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  • 1
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    Scandinavian journal of immunology 57 (2003), S. 0 
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Leprosy is an infectious disease with two polar forms, tuberculoid leprosy (TT) and lepromatous leprosy (LL), that are characterized by strong cell-mediated immunity (CMI) and CMI anergy, respectively. Transforming growth factor-β (TGF-β) belongs to a family of pleiotropic cytokines (TGF-β1, TGF-β2 and TGF-β3) that participate in the control of cell differentiation and proliferation, as well as tissue repair. This cytokine family is unique because it suppresses CMI. In this study, we compared the expression of the three TGF-β isoforms and their receptors in skin biopsies from LL and TT patients (LL = 20; TT = 20) using immunohistochemistry and automated morphometry. The percentage of cells immunostained for the three TGF-β isoforms and cells positive for the three TGF-β receptors in the inflammatory infiltrate located in the papillary dermis, reticular dermis and periadnexal tissue were significantly higher in LL than that in TT, with macrophages being the most common and strongest immunoreactive cells. Some lymphocytes, fibroblasts, keratinocytes and epithelial cells from sweat glands and hair roots were also positive. In situ reverse-transcription polymerase chain reaction corroborated the capacity of these cells to synthesize TGF-β1 and TGF-β receptor 2. This high expression of TGF-β isoforms and their receptors could contribute to CMI anergy and other clinical characteristic features of leprosy, like skin atrophy.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: To study the location and mechanism of apoptosis within the human tuberculosis (TB) and leprosy lesions, parallel sections were analyzed for mycobacterial antigens (M.Ag), Fas ligand (FasL), Fas, CD68 and Mac387 by immunohistochemistry, and apoptotic cells by the terminal deoxynucleotidyl-transferase-mediated dUTP-digoxigenin nick end labelling method. Cutaneous leishmaniasis and foreign body granulomas were analyzed for comparison. The heavily infected macrophages in multibacillary TB and leprosy granulomas very strongly expressed FasL, indicating that a mycobacterial infection can induce an increased expression of FasL in a population of infected macrophages, which may protect them from the attack of Fas-expressing lymphocytes. However, macrophages with high levels of leishmania amastigotes did not selectively express FasL, suggesting that this phenomenon is specific for the mycobacteria. Interestingly, in the well-formed TB granulomas, 84% of the multinucleated giant cells strongly expressed FasL. The expression of Fas was weak (34%) or absent. A higher number (33%) of epithelioid cells expressed FasL than Fas (23%). Lymphocytes were scanty among the epithelioid cells. The frequency of apoptotic cells was higher in the epithelioid cells (0.25%) than the mononuclear cells in the mantle zone (0.14%). Thus, the epithelioid cells and the multinucleated giant cells by virtue of the increased expression of FasL may make these granulomas an immune privileged site for mycobacteria.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background  Nerve damage is a common and disabling feature of leprosy, with unclear aetiology. It has been reported that the peroxidizing agents of myelin lipids—nitric oxide (NO) and peroxynitrite—are produced in leprosy skin lesions.Objectives  To investigate the localization of nitrotyrosine (NT)—a local end-product of peroxynitrite—in leprosy lesions where dermal nerves are affected by a granulomatous reaction.Methods  We investigated by immunohistochemistry and immunoelectron microscopy the localization of the inducible NO synthase (iNOS) and NT in biopsies exhibiting dermal nerves from patients with untreated leprosy.Results  There were abundant NT-positive and iNOS-positive macrophages in the borderline leprosy granulomas infiltrating peripheral nerves identified by light microscopy, S-100 and neurofilament immunostaining. Immunoelectron microscopy showed NT reactivity in neurofilament aggregates and in the cell wall of Mycobacterium leprae.Conclusions  Our results suggest that NO and peroxynitrite could be involved in the nerve damage following borderline leprosy.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    British journal of dermatology 148 (2003), S. 0 
    ISSN: 1365-2133
