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)

Dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) is a type II C-type lectin that functions as an adhesion receptor and mediates binding and internalization of pathogens such as virus (human immunodeficiency virus, hepatitis C), bacteria (Mycobacterium), fungi, and parasites. DC-SIGN expression in vivo is primarily restricted to interstitial dendritic cells (DC) and certain tissue macrophages. We now report that leukemic THP-1 cells, widely used as a model for monocyte-macrophage differentiation, express very low basal levels of DC-SIGN and that DC-SIGN expression in THP-1 cells is regulated during differentiation. Differentiation-inducing agents (phorbol ester, bryostatin) conveyed THP-1 cells with the ability to up-regulate DC-SIGN mRNA levels and cell surface expression in response to interleukin-4 (IL-4) or IL-13. DC-SIGN up-regulation required a functional JAK-STAT signaling pathway, was inhibited in the presence of lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha), and conferred THP-1 cells with increased pathogen recognition and T cell stimulatory capabilities. The up-regulation of DC-SIGN on THP-1 cells resembles its inducible expression on monocytes and macrophages, where DC-SIGN expression is also induced by IL-4/IL-13 and negatively regulated by TNF-alpha, LPS, and vitamin D(3). These results point to THP-1 cells as a useful cellular system to characterize the pathogen-binding capabilities of DC-SIGN and to dissect the molecular mechanisms that control its regulated and tissue-specific expression in myeloid dendritic cells, and the results suggest that DC-SIGN constitutes a marker for both DC and alternatively activated macrophages.
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PMID:Regulated expression of the pathogen receptor dendritic cell-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin in THP-1 human leukemic cells, monocytes, and macrophages. 1507 Sep 1

The phenotype and function of monocyte derived dendritic cells (MdDC) were investigated in 25 patients with common variable immunodeficiency (CVID) to test for abnormalities that might help explain the failure of antibody production. Using MHC class II DR and CD86 as markers of maturation, DCs from the majority of CVID patients were normal. However 5 patients, the majority of whom had affected family members who had previously been shown to have a susceptibility genetic locus in the MHC region, expressed abnormally low levels of DR on repeated testing, in some cases associated with a reduced capacity to support antigen stimulated T cell proliferation; nevertheless costimulatory molecules for production of IL-13, IL-10 and IFN-gamma from T cells were intact. In contrast to DCs from healthy donors, DCs from many CVID patients had high spontaneous production of IL-8 and lipopolysaccharide stimulation often caused a reduction in DR expression. Expression of other cytokines (IL-1a, IL-6 and IL-12), either before or after LPS stimulation, was normal. The data suggests there is a fundamental defect in the maturation of MdDCs in a subset of CVID patients that may compromise antigen presentation and subsequent antibody production.
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PMID:Monocyte derived dendritic cell responses in common variable immunodeficiency. 1554 26

Interleukin-7 (IL-7) is produced by bone marrow and lymphoid stromal cells and is involved in the synthesis, survival and homeostasis of T cells. These attributes are the basis for current strategies to utilize IL-7 as an immune modulator for several clinical conditions to replenish depleted T-cell numbers. Because we had previously determined that IL-7 can induce potent human immunodeficiency virus replication in the otherwise non-permissive CD4(+) naive T-cell compartment, we evaluated here the impact of IL-7 on the phenotype and functional potential of naive CD4(+) T cells in an attempt to understand the mechanism of this induction. We demonstrate that IL-7 mediated the up-regulation of CD25, CD95 and human leucocyte antigen-DR, while it did not alter the expression of CD45RO, CD69, CD40, or CD154. Examination of the cytokine profile of IL-7-treated naive T cells using a Type1/Type2 Proteome Array indicated a remarkable IL-7-mediated induction of interferon-gamma production, while the other cytokines evaluated (IL-2, IL-12, tumour necrosis factor-alpha, IL-4, IL-5, IL-10 and IL-13) were not affected. Intracellular staining of IL-7-treated naive T cells for interferon-gamma verified the Proteome data. IL-7 did not induce cell cycle proliferation of naive CD4(+) T cells, as evaluated by 7-AAD/pyronin immunostaining and carboxyfluorescein diacetate succinimidyl ester dye tracking. IL-7 treatment of naive CD4(+) T cells induced their ability to prime monocytes, as was indicated by induction of CD80 and CD86 expression on monocytes cocultured with IL-7-treated naive CD4(+) T cells. Collectively, these data indicate that IL-7 signalling is sufficient to phenotypically and functionally prime human CD4(+) naive T cells independent of antigen stimulation.
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PMID:Interleukin-7 signalling is sufficient to phenotypically and functionally prime human CD4 naive T cells. 1572 Apr 34

