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)

Defects in the enzymes involved in the pathway of S-adenosylmethionine (AdoMet) metabolism, or inhibition of those enzymes, results in profound immunodeficiency. We have examined MDL 28,842, a novel irreversible inhibitor of S-adenosyl-L-homocysteine hydrolase (AdoHcyase), an enzyme involved in AdoMet metabolism, to determine its effect on the immune system and to investigate its potential as an immunosuppressive agent. The stimulation of human mononuclear cell proliferation in vitro with Con A, a T cell mitogen, and PWM, a T-dependent B cell mitogen, were inhibited by MDL 28,842. The 50% inhibitory concentration for both were 0.33 microM. In murine spleen cells, MDL 28,842 was a potent, nontoxic, inhibitor of Con A-stimulated T cell proliferation (IC50 = 0.19 microM) but did not affect LPS-induced B cell proliferation. This selective suppression was also observed when enriched murine T and B cells were stimulated with mitogens, although S-adenosyl-L-homocysteine (AdoHcy), the substrate of AdoHcyase, was similarly elevated in both populations. In addition to proliferation in response to a number of stimuli, IL-2 production and the expression of IL-2R by mitogen-stimulated T cells were inhibited by MDL 28,842. These results suggest a direct effect of MDL 28,842 on T cells. In vivo, the antibody response to a T cell-dependent Ag, OVA, was inhibited by MDL 28,842. The response of splenic T cells from these animals to OVA in vitro were similarly depressed compared with controls. The results demonstrate that MDL 28,842 is a potent nontoxic immunosuppressive agent, which has selectivity for T cells and therefore may be useful in the treatment of T cell-mediated disorders, such as autoimmune disease and tissue transplantation.
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PMID:Selective inhibition of T cell activation by an inhibitor of S-adenosyl-L-homocysteine hydrolase. 846 68

To examine the role of nitric oxide (NO) in murine AIDS (MAIDS) pathogenesis, we determined NO production and inducible NOS (iNOS) mRNA expression in the macrophages of LP-BM5-infected mice, together with the in vivo effects of L-NAME, a competitive inhibitor of NO synthase. LP-BM5 infection induced neither spontaneous nitrite production nor iNOS mRNA expression. No differences in IFN gamma + LPS-induced nitrite production or iNOS mRNA expression were observed in macrophages, from non-infected or infected mice. Spleen weight, ecotropic MuLV replication, the blood lymphocyte phenotype and proliferative response of splenocytes were not modified by L-NAME. LP-BM5 infection did not increase macrophage NO production and NO production did not appear to protect against LP-BM5-induced immunodeficiency.
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PMID:Absence of involvement of nitric oxide in LP-BM5-induced immunodeficiency syndrome. 888 Jan 43

Leukosialin (CD43 or sialophorin) is a cell surface sialoglycoprotein implicated in cell adhesion and proliferation whose tightly regulated expression in B lymphocytes is likely important for their normal development and/or function. To examine the physiologic role of mouse CD43 (mCD43) in vivo, we exploited transgenic (TG) mice whose developmental expression of mCD43 was extended during B cell differentiation so that mCD43 was now expressed on peripheral B cells. Despite having increased B cells, localization of lymphocytes in the TG spleens appeared normal by immunocytochemistry with anti-CD4, anti-CD8, and anti-B220 mAbs. However, the numbers of splenic germinal centers and the resting sera Ig levels were decreased in the TG mice compared with littermate controls. TG mice had decreased humoral responses to the T-dependent Ags keyhole limpet hemocyanin and OVA, as well as reduced Ag-specific B cell numbers. In contrast, in vitro LPS stimulation of purified TG or control B cells resulted in similar proliferation and IgM responses. Thus, the alteration of B cell mCD43 expression that resulted in profound immunodeficiency in vivo was not due to absolute defects in B cell development or Ab production. However, TG B cells had a decreased ability to homotypically aggregate and to present Ag to the T cell hybridoma B3Z. These data suggest that the immunodeficiency seen in vivo is due to the anti-adhesive forces of mCD43 preventing normal T-B cell interaction. This likely reflects a general property of mucins in regulating cell interactions.
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PMID:Disregulated expression of CD43 (leukosialin, sialophorin) in the B cell lineage leads to immunodeficiency. 894 91

