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)

The role of placenta in vertical transmission is not yet fully understood. A protective role of the placenta during gestation is suggested by the finding that caesarian sections reduce the risk of transmission of human immunodeficiency virus (HIV)-1 from mother to child three- to fourfold. Here we investigated whether the immunological milieu of the placenta might be important in HIV-1 transmission. In situ imaging of immunohistochemically stained placenta sections and reverse transcriptase-polymerase chain reaction demonstrated a fourfold increase in CCR5:CXCR4 expression ratio in placentae from transmitting women compared to placentae from nontransmitting women. This chemokine receptor repertoire was consistent with an up-regulation of interleukin-4 and interleukin-10 expression in placentae from nontransmitting placentae compared to transmitting placentae. In situ imaging demonstrated that CCR5 and CXCR4 were expressed on placental macrophages and lymphocytes but not in trophoblasts. Simultaneous immunofluorescence/ultrasensitive in situ hybridization for HIV-1 gag-pol mRNA revealed that HIV-1 infects primarily CXCR4-expressing cells in placentae from nontransmitting women whereas predominantly CCR5-expressing cells were infected in placentae from transmitting women. These data are consistent with transmission of a homogeneous population of nonsyncytium-inducing HIV-1 isolates that use CCR5 as co-receptor.
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PMID:Up-regulation of CCR5 expression in the placenta is associated with human immunodeficiency virus-1 vertical transmission. 1110 53

ZAP-70 deficiency is a rare primary immunodeficiency characterized by the absence of peripheral CD8+ T cells and defects in T-cell receptor (TCR) signalling. T cells in ZAP-70-deficient patients are assumed to have no helper functions for B-cell immunoglobulin synthesis, whereas the patients rarely have antigen-specific antibodies. We experienced a ZAP-70-deficient patient, who had immunoglobulin E (IgE) antibodies specific to food allergens, and we investigated the mechanisms of switching to IgE in the patient. Peripheral blood mononuclear cells from the patient did not proliferate upon stimulation with the antigens but produced distinct levels of interleukin-4 (IL-4). Cell sorting analysis indicated that the cells that produced IL-4 in response to the antigens were enriched in CD4+ T cells. Purified CD4+ T cells from the patient produced IL-4 and expressed CD40L upon stimulation with anti-CD3. Moreover, CD4+ T cells pretreated with anti-CD3 induced mature epsilon transcript on naive B cells. Since the results indicated that there remained sufficient T-cell receptor (TCR)-signalling in the patient's T cells to exert antigen-specific IgE switching on B cells, we next investigated the expression of the ZAP-70-homologous kinase Syk. Syk was present in high levels in patient's CD4+ T cells and was tyrosine-phosphorylated after TCR stimulation. Inhibition of Syk by piceatannol resulted in decreased production of IL-4 and expression of CD40L on patient's CD4+ T cells. Moreover, Syk was expressed on all human T-cell leukaemia virus (HTLV-1)-transformed T-cell lines derived from peripheral blood of the patient, whereas it was low or undetectable in control lines. It was therefore concluded that specific IgE responses in the patient were most likely to be mediated by Syk-dependent TCR-signalling.
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PMID:Specific immunoglobulin E responses in ZAP-70-deficient patients are mediated by Syk-dependent T-cell receptor signalling. 1141 3

Patients with the immunodeficiency disorder Wiskott-Aldrich syndrome (WAS) have lymphocytes with aberrant microvilli, and their T cells, macrophages, and dendritic cells are impaired in cytoskeletal-dependent processes. WAS is caused by a defective or a missing WAS protein (WASP). Signal mediators interleukin-4 (IL-4) and CD40 are important for actin-dependent morphology changes in B cells. A possible function of WASP and its interacting partners, Cdc42 and Rac1, was investigated for these changes. It was found that active Cdc42 and Rac1 induced filopodia and lamellipodia, respectively, in activated B cells. Evidence is given that IL-4 has a specific role in the regulated cycling of Cdc42 because IL-4 partially and transiently depleted active Cdc42 from detergent extract of activated B cells. WASP-deficient B lymphocytes were impaired in IL-4-- and CD40-dependent induction of polarized and spread cells. Microvilli were expressed on WASP-deficient B cells, but they appeared shorter and less dense in cell contacts than in wild-type cells. In conclusion, evidence is provided for the involvement of Cdc42, Rac1, and WASP in the cytoskeletal regulation of B lymphocytes. Aberrations in WASP-deficient B lymphocytes, described here, provide further evidence that WAS is a cytoskeletal disease of hematopoietic cells. (Blood. 2001;98:1086-1094)
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PMID:Cdc42, Rac1, and the Wiskott-Aldrich syndrome protein are involved in the cytoskeletal regulation of B lymphocytes. 1149 55

