Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the conditions of in vitro binding of platelet glycoprotein IIb/IIIa (GPIIb/IIIa) to fibrinogen and applied the results to identify and measure the serum inhibitors to the binding. For the enzyme-linked immunosorbent assay, platelet extract was delivered to a fibrinogen-coated microtiter plate that was incubated for 2 hours, followed by incubation with anti-GPIIb/IIIa monoclonal antibody for another 2 hours. The plate was then incubated with peroxidase-conjugated anti-mouse IgG for color development. The binding was shown to be calcium-dependent. The binding was partially blocked by treating the coated fibrinogen with anti-fibrinogen antibody. Reduction or dissociation of GPIIb/IIIa resulted in the total loss of its ability to bind to fibrinogen. Platelet extracts of patients with hemophilia showed decreased binding (25% and 14%, compared with control platelet extract), and an extract from a patient with Glanzmann's thrombasthenia showed no binding. With the enzyme-linked immunosorbent assay we have measured serum inhibitors to GPIIb/IIIa binding to fibrinogen in 35 hemophilia A, 17 immune thrombocytopenic purpura, 22 human immunodeficiency virus-related immune thrombocytopenic purpura, and 29 systemic lupus erythematosus serum samples. In those patients with inhibition by serum, polyethylene glycol precipitation of circulating immune complexes (CICs) decreased the inhibition by the supernatants, and all the resolubilized CIC precipitates demonstrated inhibition, which indicates that CICs play a major role in the inhibition of GPIIb/IIIa binding to fibrinogen. This, then, provides evidence of CIC-mediated impaired GPIIb/IIIa binding to fibrinogen in hemophilia A, HIV-ITP, and SLE.
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PMID:Inhibition of platelet GPIIb/IIIa binding to fibrinogen by serum factors: studies of circulating immune complexes and platelet antibodies in patients with hemophilia, immune thrombocytopenic purpura, human immunodeficiency virus-related immune thrombocytopenic purpura, and systemic lupus erythematosus. 200 77

Stable transformants of the Jurkat T-cell line have been obtained that express either of two distinct forms of the type 1 human immunodeficiency virus nef gene: the nef-1-encoded protein (Nef-1) contains alanine, glycine, and valine at positions 15, 29, and 33, respectively; the protein specified by nef-2 (Nef-2) has threonine, arginine, and alanine at the corresponding positions. When Jurkat cells or their Nef-2-expressing transformants are treated with phorbol 12-myristate 13-acetate (PMA) plus either phytohemagglutinin (PHA) or antibodies against CD3 epsilon, T-cell receptor beta chain, or CD2, there is a prompt increase in interleukin 2 (IL-2) mRNA and intracellular calcium and in the IL-2 receptor alpha chain on the cell surface. Although cells expressing Nef-1 also induce calcium mobilization and the production of IL-2 receptor alpha chain, the formation of IL-2 mRNA is blocked in response to these stimuli. Moreover, Nef-1-expressing cells transfected with a plasmid in which the IL-2 promoter is fused to the chloramphenicol acetyltransferase (CAT) gene fail to induce CAT following treatment with PMA and PHA. By contrast, the parental and Nef-2-containing cells induce CAT normally. Nef-1-expressing cells can produce IL-2 mRNA in response to a combination of PMA and ionomycin, although much less efficiently than the parental Jurkat cells or Nef-2-expressing cells. These findings, and others described herein, suggest that the virally encoded Nef protein interferes with a signal emanating from the T-cell receptor complex that induces IL-2 gene transcription.
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PMID:Expression of the type 1 human immunodeficiency virus Nef protein in T cells prevents antigen receptor-mediated induction of interleukin 2 mRNA. 205 9

Calcium-free calmodulin-(CaM) is rapidly hydrolyzed by proteases from both human immunodeficiency viruses (HIV) 1 and 2. Kinetic analysis reveals a sequential order of cleavage by both proteases which initiates in regions of the molecule known from X-ray crystallographic analysis of Ca2+/CaM to be associated with calcium binding. Although HIV-1 and HIV-2 proteases hydrolyze two bonds in common, the initial site of cleavage required for subsequent events differs in each case. The first bond hydrolyzed by the HIV-1 protease is the Asn-Tyr linkage in the sequence, -N-I-D-G-D-G-Q-V-N-Y-E-E-, found in the fourth calcium binding loop. In contrast, it is an Ala-Ala bond in the third calcium loop, -D-K-D-G-N-G-Y-I-S-A-A-E-, that is first hydrolyzed by the HIV-2 enzyme, followed in short order by cleavage of the same Asn-Tyr linkage described above. Thereafter, both enzymes proceed to hydrolyze additional peptide bonds, some in common, some not. Considerable evidence exists that inhibitors are bound to the protease in an extended conformation and yet all of the cleavages we observed occur within, or at the beginning of helices in Ca2+/CaM, regions that also appear to be insufficiently exposed for protease binding. Molecular modeling studies indicate that CaM in solution must adopt a conformation in which the first cleavage site observed for each enzyme is unshielded and extended, and that subsequent cleavages involve further unwinding of helices.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calcium-free calmodulin is a substrate of proteases from human immunodeficiency viruses 1 and 2. 206 25

