Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026918 (Mycobacterium)
 52,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gammadelta T lymphocytes play an important role in the immune defense against infection, based on the unique reactivity of human Vdelta2Vgamma9 gammadelta T cells toward bacterial phosphoantigens. Chemokines and their corresponding receptors orchestrate numerous cellular reactions, including leukocyte migration, activation, and degranulation. In this study we investigated the expression of various receptors for inflammatory and homeostatic chemokines on peripheral blood gammadelta T cells and compared their expression patterns with those on alphabeta T cells. Although several of the analyzed receptors (including CCR6, CCR7, CXCR4, and CXCR5) were not differentially expressed on gammadelta vs alphabeta T cells, gammadelta T cells expressed strongly increased levels of the RANTES/macrophage inflammatory protein-1alpha/-1beta receptor CCR5 and also enhanced levels of CCR1-3 and CXCR1-3. CCR5 expression was restricted to Vdelta2 gammadelta T cells, while the minor subset of Vdelta1 gammadelta T cells preferentially expressed CXCR1. Stimulation with heat-killed extracts of Mycobacterium tuberculosis down-modulated cell surface expression of CCR5 on gammadelta T cells in a macrophage-dependent manner, while synthetic phosphoantigen isopentenyl pyrophosphate and CCR5 ligands directly triggered CCR5 down-modulation on gammadelta T cells. The functionality of chemokine receptors CCR5 and CXCR3 on gammadelta T cells was demonstrated by Ca(2+) mobilization and chemotactic response to the respective chemokines. Our results identify high level expression of CCR5 as a characteristic and selective feature of circulating Vdelta2 gammadelta T cells, which is in line with their suspected function as Th1 effector T cells.
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PMID:Patterns of chemokine receptor expression on peripheral blood gamma delta T lymphocytes: strong expression of CCR5 is a selective feature of V delta 2/V gamma 9 gamma delta T cells. 1199 42

We recently reported that dendritic cells (DC) infected with Mycobacterium tuberculosis (Mtb) produce Th1/IFN-gamma-inducing cytokines, IFN-alpha beta and IL-12. In the present article, we show that maturing Mtb-infected DC express high levels of CCR7 and they become responsive to its ligand CCL21. Conversely, CCR5 expression was rapidly lost from the cell surface following Mtb infection. High levels of CCL3 and CCL4 were produced within 8 h after infection, which is likely to account for the observed CCR5 down-modulation on Mtb-infected DC. In addition, Mtb infection stimulated the secretion of CXCL9 and CXCL10. Interestingly, the synthesis of CXCL10 was mainly dependent on the Mtb-induced production of IFN-alpha beta. Indeed, IFN-alpha beta neutralization down-regulated CXCL10 expression, whereas the expression of CXCL9 appeared to be unaffected. The chemotactic activity of the Mtb-infected DC supernatants was evaluated by migration assays using activated NK, CD4(+), and CD8(+) cells that expressed both CCR5 and CXCR3. Mtb-induced expression of CCL3, CCL4, CXCL9, and CXCL10 was involved in the stimulation of NK and T cell migration. In accordance with the data on the IFN-alpha beta-induced expression of CXCL10, neutralization of IFN-alpha beta significantly reduced the chemotactic activity of the supernatant from Mtb-infected DC. This indicates that IFN-alpha beta may modulate the immune response through the expression of CXCL10, which along with CXCL9, CCL3, and CCL4 participates in the recruitment and selective homing of activated/effector cells, which are known to accumulate at the site of Mtb infection and take part in the formation of the granulomas.
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PMID:IFN-alpha beta released by Mycobacterium tuberculosis-infected human dendritic cells induces the expression of CXCL10: selective recruitment of NK and activated T cells. 1253 73