The chemokine stromal cell-derived factor (SDF)-1 and its receptor, CXCR4, play important roles in human immunodeficiency virus type 1 (HIV-1) pathophysiology, leukocyte trafficking, inflammation, hematopoiesis, embryogenesis, angiogenesis, and cancer metastasis. The effects of cytokines on the regulation of CXCR4 function were investigated in human primary monocytes-macrophages. The expression of functional CXCR4 on the cell surface was demonstrated by the detection of ligand-induced Ca(2+) mobilization, chemotaxis, and ligand-induced receptor endocytosis. Surface CXCR4 expression was down-regulated by cytokines interleukin-4 (IL-4), IL-13, and granulocyte-macrophage colony-stimulating factor (GM-CSF) and up-regulated by IL-10 and transforming growth factor-beta 1. Down-regulation was mediated post-translationally, in the absence of protein degradation, through an endocytotic mechanism. In contrast to SDF-1 alpha-induced CXCR4 endocytosis, cytokine-induced endocytosis of this receptor was independent of actin filament polymerization. GM-CSF increased the expression of G protein-coupled receptor kinase 3 (GRK3), beta-arrestin-1, Pyk2, and focal adhesion kinase (FAK). Cytokine treatment also increased the total and tyrosine-specific phosphorylation of CXCR4 as well as the phosphorylation of FAK on tyrosine 397. It also induced the formation of GRK3.CXCR4 or FAK.CXCR4 complexes. Infection of macrophages by primary R5X4 and X4 isolates of HIV-1 was inhibited by IL-4, IL-13, and GM-CSF, an effect that was associated with down-regulation of surface CXCR4 expression. These data indicate that ligand-dependent and ligand-independent endocytoses of CXCR4 are mediated by different mechanisms. Cytokine-induced endocytosis of chemokine receptors may be of therapeutic value in HIV-1 infection, inflammation, tumor metastasis, and defective hematopoiesis.
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PMID:Role of tyrosine phosphorylation in ligand-independent sequestration of CXCR4 in human primary monocytes-macrophages. 1166 82

We describe a patient with transient disappearance of B-cells, hypogammaglobulinemia, and mild pancytopenia after acute hepatitis. Both HLA-DR+CD8+ and intracellular interferon-gamma+/interleukin-4- cell levels were markedly increased, resulting in an increase in the cytotoxic T-cell (T(C))1/Tc2 and helper T-cell (T(H))1/T(H)2 ratios. After immunosuppressive therapy with cyclosporine A, these parameters of T-cell activation were clearly decreased, and hematologic recovery, including an increase in B-lymphocytes and immunoglobulin concentration, was obtained. These results suggest that there had been suppression of B-cells by activated T-cells. Some patients with common variable immunodeficiency show similar activation of T-cell function, and the present findings suggest the possibility of immunosuppressive therapy for such patients.
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PMID:Successful immunosuppressive therapy with cyclosporine A for posthepatitis B-cell deficiency with activated cytoplasmic interferon--gamma-positive T-lymphocytes. 1199 57