Human immunodeficiency virus (HIV)-related opportunistic infections continue to occur in patients who are newly diagnosed with HIV infection, those in the early course of highly active antiretroviral therapy or nonadherent to HIV care, and other immunosuppressed individuals. One of the most common opportunistic infections in these patients is Pneumocystis pneumonia. CD8+ T cells are recruited to the lung after P. carinii infection and have been associated with both lung injury and host defense. This variability may be due to subpopulations of CD8+ T cells recruited to the lung. We have previously shown using adoptive transfer studies that in vivo-generated T-cytotoxic-1 (Tc1) CD8+ T cells, defined by the secretion of gamma interferon (IFN-gamma), have effector activity against Pneumocystis spp. in vitro as well as in vivo. To better understand the mechanisms of these effects, we generated, expanded, and tested Tc1 and Tc2 CD8+ T cells specific for P. murina ex vivo. Tc1-polarized CD8+ T cells secreted higher levels of IFN-gamma and granulocyte-macrophage colony-stimulating factor (GM-CSF) and lower levels of interleukin-4 (IL-4), IL-5, IL-10, and IL-13 than Tc2 CD8+ T cells when stimulated with P. murina antigen. Moreover, Tc1 CD8+ T cells demonstrated enhanced effector activity in a macrophage-mediated killing assay which was independent of cell contact. The augmentation in macrophage-mediated P. murina killing was significantly abrogated when GM-CSF was neutralized in the Tc1 CD8+ T cells. These data support the possibility that antigen-specific GM-CSF secretion is critical for effector activity of P. murina-specific Tc1 CD8+ T cells in vitro.
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PMID:In vitro effector activity of Pneumocystis murina-specific T-cytotoxic-1 CD8+ T cells: role of granulocyte-macrophage colony-stimulating factor. 1623 46

Although recent studies indicated that IL-21 is an important regulator of human B cell activation, detailed comparison of the effects of IL-21 on distinct B cell subsets have not been performed. Our studies revealed that IL-21R is expressed by naive and germinal center B cells, but not memory or plasma cells. IL-21R was increased on naive and memory B cells following in vitro activation. Investigation into the kinetics and magnitude of responses of human B cells to IL-21 revealed that IL-21 potently augmented proliferation of CD40L-stimulated neonatal, splenic naive, and memory and tonsil germinal center B cells. This response exceeded that induced by IL-4, IL-10, and IL-13, cytokines that also induce B cell proliferation. Remarkably, CD40L/IL-21-stimulated naive B cells underwent the same number of divisions as memory cells and exhibited a greater enhancement in their response compared with CD40L alone than memory B cells. Therefore, IL-21 is a powerful growth factor for naive B cells. This may result from the higher expression of IL-21R on naive, compared with memory, B cells. Stimulation of human B cells with CD40L/IL-21 also induced IL-10 production and activation of STAT3. We propose that IL-21 may have therapeutic application in conditions of immunodeficiency where it could expand naive B cells, the predominant B cell subset in such patients. Conversely, because IL-21 is increased in murine models of lupus, dysregulated IL-21 production may contribute to perturbed B cell homeostasis observed in systemic lupus erythematosus. Thus, antagonizing IL-21 may be a novel strategy for treating Ab-mediated autoimmune diseases.
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PMID:Kinetics of human B cell behavior and amplification of proliferative responses following stimulation with IL-21. 1701 9