The aim of this work was to characterize a leucocyte-differentiation antigen or chemokine receptor that allows the identification of type 1 (T helper 1 (Th1), Tc1) and type 2 (Th2, Tc2) lymphocytes in short-term-cultured human peripheral blood mononuclear cells. In addition, we assessed the type of response induced by mycobacterial antigens in tuberculosis patients and healthy contacts. Cells were stimulated with an unfractionated culture filtrate or 30 kDa antigen from Mycobacterium tuberculosis. Then, CD4 and CD8 cell labelling was combined with CD30, CD27, CD28, CD45RA or CD45R0 staining, detection of intracellular interferon-gamma (IFN-gamma) or interleukin-4 (IL-4) and analysis by three-colour flow cytometry. In separate experiments, the expression of different chemokine receptors (CCR1, CCR3, CCR5, CXCR3 and CXCR4) was also studied. We found that none of the cell-surface molecules studied was preferentially expressed by Th1 or Th2 cells. Thus, our results indicate that these lymphocyte subsets cannot be identified in short-term-cultured mononuclear cells on the basis of preferential expression of the cell markers studied, and that it is necessary to look for additional molecules that allow the discrimination of Th1 and Th2 cells.
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PMID:Cytokine production and expression of leucocyte-differentiation antigens by human mononuclear cells in response to mycobacterium tuberculosis antigens. 1258 57

Granuloma is a typical feature of tuberculosis. We evaluated the chemotaxis of selected human leucocyte subsets induced by macrophages incubated with Mycobacterium tuberculosis (MT)-derived products in vitro. The release of monocyte chemotactic protein 1 (MCP-1) and interleukin-8 (IL-8) correlated with the specific induction of strong chemotaxis towards monocytes and polymorphonuclear leucocytes (PMNs). gammadelta and T helper type 1 (Th1) alphabeta lymphocytes were chemoattracted, while T-resting, IL-2-activated and Th2 lymphocytes were unaffected. Activation with mycobacterium-derived, phosphate-containing components, modulated the chemokine receptor profile of gammadelta T lymphocytes as well as their pattern of cyto-chemokine production, disclosing a potential for their active participation in granuloma formation. In particular, CXCR3 and IP-10, which we found to be released by MT-pulsed alveolar macrophages, seem to represent the receptor-counter-receptor pair implicated in the chemotaxis of gammadelta lymphocytes. Immunohistochemical analysis and in situ hybridization revealed the in vivo presence of IL-8, MCP-1 and IL-10 in lymph node and lung tuberculous granulomas. Our results underscore the role of MT extracts in the induction of macrophage-derived chemokines responsible for the orchestrated recruitment of PMNs, monocytes, and Th1 and gammadelta T cells, as well as in the regulation of gammadelta function.
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PMID:Macrophages exposed to Mycobacterium tuberculosis release chemokines able to recruit selected leucocyte subpopulations: focus on gammadelta cells. 1260 3

Tuberculosis remains a major public health problem worldwide. Chemokines and cytokines organize and direct infiltrating cells to sites of infection, and these molecules likely play crucial roles in granuloma formation and maintenance. To address this issue, we used in situ hybridization (ISH) to measure chemokine and cytokine mRNA expression levels and patterns directly in lung tissues from cynomolgus macaques (Macaca fascicularis) experimentally infected with a low dose of virulent Mycobacterium tuberculosis. We examined more than 300 granulomas and observed abundant expression of gamma interferon (IFN-gamma)-inducible chemokine mRNAs (CXCL9/monokine induced by IFN-gamma, CXCL10/IFN-gamma-inducible protein, and CXCL11/IFN-gamma-inducible T-cell alpha-chemoattractant) within solid and caseous granulomas, and there was only minimal expression in nongranulomatous regions of tissue. The mRNA expression patterns of IFN-gamma and tumor necrosis factor alpha were examined in parallel, and the results revealed that cytokine mRNA(+) cells were abundant and generally localized to the granulomas. Mycobacterial 16S rRNA expression was also measured by ISH, and the results revealed that there was localization predominantly to the granulomas and that the highest signal intensity was in caseous granulomas. We observed several granulomatous lesions with exceptionally high levels of RNA for mycobacterial 16S rRNA, IFN-gamma, and IFN-gamma-inducible chemokines, suggesting that the local presence of mycobacteria is partially responsible for the upregulation of IFN-gamma-inducible chemokines and recruitment of CXCR3(+) cells, which were also abundant in granulomatous lesions. These results suggest that expression of CXCR3 ligands and the subsequent recruitment of CXCR3(+) cells are involved in granuloma formation and maintenance.
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PMID:In situ study of abundant expression of proinflammatory chemokines and cytokines in pulmonary granulomas that develop in cynomolgus macaques experimentally infected with Mycobacterium tuberculosis. 1463 92