Simian immunodeficiency virus from macaques (SIVmac) is closely related in its structure and biological activity to human immunodeficiency virus, and is the best animal model for the acquired immunodeficiency syndrome. We investigated the kinetics of membrane fusion between SIVmac and phospholipid vesicles and the effects of various parameters on this process. Purified SIVmac was labelled with octadecyl rhodamine B chloride, and fusion was continuously monitored as the dilution of the probe in target membranes. These studies show that SIVmac fusion is strongly dependent upon the liposome composition. Fusion with pure cardiolipin (CL) liposomes is significantly faster than with CL/dioleoylphosphatidylcholine (DOPC) (3:7), phosphatidylserine (PS) or disialoganglioside (GD1a)/DOPC (1.5:8.5) vesicles. SIVmac does not fuse appreciably with pure DOPC liposomes. Reduction of pH from 7.5 to 4.5 greatly enhances the rate of SIVmac fusion with CL, CL/DOPC and PS membranes, but does not affect fusion with DOPC or GD1a/DOPC membranes. Calcium stimulates viral fusion with CL liposomes, but not with CL/DOPC or DOPC liposomes. SIVmac fuses with human erythrocyte ghost membranes only slowly at reduced pH. Our results indicate that SIVmac can fuse with membranes lacking the known viral receptor, CD4. Although the mechanism of SIVmac fusion with model and biological membranes remains to be determined, the fusion activity of SIVmac shares similarities with other lipid-enveloped viruses such as Sendai and influenza viruses.
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PMID:Fusion of simian immunodeficiency virus with liposomes and erythrocyte ghost membranes: effects of lipid composition, pH and calcium. 212 Mar 85

The chronically infected promonocytic clone U1 expresses low-to-undetectable constitutive levels of human immunodeficiency virus (HIV). Virus replication in these cells can be increased up to 25-fold by phorbol esters (phorbol-12-myristate-13-acetate), recombinant cytokines such as tumor necrosis factor-alpha, and cytokine-enriched mononuclear cell supernatants. We have tested specific activators of protein kinases (PK) and PK inhibitors (isoquinolinesulfonamide derivatives), as well as calcium-mobilizing agents, for their effect on constitutive and induced virus expression in U1 cells. Virus expression was measured by reverse transcriptase, Western blot, and nuclear run-on analysis. Activation of PKC by 1-oleyl,2-acetylglycerol, a synthetic analog of the natural ligand 1,2-diacylglycerol, and bryostatin 1 (a recently described specific PKC activator) resulted in a two- to eightfold increase in virus production. In contrast, activators of cyclic-nucleotide-dependent PKs were not effective in inducing virus expression. PK inhibitors were tested for their effect on HIV upregulation by cytokines and other inducing agents. The isoquinolinesulfonamide derivative H7, a potent inhibitor of PKC activation, effectively blocked (70 to 90%) HIV induction by cytokines and phorbol-12-myristate-13-acetate. The derivative HA1004, which is more selective for cyclic-nucleotide-dependent kinases, did not suppress viral induction. In addition, increases in intracellular calcium levels dramatically enhanced HIV production induced by both specific PKC activators and cytokines. These results indicate that activation of PKC is a common pathway involved in the upregulation of HIV expression in chronically infected cells stimulated by cytokines and other inducing agents.
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PMID:Direct and cytokine-mediated activation of protein kinase C induces human immunodeficiency virus expression in chronically infected promonocytic cells. 220 Aug 85

Massive transfusion, or the rapid administration of a quantity of blood products that approximates an individual's blood volume, is associated with many potentially lethal complications. If the need for transfusion is immediate, ie, before adequate typing and crossmatching procedures can be completed, O negative RBCs can be given safely in the interim. Hypothermia caused by cold banked blood is aggravated by multiple environmental factors and should be aggressively avoided through the use of heat lamps, warming coils, blankets, and other warming devices. The coagulopathy seen in massive transfusion probably has a mixed etiology involving dilution and consumption of clotting factors and platelets. Although fresh frozen plasma and platelets both play a critical role in blood replacement, deficiencies should be treated with appropriate component therapy dictated by coagulation studies rather than by protocol. Transfusion reactions, the most serious type of which is the hemolytic reaction, may go unrecognized in the bleeding patient in critical condition. Hemolytic reactions can usually be prevented by careful attention to administrative and clerical accuracy. Although the overwhelming majority of the 10 million units of blood transfused annually are uncontaminated, transmission of hepatitis and the human immunodeficiency virus through blood products remains a significant screening problem. Posttransfusion hyperkalemia and acidosis are more likely to be related to inadequate resuscitation from shock than to administration of blood. Citrate toxicity and hypocalcemia are usually self-limiting disturbances. Prophylactic use of calcium chloride is dangerous and unnecessary. The complexity of the conditions necessitating massive transfusion demands frequent reevaluation of multiple laboratory and clinical factors for effective resuscitation and for safe administration of blood.
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PMID:Massive transfusion: complications and their management. 220 22