The reviews on HIV-1/AIDS [1-8] highlighted the mechanism by which HIV-1 virions utilize dendritic cells (DCs) for transport from the genitals, the portal of virus infection, to the draining lymph nodes where DCs carry HIV-1 virions and present viral antigens by HLA class I and II to CD4(+) T cells. Interaction of the T cells with viral antigens presented by HLA class II molecules polarizes them to become Th2 cells, the targets of HIV-1 infection and producers of HIV-1 progeny virions. The T cells which interact with viral antigen presented by HLA class I polarize to become Th1 cells, which stimulate the CD8(+) T cell precursors to develop into antiviral cytotoxic T cells. In addition, HIV-1 virions shed gp120 glycoprotein molecules which bind to IgE immunoglobulin molecules bound to FCepsilonRI+ innate system cells (basophils, mast cells and monocytes) and induce them to release large amounts of Th2 cytokines (IL-4, IL-5, IL-10, IL-13), thereby creating an allergy-like condition. The present review attempts to define the role of chemokine receptors like CCR5 and CXCR4, and especially fractalkine receptor CX3CR1 in the trafficking of lymphocytes in healthy individuals and HIV-1/AIDS patients. The role of chemokine receptors as co-receptors for HIV-1 virion gp120 glycoprotein has been defined, but the role of fractalkine and fractalkine receptor has been clarified only recently [9-19]. In healthy individuals fractalkine is expressed by blood vessel endothelial cells and the CX3CR1 receptors are expressed on leukocytes that migrate in the peripheral blood in the direction of increased fractalkine concentration. In HIV-1/AIDS patients the virus-infected CD4(+) Th2 cells migrate to organs that harbor the adaptive immune system cells in the thymus, genitals, gastrointestinal tract, and to the brain. A most significant finding which revealed the importance of the human CX3CR1 gene expression to the progression of the infection to the stage of AIDS was recently reported by Faure and collaborators [20, 21] who showed that the delayed or rapid progression to AIDS was affected in HIV-1-infected individuals who had inherited a fractalkine receptor gene with the polymorphisms V249I or T280M, respectively, located in the sixth and seventh transmembrane domains of CX3CR1 protein. The T280M mutation in the CX3CR1 gene caused a rapid progression to AIDS, while in patients with the V249I mutation progression to AIDS was much slower. These studies led to the idea that it might be possible to slow or prevent HIV-1/AIDS progression in HIV-1 patients by treating them with fractalkine antagonists that will bind to and inhibit the activity of the fractalkine receptor. It is hypothesized that treatment of HIV-1/AIDS patients with a combination of fractalkine antagonists, IL-4 antagonist IL-4delta2 and the adjuvant CpG ODN induced release of type I IFN from PDF, and may inhibit HIV-1 infection, especially in HAART-treated patients infected with drug-resistant HIV-1 mutants due to prevention of the availability of immune cells needed for the viral evasion of the immune response. The hypothesis implies that the advantage of the suggested mode of treatment of HIV-1-infected people is prevention of cellular processes that are used by the viral protein to cause immunodeficiency, and prevention of HIV-1 replication without induction of resistant mutants.
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PMID:The spreading of HIV-1 infection in the human organism is caused by fractalkine trafficking of the infected lymphocytes--a review, hypothesis and implications for treatment. 1715 39

Naive B cells can alter the effector function of their Ig molecule by isotype switching, thereby allowing them to secrete not only IgM, but also the switched isotypes IgG, IgA, and IgE. Different isotypes are elicited in response to specific pathogens. Similarly, dysregulated production of switched isotypes underlies the development of various diseases, such as autoimmunity and immunodeficiency. Thus, it is important to characterize mediators controlling isotype switching, as well as their contribution to the overall B cell response. Isotype switching in human naive B cells can be induced by CD40L together with IL-4, IL-10, IL-13, and/or TGF-beta. Recently, IL-21 was identified as a switch factor for IgG1 and IgG3. However, the effect of IL-21 on switching to IgA, as well as the interplay between IL-21 and other switch factors, remains unknown. We found that IL-4 and IL-21 individually induced CD40L-stimulated human naive B cells to undergo switching to IgG, with IL-4 predominantly inducing IgG1(+) cells and IL-21 inducing IgG3. Culture of naive B cells with CD40L and IL-21, but not IL-4, also yielded IgA(+) cells. Combining IL-4 and IL-21 had divergent effects on isotype switching. Specifically, while IL-4 and IL-21 synergistically increased the generation of IgG1(+) cells from CD40L-stimulated B cells, IL-4 concomitantly abolished IL-21-induced switching to IgA. Our findings demonstrate the dynamic interplay between IL-4 and IL-21 in regulating the production of IgG subclasses and IgA, and suggest temporal roles for these cytokines in humoral immune responses to specific pathogens.
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PMID:IL-21-induced isotype switching to IgG and IgA by human naive B cells is differentially regulated by IL-4. 1864 14