We recently described a model of Th1 recall responses based on segmental antigen challenge with purified protein derivative of Mycobacterium tuberculosis (PPD). Bronchoscopic instillation of 0.5 tuberculin units of PPD resulted in localized lymphocytic inflammation in PPD-positive subjects only. Recruited lymphocytes were predominantly CD4+ and were enriched for cells capable of PPD-specific interferon (IFN)-gamma production. In the current study, we investigated the mechanisms by which this localized recall response is mobilized. Bronchoscopic PPD challenge of skin test-positive subjects resulted in the production of CXCR3 ligands IFN-gamma-inducible protein (IP)-10 and monokine induced by IFN-gamma (Mig), but not of CCR5 ligands macrophage inflammatory protein-1alpha and regulated-upon activation, normal T-cell expressed and secreted, whereas skin test-negative subjects produced none of these chemokines. Baseline bronchoalveolar lavage (BAL) cells of skin test-positive subjects produced IP-10 and Mig in response to in vitro stimulation as well. Because IP-10 and Mig are IFN-gamma-inducible chemokines, these findings suggested that chemokine responses to PPD were facilitated by resident memory cells of the lung. Further studies confirmed that baseline BAL lymphocytes of PPD-positive subjects produce IFN-gamma in response to PPD, and that, compared with peripheral blood, BAL cells are preferentially enriched for PPD-specific lymphocytes. This IFN-gamma production is predominantly a function of CD4+ T cells that display the CD45RO+/CCR7- surface phenotype characteristic of effector memory cells.
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PMID:Resident Th1-like effector memory cells in pulmonary recall responses to Mycobacterium tuberculosis. 1577 93

Containment of Mycobacterium tuberculosis critically depends on orchestrated generation of Th1 cells and their selective recruitment at the pathologic sites. Understanding the mechanism involved in this process is important for defining better intervention strategies. We investigated the surface phenotype of Th1 cells and the role of chemotactic factors in their selective recruitment in tuberculosis pleural effusion and tuberculin site. Memory T cells obtained from the pleural fluid expressed a battery of homing receptors such as CD11a, CCR5 and CXCR3. Similar expression profile was noted on T cells infiltrating the tuberculin site. Expression of their respective ligands such as ICAM-1, RANTES, MIP1-alpha, Mig and IP-10 were detected at pathologic sites. In vitro assay of T cell adherence to activated human umbilical vein endothelial cells (HUVEC) expressing chemotactic ligands suggests an important role of these homing molecules in their selective trafficking. Here, we demonstrate a hierarchy of CXCR3 in effector cell adhesion to HUVEC in vitro, although CD11a and CCR5 were also observed to mediate cell adhesion in an additive fashion. Findings of the present study provide mechanistic insights into the critical events of T cell trafficking in tuberculosis and may help designing better therapeutic modalities.
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PMID:Polarized helper T cells in tubercular pleural effusion: phenotypic identity and selective recruitment. 1602 63