It has been demonstrated that morphine stimulates the replication of human immunodeficiency virus in peripheral blood mononuclear cells as well as in Kupffer cells. Since the mechanism of action of this drug is still unknown, we have studied its effects on different properties of isolated human blood monocytes. In the presence of morphine, cultured monocytes showed an increase in the fluidity of their membranes as well as an inhibition in their capacity to differentiate into macrophages. Furthermore, the response of the cells to interferon-gamma was significantly decreased and the release of superoxide anions was altered. Finally the production of interferon-alpha and of prostaglandin E2 induced by stimulation of the cells with endotoxin (LPS) was diminished. We conclude that morphine decreases the functions of monocytes that are essential for their antiviral defence and inhibits their response to activating stimuli, which may explain the increased multiplication of HIV in morphine treated monocytes.
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PMID:Effects of morphine on purified human blood monocytes. Modifications of properties involved in antiviral defences. 927 79

Leukocyte chemoattractants act through a rapidly growing subfamily of G protein-coupled receptors. We report the cloning of a novel human gene encoding an orphan receptor (ChemR23) related to the C3a, C5a and formyl Met-Leu-Phe receptors, and more distantly to the subfamilies of chemokine receptors. ChemR23 transcripts were found to be abundant in monocyte-derived dendritic cells and macrophages, treated or not with LPS. Low expression could also be detected by reverse transcription-PCR in CD4+ T lymphocytes. The gene encoding ChemR23 was assigned by radiation hybrid mapping to the q21.2-21.3 region of human chromosome 12, outside the gene clusters identified so far for chemoattractant receptors. Given the increasing number of chemoattractant receptors used by HIV-1, HIV-2 and SIV as coreceptors, ChemR23 was tested in fusion assays for potential coreceptor activity by a range of viral strains. None of the tested HIV-2 strains made use of ChemR23 as a coreceptor, but several SIV strains (SIVmac316, SIVmac239, SIVmacl7E-Fr and SIVsm62A), as well as a primary HIV-1 strain (92UG024-2) used it efficiently. ChemR23 therefore appears as a coreceptor for immunodeficiency viruses that does not belong to the chemokine receptor family. It is also a putative chemoattractant receptor relatively specific for antigen-presenting cells, and it could play an important role in the recruitment or trafficking of these cell populations. Future work will be required to identify the ligand(s) of this new G protein-coupled receptor and to define its precise role in the physiology of dendritic cells and macrophages.
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PMID:ChemR23, a putative chemoattractant receptor, is expressed in monocyte-derived dendritic cells and macrophages and is a coreceptor for SIV and some primary HIV-1 strains. 960 76

Immunodeficiency follows extensive burns. We investigated some underlying mechanisms in rats, 10 days after a full-thickness skin burn affecting 20% of total body surface area. In both normal and burned rats the splenocyte proliferative response to Con A was linearly and negatively correlated with nitric oxide (NO) production. In all burned rats, the proliferative response was depressed by more than 80% and NO production corresponded to a nitrite concentration above 20 microM. Proliferative responses in burned rats were fully restored in the presence of 250 microM NG-monomethyl-L-arginine (NMMA). A time course study of NO production in response to Con A, LPS, anti-CD3, and IFN-gamma showed that splenic macrophages from burned rats responded to direct and indirect stimuli more rapidly and more intensively than normal macrophages. In the second part of this work, the effect of the overproduction of NO on the synthesis of immunoregulatory and proinflammatory cytokines was investigated. Although it was inhibited, IFN-gamma production by splenocytes from burned rats remained sufficient for NO synthase induction and was restored by NMMA. Concomitantly, IL-2 concentration was enhanced but returned to normal in the presence of NMMA. TNF production was halved after burn injury and NMMA partially restored it. In contrast, IL-6 production was enhanced and increased further in the presence of NMMA. Therefore, cytokines were differently affected by burn injury and variously regulated by NO.
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PMID:Role of nitric oxide in depressed lymphoproliferative responses and altered cytokine production following thermal injury in rats. 966 54

Filgrastim induces lymphocytosis, including all T cell subsets, and increased ex vivo interleukin (IL)-2 release as well as lymphocyte proliferation. Since Filgrastim is increasingly used in patients with human immunodeficiency virus (HIV) infection, the effect of Filgrastim on ex vivo cytokine production was determined. Whole blood from 8 healthy volunteers, 5 high-risk volunteers, and 31 HIV-infected outpatients was assayed for cytokine production in response to endotoxin (LPS) or staphylococcal enterotoxin B (SEB) in the presence or absence of 100 ng/mL Filgrastim. LPS-inducible blood cytokine release of HIV-infected patients was not different from that of normal or high-risk volunteers. The suppressive effect of Filgrastim on LPS-inducible blood tumor necrosis factor-alpha and interferon-gamma formation in normal volunteers was not found in HIV-infected patients. Patients with advanced HIV infection showed reduced IL-2 and IL-4 release in the presence of SEB. In the presence of Filgrastim, IL-2 production was partially restored.
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PMID:Filgrastim restores interleukin-2 production in blood from patients with advanced human immunodeficiency virus infection. 972 36