Biomarkers for treatment response would facilitate the testing of urgently needed new anti-tuberculous drugs. The present study investigated the profiles of 30 proinflammatory, anti-inflammatory and angiogenic factors [epidermal growth factor, eotaxin, fractalkine, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interleukin (IL)-1alpha, IL-1beta, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p40, IL-12p70, IL-13, IL-15, IL-17, interferon-gamma, interferon-inducible protein-10, Krebs von den Lungen-6, monocyte chemotactic protein-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, sCD40L, transforming growth factor-alpha, tumour necrosis factor-alpha and vascular endothelial growth factor] in the plasma of 12 healthy tuberculin skin test-positive community controls and 20 human immunodeficiency virus-negative patients with active tuberculosis (TB) and identified potential biomarkers for early treatment response. We showed differences in the level of circulating cytokines between healthy controls and TB patients, but also between fast responders and slow responders to anti-tuberculosis treatment. The general discriminant analysis based on pre-treatment and week 1 measurements identified 10 sets of three-variable models that could classify fast and slow responders with up to 83% accuracy. Overall, this study shows the potential of cytokines as indicators of anti-tuberculosis treatment response.
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PMID:Differential cytokine secretion and early treatment response in patients with pulmonary tuberculosis. 1919 52

The pathogenic yeast Cryptococcus neoformans and C. gattii commonly cause severe infections of the central nervous system in patients with impaired immunity but also increasingly in immunocompetent individuals. Cryptococcus is phagocytosed by macrophages but can then survive and proliferate within the phagosomes of these infected host cells. Moreover, Cryptococcus is able to escape into the extracellular environment via a recently discovered nonlytic mechanism (termed expulsion or extrusion). Although it is well established that the host's cytokine profile dramatically affects the outcome of cryptococcal disease, the molecular basis for this effect is unclear. Here, we report a systematic analysis of the influence of Th1, Th2, and Th17 cytokines on the outcome of the interaction between macrophages and cryptococci. We show that Th1 and Th17 cytokines activate, whereas Th2 cytokines inhibit, anticryptococcal functions. Intracellular yeast proliferation was significantly lower after treatment with the Th1 cytokines gamma interferon and tumor necrosis factor alpha and the Th17 cytokine interleukin-17 (IL-17). Interestingly, however, the Th2 cytokines IL-4 and IL-13 significantly increased intracellular yeast proliferation while reducing the occurrence of pathogen expulsion. These results help explain the observed poor prognosis associated with the Th2 cytokine profile (e.g., in human immunodeficiency virus-infected patients).
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PMID:Cytokine signaling regulates the outcome of intracellular macrophage parasitism by Cryptococcus neoformans. 2786 24

Macrophages constitute major human immunodeficiency virus type 1 (HIV-1) reservoirs at the mucosal level, and their functional activity is modulated by cytokine environments that could play a role in HIV-1 mucosal spread. As proof of concept, we herein evaluated the modulation of HIV/macrophages interactions associated with two ubiquitous T(h)2 cytokines, namely, interleukin (IL)-4 and IL-13, using the in vitro model of R5-HIV-1 transfer from macrophages to T lymphocytes. Monocyte-derived macrophages differentiated in the presence of IL-4 (M-4) transferred the virus to T cells more efficiently than those differentiated in the presence of interleukin-13 (M-13), likely because to their high capacity to capture and produce HIV-1 and to recruit HIV-1 target T cell. However, M-13 harbored high levels of HIV DNA, similarly to M-4, and secreted HIV-activating factors. Notably, uninfected macrophages recruited HIV-1 target T cells (CCR4(+)IL-13(+) T(h)2 cells and CD4(+)CCR5(+) T cells), indicating their role in facilitating the HIV-1 spread by a passive manner. Strikingly, R5-HIV-1 reprogrammed macrophages toward a T(h)1 secretion pattern. Thus, T(h)2 microenvironment facilitates the emergence of HIV-1 macrophage reservoir and HIV-1 spread. In conclusion, secreted cytokines within mucosae may differentially influence both the HIV-1 production within the mucosal target cells reservoir and its spread thorough the mucosal tissue.
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PMID:Differential modulation of CCR5-tropic human immunodeficiency virus-1 transfer from macrophages towards T cells under interleukin-4/interleukin-13 microenvironment. 1970 16


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