In 1985 a mixture of red cells collected in citrate anticoagulant with plasma derived from heparinized blood was introduced in Amsterdam to perform exchange transfusions in newborns. This heparin mixture has physiological levels of electrolytes, calcium and glucose, can be delivered on short notice and carries a minimal risk of transmission of infectious diseases because all blood components are tested for hepatitis B antigen and antibodies against syphilis and the human immunodeficiency virus. Retrospectively we evaluated 54 children treated in 1986 and 1987 with exchange transfusions using this heparin mixture. An adequate decrease in bilirubin values when necessary was observed while neither changes in sodium, potassium, calcium or glucose values nor adverse effects on the pH value were recorded. However, a remarkable transient thrombocytopenia was found following exchange transfusion with a decrease of the platelet count to an average of 39% of the initial value.
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PMID:[The use of a mixture of citrated erythrocytes and heparin plasma for exchange transfusions]. 221 59

A primary immunodeficiency patient was analysed whose serum IgG and IgE were extremely low but whose IgM and IgA levels were within the normal range or elevated. Southern blot analysis indicated no deletion of structural genes coding for C gamma, C epsilon, or C alpha. The majority of the patient's peripheral B cells expressed IgM and IgD on the surface yet IgG-positive B cells were not detected, suggesting that the defect is in a switch-recombination process from IgM to IgG. The RFLP pattern detected with the S mu and S gamma DNA regions revealed that there was no deletion or large mutation in the switch region DNA. An in vitro IgG production system with pokeweed mitogen showed an abnormality at the transcriptional level and the defects were in both the patient's T and B cells. Addition of recombinant IL-4 (rIL-4) to the normal B cells enhanced IgG production but the patient's B cells did not respond to rIL-4, although the IL-4 receptor was present at the normal level. Messenger RNA and IL-4 protein were not produced in the patient's T cells upon stimulation with phorbol ester and calcium ionophore, whereas IL-2 was normally produced. The patient's lymphocytes showed a proliferative response to various mitogens, including phorbol ester. The transcripts of unrearranged C gamma region genes were not detected in the patient's lymphocytes, suggesting that the chromatin structure of the S gamma region may not be open. These results suggest that the transcriptional defects at the S gamma region gene in B cells and at the IL-4 gene in the T cells may be responsible for the present IgG immunodeficiency. There might be a common transcriptional system operating in a certain step in the activation of both genes.
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PMID:Selective IgG deficiency with a transcriptional disorder of the gamma switching region gene and the IL-4 gene. 227 96

Deoxyadenosine (dAdo) has been recognized as the toxic metabolite in the immunodeficiency disease associated with adenosine deaminase (ADA) deficiency. Under ADA deficient conditions, dAdo accumulates intracellularly as deoxyadenosine triphosphate (dATP) which by interference with ribonucleotide reductase, prevents DNA synthesis. Recently, we and others have demonstrated that in cells rendered ADA deficient by treatment with deoxycoformycin, dAdo affects T-cell activation events which precede DNA synthesis, such as interleukin 2 receptor (IL-2R) expression and IL-2 production. Here we have analyzed interference of dAdo with the early events of T-cell activation. It is shown that dAdo affects the mitogen induced phosphatidyl inositol turnover. Furthermore dAdo interferes with increase of intracellular calcium. Deoxycytidine, although capable of preventing intracellular accumulation of dATP, cannot reverse the functional consequences of dAdo treatment. The ability of a cell to increase its cytoplasmic free Ca2+, as induced by ionomycin, is not affected by dAdo. The exact target for this novel effect of dAdo is at the present unknown.
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PMID:Interference of deoxyadenosine with transmembrane signaling events in human T lymphocytes. 230 14

Coat protein gp120 from the human immunodeficiency virus type-1 (HIV-1) increased intracellular free calcium and injured rodent retinal ganglion cells and hippocampal neurons in culture. Highly purified recombinant gp120 envelope protein produced these effects in a dose-dependent fashion at picomolar concentrations. Immunoprecipitation with antibody to gp120, but not with control immunoglobulin-containing serum, depleted solutions of the viral envelope protein and also prevented both the rise in intracellular calcium and neuronal toxicity. The gp120-induced increase in intracellular calcium was abrogated by transiently lowering extracellular calcium or by adding the dihydropyridine calcium channel antagonist nimodipine (100 nM). Calcium channel antagonists also prevented gp120-induced neuronal injury. In addition, intracellular stores appeared to contribute substantially to the increase in calcium elicited by gp120. Since increases in intracellular calcium have been associated with neurotoxicity, it is possible that an injurious effect of gp120 on neurons might be related to this mechanism and that treatment with calcium channel antagonists may prove useful in mitigating HIV-1-related neuronal injury.
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PMID:HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists. 232 43


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