, leading to subsequent exertion of T cell effector function, is still not clearly defined. In this article, we demonstrate that CD26 localizes into lipid rafts, and targeting of CD26 to rafts is necessary for signaling events through CD26. Importantly, aggregation of CD26 by anti-CD26 mAb crosslinking also causes coaggregation of CD45 into rafts. Moreover, we show that CD26 directly binds to the cytoplasmic domain of CD45. Our results therefore indicate a mechanism whereby CD26 engagement promotes aggregation of lipid rafts and facilitates colocalization of CD45 to T cell receptor signaling molecules p56(Lck), ZAP-70, and TCRzeta, thereby enhancing protein tyrosine phosphorylation of various signaling molecules and subsequent interleukin-2 production.
...
PMID:CD26-mediated signaling for T cell activation occurs in lipid rafts through its association with CD45RO. 1159 28

Thymocyte development past the CD4(-)CD8(-) stage is markedly inhibited in adenosine deaminase-deficient (ADA-deficient) murine fetal thymic organ cultures (FTOCs) due to the accumulation of ADA substrates derived from thymocytes failing developmental checkpoints. Such cultures can be rescued by overexpression of Bcl-2, suggesting that apoptosis is an important component of the mechanism by which ADA deficiency impairs thymocyte development. Consistent with this conclusion, ADA-deficient FTOCs were partially rescued by a rearranged T cell receptor beta transgene that permits virtually all thymocytes to pass the beta-selection checkpoint. ADA-deficient cultures were also rescued by the adenosine kinase inhibitor 5'-amino-5'-deoxyadenosine (5'A5'dAdo), indicating that the metabolite responsible for the inhibition of thymocyte development is not adenosine or deoxyadenosine, but a phosphorylated derivative of an ADA substrate. Correction of ADA-deficient FTOCs by 5'A5'dAdo correlated with reduced accumulation of dATP, implicating this compound as the toxic metabolite. In ADA-inhibited FTOCs rescued with a Bcl-2 transgene, however, dATP levels were superelevated, suggesting that cells failing positive and negative selection continued to contribute to the accumulation of ADA substrates. Our data are consistent with dATP-induced mitochondrial cytochrome c release followed by apoptosis as the mechanism by which ADA deficiency leads to reduced thymic T cell production.
...
PMID:Adenosine kinase inhibition promotes survival of fetal adenosine deaminase-deficient thymocytes by blocking dATP accumulation. 1216 59

Although T cell receptor (TCR) signals are essential for intrathymic T cell-positive selection, it remains controversial whether they only serve to initiate this process, or whether they are required throughout to promote thymocyte differentiation and survival. To address this issue, we have devised a novel approach to interfere with thymocyte TCR signaling in a developmental stage-specific manner in vivo. We have reconstituted mice deficient for Zap70, a tyrosine kinase required for TCR signaling and normally expressed throughout T cell development, with a Zap70 transgene driven by the adenosine deaminase (ADA) gene enhancer, which is active in CD4(+)CD8(+) thymocytes but inactive in CD4(+) or CD8(+) single-positive (SP) thymocytes. In such mice, termination of Zap70 expression impaired TCR signal transduction and arrested thymocyte development after the initiation, but before the completion, of positive selection. Arrested thymocytes had terminated Rag gene expression and up-regulated TCR and Bcl-2 expression, but failed to differentiate into mature CD4 or CD8 SP thymocytes, to be rescued from death by neglect or to sustain interleukin 7R alpha expression. These observations identify a TCR-dependent proofreading mechanism that verifies thymocyte TCR specificity and differentiation choices before the completion of positive selection.
...
PMID:Restricting Zap70 expression to CD4+CD8+ thymocytes reveals a T cell receptor-dependent proofreading mechanism controlling the completion of positive selection. 1256 20

Severe Combined Immunodeficiency (SCID) is a rare primary immunodeficiency disease often characterized by a block in T cell development, which may also affect the normal development of B cells and NK cells. Several different mutations are known to give rise to SCID, and multiple genes are involved. Consequently, there are several different forms of SCID, which can be classified according to the metabolic and cellular defects that impede normal lymphocyte function. The two most prevalent forms of SCID are X-linked SCID and adenosine deaminase (ADA) deficiency SCID, together accounting for approximately 70-80% of disease cases. Other genetic abnormalities associated with this syndrome range from defective T cell receptor rearrangement to non-functional signaling molecules. Recently, a new genetic defect has been described in which mutations in a key component of Ca(2+) release activated-channels (CRAC) result in T lymphocyte malfunction.
...
PMID:Immunodeficiency is a tough nut to CRAC: the importance of calcium flux in T cell activation. 1703 65


1

---