IFN-gamma responses to Mycobacterium tuberculosis antigens ESAT-6 and CFP-10 have been proposed as specific markers of M. tuberculosis infection. Monokine induced by gamma interferon (MIG/CXCL9) has been shown to be expressed by IFN-gamma stimulated mononuclear cells and to attract activated T-cells through the chemokine receptor CXCR3. Since MIG is induced early in the response to IFN-gamma, measuring MIG may provide an interesting marker to assess downstream IFN-gamma induced responses, in contrast to assays that mainly focus on quantifying production of IFN-gamma per se. We, therefore, investigated MIG and IFN-gamma responses to a fusion protein of ESAT-6 and CFP-10, and compared responses to the conserved mycobacterial antigen 85B (Ag85B) and purified protein derivative (PPD) of M. tuberculosis, in 29 BCG vaccine controls and 24 TB patients. IFN-gamma secreting cells were determined by ELISPOT, and MIG production was measured by ELISA and flow cytometry. Production of MIG in response to ESAT-6/CFP-10, Ag85B and PPD correlated overall with increased numbers of IFN-gamma secreting cells (r=0.55, P<0.0001). A significant increase was noted among patients compared to controls in the secretion of IFN-gamma and MIG following stimulation with ESAT-6/CFP-10 or PPD (P<0.05). Moreover, MIG intracellular expression was higher in TB patients compared to BCG vaccines (P<0.05) in response to ESAT-6/CFP-10 or PPD. We conclude that MIG production correlates significantly with enhanced T-cell IFN-gamma production induced by M. tuberculosis-specific antigens ESAT-6/CFP-10. These results point to MIG as a potential novel biomarker that may be helpful in assessing downstream responses induced by IFN-gamma in TB.
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PMID:Monokine induced by interferon gamma and IFN-gamma response to a fusion protein of Mycobacterium tuberculosis ESAT-6 and CFP-10 in Brazilian tuberculosis patients. 1626 63

Little is known regarding the early events of infection of humans with Mycobacterium tuberculosis. The cynomolgus macaque is a useful model of tuberculosis, with strong similarities to human tuberculosis. In this study, eight cynomolgus macaques were infected bronchoscopically with low-dose M. tuberculosis; clinical, immunologic, microbiologic, and pathologic events were assessed 3 to 6 weeks postinfection. Gross pathological abnormalities were observed as early as 3 weeks, including Ghon complex formation by 5 weeks postinfection. Caseous granulomas were observed in the lung as early as 4 weeks postinfection. Only caseous granulomas were observed in the lungs at these early time points, reflecting a rigorous initial response. T-cell activation (CD29 and CD69) and chemokine receptor (CXCR3 and CCR5) expression appeared localized to different anatomic sites. Activation markers were increased on cells from airways and only at modest levels on cells in peripheral blood. The priming of mycobacterium-specific T cells, characterized by the production of gamma interferon occurred slowly, with responses seen only after 4 weeks of infection. These responses were observed from T lymphocytes in blood, airways, and hilar lymph node, with responses predominantly localized to the site of infection. From these studies, we conclude that immune responses to M. tuberculosis are relatively slow in the local and peripheral compartments and that necrosis occurs surprisingly quickly during granuloma formation.
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PMID:Early events in Mycobacterium tuberculosis infection in cynomolgus macaques. 1679 Jul 51

The chemokine receptor CXCR3 plays a significant role in regulating the migration of Th1 cells. Given the importance of Th1 immunity in the control of tuberculous infection, the results of the present study demonstrating that CXCR3-deficient BALB/c mice are more resistant to Mycobacterium tuberculosis, compared with wild-type mice, is surprising. This enhanced resistance manifests in the chronic but not the acute phase of infection. Remarkable differences in the cellular composition of the pulmonic granuloma of the CXCR3(-/-) and wild-type mice were found, the most striking being the increase in the number of CD4(+) T cells in the knockout strain. In the chronic phase of infection, the number of CD69-expressing CD4(+) T lymphocytes in the lungs of CXCR3(-/-) mice was higher than in wild-type mice. Additionally, at 1 mo postinfection, the number of IFN-gamma-producing CD4(+) T cells in the lungs and mediastinal lymph nodes of the CXCR3-deficient strain was elevated compared with wild-type mice. Pulmonic expression of IFN-gamma, IL-12, TNF-alpha, or NO synthase 2, the principal antimycobacterial factors, were equivalent in the two mouse strains. These results indicate that: 1) CXCR3 plays a role in modulating the cellular composition of tuberculous granuloma; 2) CXCR3 impairs antimycobacterial activity in chronic tuberculosis; and 3) in the absence of CXCR3, mice exhibit a heightened state of CD4(+) T lymphocyte activation in the chronic phase of infection that is associated with enhanced CD4(+) T cell priming. Therefore, CXCR3 can attenuate the host immune response to M. tuberculosis by adversely affecting T cell priming.
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PMID:The chemokine receptor CXCR3 attenuates the control of chronic Mycobacterium tuberculosis infection in BALB/c mice. 1723 22


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