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

Opioids, via the mu opioid receptor (MOR), can exacerbate bacterial infections and the immunopathogenesis of human immunodeficiency virus type 1 (HIV-1) infection. Recently, an HIV-1 transgenic (HIV-1Tg) rat model containing circulating HIV-1 gp120 was created. Using real-time reverse transcription-PCR, we found that MOR mRNA levels were significantly higher in the peritoneal macrophages of the HIV-1Tg rat than those in control animals. Lipopolysaccharide, a bacterial endotoxin, induced secretion of the inflammatory cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-beta (IL-beta), and IL-10 in the HIV-1Tg rat and further increased MOR expression. Ex vivo studies showed that MOR expression was up-regulated in the peritoneal macrophages of F344 control rats by exposure to serum from HIV-1Tg rats and that MOR up-regulation was abolished by addition of gp120 antibody to the serum. In human TPA-differentiated HL-60 cells, which are macrophage-like cells, LPS-induced MOR mRNA up-regulation was greater in gp120-pretreated cells than in vehicle-pretreated cells. Our data suggest that in individuals infected with HIV-1, the MOR is up-regulated, possibly by circulating HIV-1 proteins such as gp120, and HIV-1 proteins may play a significant role in modulating the response to bacterial infection in opioid-using HIV-infected individuals. Furthermore, our results demonstrate that the new HIV-1Tg rat model can be a valuable tool with which to study MOR gene expression and its effects in the continuous presence of HIV viral proteins.
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PMID:Expression of the mu opioid receptor in the human immunodeficiency virus type 1 transgenic rat model. 1755 97

We describe a 26-year-old female referred to us because of recurrent bacterial pneumonia. Her immunoglobulin profile on admission was; IgG 1920 mg/l, IgA 60 mg/l, IgM 260 mg/l, IgD below 20 mg/l, IgE below 1 kU/l. Antinuclear antibodies, EBV VCA IgM, anti-parvovirus B19 IgM antibodies and hepatitis infection markers were all negative. Bone marrow aspiration revealed normal cellularity without abnormal cells, especially plasma cell proliferation. No rearrangement for IgH and TCR was observed as determined by Southern blot analysis. By the given data, a diagnosis of common variable immunodeficiency (CVID) was made. The genesis of this disease remained unclear. In this study, proliferation and immunoglobulin production with or without several stimulators were examined. Proliferation stimulated by PHA, Con-A, LPS, or IL-2 was decreased compared to that of healthy individuals. Immunoglobulin production after stimulation with several agents was quite low. Interestingly, however, IL-2 or IL-4 could increase IgM production on 6 days culture significantly. These results indicate that IL-2 or IL-4 possibly restore T cell responses to several antigens and induce B cell differentiation.
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PMID:Partial restoration of immunoglobulin production by cytokines in common variable immunodeficiency. 1782 53

Protein-energy malnutrition (PEM) modifies resistance to infection, impairing a number of physiological processes, including hematopoiesis. In this study, we examined a few aspects of the inflammatory response to LPS in a model of PEM. We evaluated the cellularity of the blood, bone marrow and spleen, as well as phagocytic, fungicidal and spreading activity, the production in vivo and in vitro of TNF-alpha, IL-1alpha and IL-6, and the expression of CD14 and TLR-4/MD-2 receptors in macrophages. Two-month-old male Swiss mice were submitted to PEM with a low-protein diet containing 4% protein as compared to 20% protein in the control diet. When the experimental group had attained about 20% loss of their original body weight, they were used in the experiments. Malnourished animals presented anemia, leucopenia and severe reduction in bone marrow, spleen and peritoneal cavity cellularity. The production of TNF-alpha, IL-1alpha and IL-6 stimulated in vivo with LPS and the production of IL-6 in bone marrow cells cultured with LPS and the production of TNF-alpha in bone marrow, spleen and peritoneal cells cultured with LPS were significantly lower in malnourished animals. The expression of CD14 and TLR-4/MD-2 receptors was found to be significantly lower in macrophages of malnourished animals. These findings suggest that malnourished animals present a deficient response to LPS. The lower expression of the CD14 and TLR-4/MD-2 receptors may be partly responsible for the immunodeficiency observed in the malnourished mice. These data lead us to infer that the nutritional state interferes with the activation of macrophages and with the capacity to mount an immune response.
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PMID:Protein-energy malnutrition decreases the expression of TLR-4/MD-2 and CD14 receptors in peritoneal macrophages and reduces the synthesis of TNF-alpha in response to lipopolysaccharide (LPS) in mice. 1795 Jun 15