Bacterial polysaccharides (PS) are T-independent type 2 Ags that elicit restricted Ab responses of IgM and IgG3 in mice and IgM and predominantly IgG2 in humans. Immunodeficiency in the dominant IgG subclass made to PS is associated with chronic sinus and pulmonary infections with PS-encapsulated bacteria. To elucidate the biologic role of the dominant IgG subclass in the immune response to PS and to make an animal model of human IgG subclass deficiency, we generated mice with a targeted disruption of the exon encoding the CH1 domain of the gamma 3 heavy-chain constant region gene. Homozygotes had no detectable serum IgG3, and their splenocytes did not produce IgG3 after LPS stimulation. IgG3(-/-) mice immunized with PS from Pseudomonas aeruginosa LPS O-side chain or Streptococcus pneumoniae type 19F capsule did not produce any IgG3 anti-PS Abs, in contrast to wild-type mice in which IgG3 was the major IgG subclass. Immunizing both wild-type and IgG3(-/-) mice with 19F PS-protein conjugate elicited IgG1 Abs. We conclude that IgG3(-/-) mice have a selective deficiency in the dominant murine IgG subclass made to T-independent type 2 Ags and may be a useful animal model of IgG subclass deficiency. In addition, we show that the anti-PS Ab class switching to IgG1 that occurs when mice are immunized with a PS-protein conjugate vaccine does not require sequential Ig expression or an intact, upstream gamma 3 heavy-chain gene.
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PMID:Gamma 3 gene-disrupted mice selectively deficient in the dominant IgG subclass made to bacterial polysaccharides undergo normal isotype switching after immunization with polysaccharide-protein conjugate vaccines. 975 56

CC chemokine receptor 5 (CCR5) is a cell entry cofactor for macrophage-tropic isolates of human immunodeficiency virus 1 (HIV-1). An inactive CCR5 allele with a 32-nucleotide deletion (CCR5Delta32) has been described that confers resistance to HIV-1 infection in homozygotes and slows the rate of progression to AIDS in heterozygotes. We found the allele CCR5Delta32 to be not rare in 399 Swiss blood donors with a frequency of 0.080. To assess the influence of defective CCR5 on production of its ligands we determined the capacity to produce the chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and RANTES in comparison with the production of the CXC chemokine IL-8 which does not bind to CCR5. Production of chemokines was determined during endotoxin stimulation of whole-blood samples ex vivo. Both, basal and LPS-induced chemokine production in 32 blood donors heterozygous for CCR5Delta32 were not significantly different when compared with 55 blood donors who were homozygous for the wild type CCR5 allele.
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PMID:Heterozygous defect in HIV-1 coreceptor CCR5 and chemokine production. 1008 Aug 73

We show that LPS-stimulated circulating CD14-positive monocytes from patients with common variable immunodeficiency (CVID) express a higher proportion of intracellular IL-12-positive cells than monocytes from patients with X-linked agammaglobulinemia or normal subjects. We used four-color flow cytometry and measured IL-12 with an Ab to the p40 subunit following stimulation with LPS. The raised IL-12 is associated with an increased frequency of IFN-gamma-positive T cells, but not of IFN-gamma-positive CD56+ NK cells. These increases in frequency of cytokine-positive cells are due to a decrease in the absolute numbers of circulating monocytes and T cells that are negative for IL-12 and IFN-gamma, respectively. The increased frequency of IL-12-positive monocytes appears to be selective because TNF-alpha was not increased, and is thus unlikely to reflect a general activation. Chronic infection is also unlikely to explain our data since cells from X-linked agammaglobulinemia patients with a similar Ig deficiency do not show these changes. Our data suggest a fundamental abnormality in the IL-12/IFN-gamma circuit in CVID, with up-regulation of IL-12 being the "primary" factor. This imbalance is likely to skew the immune response away from Ab production and also explains the failure of CVID T cells to make Ag-specific memory cells and the chronic inflammatory and granulomatous complications that are a feature of CVID. This disease appears to be a rare example of a polarized Th1-type response and may in part be due to a genetic defect in the control of IL-12 production.
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PMID:Up-regulation of IL-12 in monocytes: a fundamental defect in common variable immunodeficiency. 1060 46


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