DC-SIGN, a type II membrane-spanning C-type lectin that is expressed on the surface of dendritic cells (DC), captures and promotes human and simian immunodeficiency virus (HIV and SIV) infection of CD4(+) T cells in trans. To better understand the mechanism of DC-SIGN-mediated virus transmission, we generated and functionally evaluated a panel of seven monoclonal antibodies (MAbs) against DC-SIGN family molecules. Six of the MAbs reacted with myeloid-lineage DC, whereas one MAb preferentially bound DC-SIGNR/L-SIGN, a homolog of DC-SIGN. Characterization of hematopoietic cells also revealed that stimulation of monocytes with interleukin-4 (IL-4) or IL-13 was sufficient to induce expression of DC-SIGN. All DC-SIGN-reactive MAbs competed with intercellular adhesion molecule 3 (ICAM-3) for adhesion to DC-SIGN and blocked HIV-1 transmission to T cells that was mediated by THP-1 cells expressing DC-SIGN. Similar but less efficient MAb blocking of DC-mediated HIV-1 transmission was observed, indicating that HIV-1 transmission to target cells via DC may not be dependent solely on DC-SIGN. Attempts to neutralize DC-SIGN capture and transmission of HIV-1 with soluble ICAM-3 prophylaxis were limited in success, with a maximal inhibition of 60%. In addition, disrupting DC-SIGN/ICAM-3 interactions between cells with MAbs did not impair DC-SIGN-mediated HIV-1 transmission. Finally, forced expression of ICAM-3 on target cells did not increase their susceptibility to HIV-1 transmission mediated by DC-SIGN. While these findings do not discount the role of intercellular contact in facilitating HIV-1 transmission, our in vitro data indicate that DC-SIGN interactions with ICAM-3 do not promote DC-SIGN-mediated virus transmission.
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PMID:Functional evaluation of DC-SIGN monoclonal antibodies reveals DC-SIGN interactions with ICAM-3 do not promote human immunodeficiency virus type 1 transmission. 1202 23

Hyper IgE syndrome (HIES) is a rare immunodeficiency disorder characterized mainly by high levels of polyclonal IgE in serum and recurrent staphylococcal abscesses of the skin and lungs. The raised IgE levels have led researchers to study the synthesis of cytokines that regulate switching of immunoglobulin production towards IgE such as interleukin-4 (IL-4), IL-12 and interferon-gamma (IFN)-gamma. However, the role of IL-13 in the disease pathogenesis has not been investigated extensively. In this study, we investigated intracellular expression of IL-4 and IL-13 in mononuclear cells and CD4+ cells isolated from patients with HIES and healthy controls. Cells were stained intracellularly with antibodies directed against IL-4 and IL-13 and analysed by flow cytometry before and after activation with PMA and calcium ionophore. The mean proportion of resting or activated IL-4 and IL-13 expressing mononuclear cells were comparable in the two groups as well as the proportion of IL-4 expressing CD4+ cells. In contrast, the mean proportion of IL-13 expressing CD4+ cells was increased significantly in patients with HIES in both the resting and the activated state compared to healthy controls. We conclude that increased expression of IL-13 in CD4+ cells from patients with HIES could account, at least partly, for raised IgE levels in those individuals.
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PMID:Increased expression of interleukin-13 but not interleukin-4 in CD4+ cells from patients with the hyper-IgE syndrome. 1206 9

End-stage renal failure (ESRD) induces a clinical state of immunodeficiency with a higher incidence of infections and a higher mortality due to infectious complications compared with the normal population. Using a newly developed immunofluorescent staining of intracellular cytokines for flow cytometric analysis, we studied Th subsets in 22 healthy control subjects, 28 patients with compensated chronic renal failure (CRF), 25 patients on hemodialysis (HD), and 24 patients on continuous ambulatory peritoneal dialysis (CAPD). Our results demonstrate that the percentage of both interferon-gamma-positive cells and interleukin-4-positive cells increased in compensated CRF patients compared with those in healthy subjects. Moreover, a significantly higher percentage of CD4-positive cells is characterized by a Th1-type cytokine production pattern in HD patients and by a Th2-type cytokine secretion pattern in CAPD patients. These results suggest that the altered Th1/Th2 balance may be associated with the pathogenesis of ESRD.
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PMID:Characterization of TH1/TH2 profile in uremic patients. 1211 83