Regulatory T cells (Treg) are increased and directly infected by feline immunodeficiency virus (FIV) and likely play a role in other feline autoimmune, neoplastic, and infectious diseases. Phenotypically, Treg are best characterized by surface expression of CD4 and CD25 and intranuclear expression of the forkhead transcription factor Foxp3. Our objective was to clone and sequence feline FOXP3 for the purpose of developing assays to enhance studies of feline Treg. We determined the feline FOXP3 is 1293 nucleotides in length and codes for a protein that shares high homology to other species. A splice variant devoid of exon 2 was also identified. A real-time PCR assay was developed and used to show Foxp3 mRNA expression occurs primarily in CD4+CD25+ T cells. Two cross-reacting antibodies were identified by immunocytochemical staining of HEK293 cells transfected with feline FOXP3. The antibody labeling confirmed the nuclear localization of the protein. A flow cytometric assay was also validated and used to correlate the phenotypic and functional characteristics of feline Treg induced by treatment of lymph node lymphocytes with flagellin or LPS in combination with mitogen or IL2. Together, these studies provide useful tools to further investigate Foxp3 and Tregs in cats.
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PMID:Cloning of feline FOXP3 and detection of expression in CD4+CD25+ regulatory T cells. 1818 44

The production of TNF-alpha and IFN-alpha cytokines by peripheral blood mononuclears in response to stimulation by TLR2/6, TLR4, TLR5, TLR9 ligands (zymosan, LPS, flagellin, and CpG-oligodeoxynucleotide, respectively) was studied in donors and patients with common variable immunodeficiency. Individual characteristics of TNF-alpha production by mononuclears were revealed in donors. Reduced stimulated production of TNF-alpha in response to stimulation with TLR4 and TLR5 ligands in vitro was detected in patients with common variable immunodeficiency.
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PMID:Analysis of toll-like receptor-dependent production of proinflammatory cytokines in vitro by human peripheral blood mononuclears of donors and patients with primary immunodeficiency. 1825 54

The regulatory NEMO (NF-kappaB essential modulator) protein has a crucial role in the canonical NF-kappaB signaling pathway notably involved in immune and inflammatory responses, apoptosis and oncogenesis. The regulatory domain is located in the C-terminal half of NEMO and contains a classical CCHC-type zinc finger (ZF). We have investigated the structural and functional effects of a cysteine to phenylalanine point mutation (C417F) in the ZF motif, identified in patients with anhidrotic ectodermal dysplasia with immunodeficiency. The solution structures of the wild type and mutant ZF were determined by NMR. Remarkably, the mutant adopts a global betabetaalpha fold similar to that of the wild type and retains thermodynamic stability, i.e., the ability to bind zinc with a native-like affinity, although the last zinc-chelating residue is missing. However, the mutation induces enhanced dynamics in the motif and leads to an important loss of stability. A detailed analysis of the wild type solution structure and experimental evidences led to the identification of two possible protein-binding surfaces that are largely destabilized in the mutant. This is sufficient to alter NEMO function, since functional complementation assays using NEMO-deficient pre-B and T lymphocytes show that full-length C417F pathogenic NEMO leads to a partial to strong defect in LPS, IL-1beta and TNF-alpha-induced NF-kappaB activation, respectively, as compared to wild type NEMO. Altogether, these results shed light onto the role of NEMO ZF as a protein-binding motif and show that a precise structural integrity of the ZF should be preserved to lead to a functional protein-recognition motif triggering full NF-kappaB activation.
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PMID:Solution structure of NEMO zinc finger and impact of an anhidrotic ectodermal dysplasia with immunodeficiency-related point mutation. 1831 93

Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by hypogammaglobulinemia and recurrent infections. Herein we addressed the role of unfolded protein response (UPR) in the pathogenesis of the disease. Augmented unspliced X-box binding protein 1 (XBP-1) mRNA concurrent with co-localization of IgM and BiP/GRP78 were found in one CVID patient. At confocal microscopy analysis this patient's cells were enlarged and failed to present the typical surface distribution of IgM, which accumulated within an abnormally expanded endoplasmic reticulum. Sequencing did not reveal any mutation on XBP-1, neither on IRE-1alpha that could potentially prevent the splicing to occur. Analysis of spliced XBP-1, IRE-1alpha and BiP messages after LPS or Brefeldin A treatment showed that, unlike healthy controls that respond to these endoplasmic reticulum (ER) stressors by presenting waves of transcription of these three genes, this patient's cells presented lower rates of transcription, not reaching the same level of response of healthy subjects even after 48 h of ER stress. Treatment with DMSO rescued IgM and IgG secretion as well as the expression of spliced XBP-1. Our findings associate diminished splicing of XBP-1 mRNA with accumulation of IgM within the ER and lower rates of chaperone transcription, therefore providing a mechanism to explain the observed hypogammaglobulinemia.
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PMID:Slower rescue of ER homeostasis by the unfolded protein response pathway associated with common variable immunodeficiency. 1832 93