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Summary Background Leprosy is an infectious disease with two polar forms, tuberculoid leprosy (TL) and lepromatous leprosy (LL), which are dominated by T-helper (Th) 1 and Th2 cells, respectively. High concentrations of prostaglandin E2 produced by the inducible enzyme cyclooxygenase type 2 (COX-2) in LL could inhibit Th1 cytokine production, contributing to T-cell anergy. Objectives To compare the COX-2 expression in LL and TL. Methods Skin biopsies from 40 leprosy patients (LL, n = 20; TL, n = 20) were used to determine by immunohistochemistry and automated morphometry the percentage of COX-2 immunostained cells. Results Most COX-2-positive cells were macrophages; their percentages in the inflammatory infiltrate located in the papillary dermis, reticular dermis and periadnexally were significantly higher in LL than TL (P 〈 0·001 by Student's t-test). Conclusions The high expression of COX-2 in LL may be related to high prostaglandin production contributing to T-cell anergy.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    FEMS immunology and medical microbiology 12 (1995), S. 0 
    ISSN: 1574-695X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology , Medicine
    Notes: Abstract When mice were infected with virulent Mycobacterium tuberculosis H37Rv by the intra-tracheal route, there was an early phase of adrenal hyperplasia, histologically resembling the adrenocorticotropic (ACTH)-driven changes seen in Cushing's disease. This was followed at 3 weeks by progressive atrophy until the weight of the adrenals was ∼ 50% of that seen in control uninfected mice, in spite of the fact that the adrenals were not infected. All layers of the adrenal cortex were affected, but the medulla was normal. Electron microscope studies revealed apoptosis. The switch from adrenal hyperplasia to adrenal atrophy corresponded to onset of an IgG1 response recognising a wide range of mycobacterial components in Western blots. Delayed type hypersensitivity (DTH) responses were seen throughout, but differed in their sensitivity to TNFα. Thus if TNFα was injected at 24 h into DTH sites elicited during the phase of adrenal hyperplasia, there was no increment in swelling at 48 h. However similar injections of TNFα resulted in a doubling of the swelling in DTH sites elicited during the phase of adrenal atrophy. This may be relevant to the pathogenesis of cytokine-mediated tissue damage in the human disease. If 2 months before mice received the intratracheal infection, they were pre-immunised with 1 × 107 autoclaved Mycobacterium vaccae, a stimulus previously shown to induce a Th1 pattern of response, the early increase in adrenal weight was attenuated and delayed, and the subsequent atrophy did not occur. In sharp contrast, pre-immunisation with 1 × 109 autoclaved M. vaccae, known to prime a mixed pattern of cytokine release (IFNγ) and IL-4), resulted in adrenal atrophy that began within 4 days of infection, and was complete by day 14. These results suggested that the pattern of cytokine release provoked by the infection, modulated the adrenal changes, perhaps in synergy with products derived from the organisms themselves. Since we have already shown that profound adrenal changes also occur in human tuberculosis, we now propose that a change somewhere in the cytokine-hypothalamo-pituitary-adrenal axis may underlie the T cell dysfunction and immunologically-mediated tissue damage in this disease.
    Type of Medium: Electronic Resource
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  • 6
    Publication Date: 2013-10-11
    Description: The genus Mycobacterium comprises more than 150 species, including important pathogens for humans which cause major public health problems. The vast majority of efforts to understand the genus have been addressed in studies with Mycobacterium tuberculosis . The biological differentiation between M. tuberculosis and nontuberculous mycobacteria (NTM) is important because there are distinctions in the sources of infection, treatments, and the course of disease. Likewise, the importance of studying NTM is not only due to its clinical significance but also due to the mechanisms by which some species are pathogenic while others are not. Mycobacterium avium complex (MAC) is the most important group of NTM opportunistic pathogens, since it is the second largest medical complex in the genus after the M. tuberculosis complex. Here, we evaluated the virulence and immune response of M. avium subsp. avium and Mycobacterium colombiense , using experimental models of progressive pulmonary tuberculosis and subcutaneous infection in BALB/c mice. Mice infected intratracheally with a high dose of MAC strains showed high expression of tumor necrosis factor alpha (TNF-α) and inducible nitric oxide synthase with rapid bacillus elimination and numerous granulomas, but without lung consolidation during late infection in coexistence with high expression of anti-inflammatory cytokines. In contrast, subcutaneous infection showed high production of the proinflammatory cytokines TNF-α and gamma interferon with relatively low production of anti-inflammatory cytokines such as interleukin-10 (IL-10) or IL-4, which efficiently eliminate the bacilli but maintain extensive inflammation and fibrosis. Thus, MAC infection evokes different immune and inflammatory responses depending on the MAC species and affected tissue.