None of the vaccines used in dimorphic fungal infections utilized the mucosal route for immunization, whereas only one utilized a secreted protein as antigen, despite knowing that infections caused by dimorphic fungi are usually acquired through inhalation. In this study, we investigated the usefulness of Mp1p (a secreted cell wall antigen encoded by MP1)-based vaccines for generation of protective immune responses against Penicillium marneffei infection using a mouse model, and compared the relative effectiveness of intramuscular MP1 DNA vaccine, oral mucosal MP1 DNA vaccine delivered by live-attenuated Salmonella typhimurium, and intraperitoneal recombinant Mp1p protein vaccine. The serum IgM level of the Mp1p protein vaccine group at day 7 and the serum IgG levels of the Mp1p protein vaccine group at days 7 and 21 were significantly higher than those of the other groups (P<0.0001). The serum IgG level of the MP1 DNA vaccine group was significantly higher than that of the corresponding control group and oral mucosal MP1 DNA vaccine group (one dose) at day 21 (P<0.0001 and <0.05, respectively). The groups of mice immunized with intramuscular MP1 DNA vaccine, oral mucosal MP1 DNA vaccine, and intraperitoneal Mp1p protein vaccine showed significantly higher Mp1p-specific lymphocyte proliferation index (LPI) than the control groups. The interferon-gamma (IF-gamma) levels of supernatant of splenic cell cultures obtained from mice after intramuscular MP1 DNA vaccine, mucosal MP1 DNA vaccine (three doses), or intraperitoneal Mp1p protein vaccine administration were higher than that which occurred after mucosal MP1 DNA vaccine (one dose) administration or those of controls. Interleukin-4 (IL-4) was not detectable in the supernatant of splenic cell cultures obtained from all groups of mice. The percentage survival of the mice immunized with intramuscular MP1 DNA vaccine, oral mucosal MP1 DNA vaccine (three doses), oral mucosal MP1 DNA vaccine (one dose), intraperitoneal recombinant Mp1p protein, oral live-attenuated S. typhimurium control, and intramuscular pJW4303 DNA control at day 60 after wild type P. marneffei challenge were 100, 60, 40, 40, 40, and 0%, respectively. The survival of mice in the MP1 DNA vaccine group was significantly better than those of the oral mucosal MP1 DNA vaccine (three doses) group (P<0.05), oral mucosal MP1 DNA vaccine (one dose) group (P<0.005), recombinant Mp1p protein group (P<0.005), S. typhimurium aroA strain group (P<0.05), and pJW4303 group (P<0.00001). Although, the mechanism by which intramuscular MP1 DNA vaccine offered the best protection against P. marneffei infection remains to be elucidated, the present observation prompted further clinical trials on the use of MP1 DNA immunization on asymptomatic human immunodeficiency virus carriers in P. marneffei endemic areas.
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PMID:DNA immunization using a secreted cell wall antigen Mp1p is protective against Penicillium marneffei infection. 1212 98

Previous reports have emphasized the requirements for strong type 1 cell-mediated responses in the control of human immunodeficiency virus type 1 (HIV-1). HIV-1 Gag p24-specific CD4 helper T-lymphocyte (HTL) responses have been shown to inversely correlate with viral burden in HIV-1-infected individuals. In this study, peripheral blood mononuclear cells from 70 individuals with chronic progressive HIV-1 infection (clinical progressors), 10 clinical nonprogressors, and 3 immunologically discordant progressors were assessed for HTL proliferation and type 1/type 2 cytokine production. Clinical progressors lacked functional HIV-1-specific HTLs with proliferative and cytokine-producing capacity. Clinical nonprogressors were found to respond to a wide range of HIV-1 antigens from different clades, producing both type 1 and type 2 cytokines. Immunologically discordant progressors responded strongly to clade B Gag p24 with a type 1 cytokine profile but not to other antigens. Thus, in contrast to clinical nonprogressors, neither progressors nor immunologically discordant progressors secreted interleukin-4 (IL-4) in response to HIV-1 antigens. Both clinical nonprogressors and immunologically discordant progressors responded broadly to B clade Gag p24-overlapping peptides. However, IL-4 production in the nonprogressors was restricted to a limited number of p24 peptides. No HIV-1-specific T-cell responses were seen in 20 seronegative controls. Additionally, we observed a rapid type 1 to type 2 shift in the response of one immunologically discordant progressor upon onset of clinical symptoms. These results suggest that a balanced type 1/type 2 profile correlates with successful long-term control of HIV-1.
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PMID:A balanced type 1/type 2 response is associated with long-term nonprogressive human immunodeficiency virus type 1 infection. 1218 85


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