Foals are particularly vulnerable to infection by Rhodococcus equi during the first 2 weeks of life whereas mature horses are not. While an innate immunodeficiency likely accounts for this clinically relevant vulnerability, the factors that contribute to infection by R. equi have not been fully elucidated. In this study, we demonstrate that cells of the monocyte lineage, including monocytes, macrophages, and dendritic cells, that have been activated with LPS and IFN-gamma, respond with a statistically significant, greater amount of cytokine mRNA production of IL-10, IL-12p35, and IL-12p40 than unstimulated control cells. Interestingly, activation of neonatal cells resulted in a twofold log increase in baseline cytokine mRNA expression of IL-10 compared with adult cells. In contrast, no significant differences in mean cytokine mRNA expression of IL-12p35 and IL-12p40 were detected, suggesting that the defect in chromosomal remodeling that prevents IL-12p35 gene transcription as a cause for decreased IL-12 synthesis in human neonates is not a likely occurrence in equine neonates. Collectively, these differences indicate that in vivo activation of equine cells of the monocyte lineage may result in different autocrine and paracrine cellular responses that vary according to age, with potential impact on regulation of adaptive and innate immune responses.
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PMID:Activation of peripheral blood monocytes results in more robust production of IL-10 in neonatal foals compared to adult horses. 1897 18

The NADPH oxidase (NOX), an oligomeric enzyme, plays a key role in polymorphonuclear neutrophil (PMN)-mediated host defense by producing cytotoxic superoxide anion (O(2)( )). Whereas in vitro and biochemical studies have examined the assembly and activation of this important host immune defense system, few studies have examined the function of NOX in human patients with primary immunodeficiency other than chronic granulomatous disease. We studied the activation of NOX in PMN from patients with two distinct immunodeficiencies, IL-1R-associated kinase (IRAK)4 deficiency and NF-kappaB essential modulator (NEMO or IkappaB kinase gamma) deficiency. We observed impaired O(2)( ) generation by LPS-treated and fMLP-activated IRAK4-deficient PMN that correlated with decreased phosphorylation of p47(phox) and subnormal translocation of p47(phox), p67(phox), Rac2, and gp91(phox)/Nox2 to the membranes indicating that TLR4 signaling to the NOX activation pathway requires IRAK4. NEMO-deficient PMN generated significantly less O(2)( ) in response to LPS-primed fMLP and translocated less p67(phox) than normal PMN, although p47(phox) and Rac2 translocation were normal. Generally, responses of NEMO-deficient cells were intermediate between IRAK4-deficient cells and normal cells. Decreased LPS- and fMLP-induced phosphorylation of p38 MAPK in both IRAK4- and NEMO-deficient PMN implicates additional signal transduction pathways in regulating PMN activation by LPS and fMLP. Decreased activation of NOX may contribute to the increased risk of infection seen in patients with IRAK4 and NEMO deficiency.
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PMID:Impaired priming and activation of the neutrophil NADPH oxidase in patients with IRAK4 or NEMO deficiency. 1972 66

We previously described a murine model of malnutrition that mimicked features of moderate human malnutrition, and led to increased dissemination of Leishmania donovani. In this study, we investigated the effect of malnutrition on macrophage production of cytokines, prostaglandins (PGs), and leukotrienes (LTs). Using either LPS or calcium ionophore A23187 as a stimulus, macrophages from the malnourished mice produced a 3-fold higher PG/LT ((PGE(2)+6-keto-PGF(1alpha))/(LTB(4)+cysteinyl leukotrienes)) ratio than macrophages from well-nourished mice. LPS-stimulated macrophages from the malnourished mice produced decreased levels of TNF-alpha, GM-CSF, and IL-10, but similar levels of IL-6 and NO compared to well-nourished mice. A complex crosstalk between the eicosanoids and cytokines in the LPS-stimulated macrophages from the malnourished mice was evident by the following: (1) high levels of PG secretion despite low levels of TNF-alpha; (2) supplemental IL-10 modulated the excessive PG production; (3) GM-CSF rectified the PG/LT ratio, but did not correct the abnormal cytokine profile; and (4) inhibitors of cyclooxygenase decreased the PG/LT ratio, but did not affect TNF-alpha. Thus, in this model of malnutrition, there is a relative increase in anti-inflammatory PGs compared to pro-inflammatory LTs, which may contribute to immunodeficiency.
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PMID:Malnutrition promotes prostaglandin over leukotriene production and dysregulates eicosanoid-cytokine crosstalk in activated resident macrophages. 1954 68


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