    Print ISSN: 0019-9567
    Electronic ISSN: 1098-5522
    Topics: Medicine
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  • 7
    Publication Date: 2012-09-23
    Description: Background.  One-third of the world's population has latent infection with Mycobacterium tuberculosis , and 10%–15% of cases of reactivation occur at extrapulmonary sites without active pulmonary tuberculosis. Methods.  To establish the frequency and location of mycobacterial DNA, organ specimens from 49 individuals who died from causes other than tuberculosis were studied by means of polymerase chain reaction (PCR), PCR plus DNA hybridization, in situ PCR, real-time PCR, and spoligotyping. Results.  Lung specimens from most subjects (36) were positive for M. tuberculosis , as were specimens from the spleen (from 35 subjects), kidney (from 34), and liver (from 33). By in situ PCR, mycobacterial DNA was found in endothelium, pneumocytes, and macrophages from the lung and in Bowman's parietal cells and convoluted proximal tubules from the kidney. In spleen, macrophages and sinusoidal endothelial cells were positive, whereas in liver, Kupffer cells and sinusoidal endothelium were commonly positive. Spoligotyping of 54 pulmonary and extrapulmonary positive tissues from 30 subjects showed 43 different genotypes, including 36 orphan types. To confirm the viability of mycobacteria, 10 positive tissue samples were selected for isolation of mycobacterial RNA. All samples showed 16S ribosomal RNA expression, while 8 and 4 samples showed expression of the latent infection genes encoding isocitrate lyase and α-crystallin, respectively. Conclusions.   M. tuberculosis persists in several sites and cell types that might constitute reservoirs that can reactivate infection, producing extrapulmonary tuberculosis without lung involvement.
    Print ISSN: 0022-1899
    Electronic ISSN: 1537-6613
    Topics: Medicine
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  • 8
    Publication Date: 2016-09-17
    Description: Mycobacterium tuberculosis ( Mtb ) latent infection can lead to reactivation. The design of new strategies to prevent it is an important subject. B6D2F1 mice were infected intratracheally with a low dose of Mtb H37Rv to induce chronic infection. After 7 months, mice were treated with one dose of recombinant adenoviruses encoding TNFα, β defensin-3 and LL37. Immunosupression was induced 1 month later with corticosterone. In comparison with the control group, mice treated with adenoviruses showed significantly less bacterial load and pneumonia, the adenoviruses encoding TNFα and LL37 being the most efficient. Gene therapy based in a proinflammatory cytokine or antimicrobial peptides is a potentially useful system to prevent reactivation of latent tuberculosis.
    Print ISSN: 0928-8244
    Topics: Biology , Medicine
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  • 9
    Publication Date: 2017-11-23
    Description: The emergence and spread of drug-resistant Mycobacterium tuberculosis strains possibly threaten our ability to treat this disease in the future. Even though two new antitubercular drugs have recently been introduced, there is still the need to design new molecules whose mechanisms of action could reduce the length of treatment. We show that two alternative sigma factors of M. tuberculosis (SigE and SigB) have a major role in determining the level of basal resistance to several drugs and the amount of persisters surviving long-duration drug treatment. We also demonstrate that ethambutol, a bacteriostatic drug, is highly bactericidal for M. tuberculosis mutants missing either SigE or SigB. We suggest that molecules able to interfere with the activity of SigE or SigB not only could reduce M. tuberculosis virulence in vivo but also could boost the effect of other drugs by increasing the sensitivity of the organism and reducing the number of persisters able to escape killing.
    Print ISSN: 0066-4804
    Electronic ISSN: 1098-6596
    Topics: Biology , Medicine
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  • 10
    Publication Date: 2016-01-23
    Description: Epidemiological information and animal models have shown various Mycobacterium tuberculosis phenotypes ranging from hyper- to hypovirulent forms. Recent genomic and proteomic studies suggest that the outcome of infection depends on the M. tuberculosis fitness, which is a direct consequence of its phenotype. However, little is known about the molecular and cellular mechanisms used by mycobacteria to survive, replicate and persist during infection. The aim of this study was to perform a comprehensive proteomic analysis of culture filtrate from hypo- (CPT23) and hypervirulent (CPT31) M. tuberculosis isolates. Using two-dimensional electrophoresis we observed that 70 proteins were unique, or more abundant in culture filtrate of CPT31, and 15 of these were identified by mass spectrometry. Our analysis of protein expression showed that most of the proteins identified are involved in lipid metabolism (FadA3, FbpB and EchA3), detoxification and adaptation (GroEL2, SodB and HspX) and cell wall processes (LprA, Tig and EsxB). These results suggest that overrepresented proteins in M. tuberculosis CPT31 secretome could facilitate mycobacterial infection and persistence.
    Print ISSN: 0928-8244
    Topics: Biology , Medicine
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