<i>In Situ</i> Expression of CD40, CD40L (CD154), IL‐12, TNF‐α, IFN‐γ and TGF‐β1 in Murine Lungs during Slowly Progressive Primary Tuberculosis

Mogga, S. J.; Mustafa, Tehmina; Sviland, Lisbet; Nilsen, Rune

doi:10.1046/j.1365-3083.2003.01304.x

Cited by 9 publications

(8 citation statements)

References 46 publications

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“…We reported that slowly progressive pulmonary tuberculosis in mice is a model of early stages of post primary tuberculosis 31 . The finding of mycobacterial antigen in foamy macrophages is additional evidence for the validity of this model 73, 74 . Such exudative lesions with foamy macrophages are found in several species including mice, rats and monkeys, but they are usually dismissed as nonspecific rather than as models of developmental stages of post primary disease 3 .…”

Section: Discussionmentioning

confidence: 68%

Pathology of post primary tuberculosis of the lung: An illustrated critical review

2011

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Post primary tuberculosis occurs in immunocompetent adults, is restricted to the lungs and accounts for 80% of all clinical cases and nearly 100% of transmission of infection. The supply of human tissues with post primary tuberculosis plummeted with the introduction of antibiotics decades before the flowering of research using molecular methods in animal models. Unfortunately, the paucity of human tissues prevented validation of the models. As a result, it is a paradigm of contemporary research that caseating granulomas are the characteristic lesion of all tuberculosis and that cavities form when they erode into bronchi. This differs from descriptions of the preantibiotic era when many investigators had access to thousands of cases. They reported that post primary tuberculosis begins as an exudative reaction: a tuberculous lipid pneumonia of foamy alveolar macrophages that undergoes caseation necrosis and fragmentation to produce cavities. Granulomas in post primary disease arise only in response to old caseous pneumonia and produce fibrosis, not cavities. We confirmed and extended these observations with study of 104 cases of untreated tuberculosis. In addition, studies of the lungs of infants and immunosuppressed adults revealed a second type of tuberculous pneumonia that seldom produces cavities. Since the concept that cavities arise from caseating granulomas was supported by studies of animals infected with Mycobacterium bovis, we investigated its pathology. We found that M. bovis does not produce post primary tuberculosis in any species. It only produces an aggressive primary tuberculosis that can develop small cavities by erosion of caseating granulomas. Consequently, a key unresolved question in the pathogenesis of tuberculosis is identification of the mechanisms by which Mycobacterium tuberculosis establish a localized safe haven in alveolar macrophages in an otherwise solidly immune host where it can develop conditions for formation of cavities and transmission to new hosts.

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Section: Discussionmentioning

confidence: 68%

Pathology of post primary tuberculosis of the lung: An illustrated critical review

2011

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“…A common feature of these molecules is their expression during the immunopathological response to TB infection. For instance, CD40L is expressed on alveolar macrophages of tuberculoid granulomas, and increased mRNA for CD40L is present in M. tuberculosis ‐infected macrophages 52 , 53 . CD40–CD40L interaction induces a cascade of events, including the production of cytokines and chemokines.…”

Section: Microarchitecture Of the Granulomamentioning

confidence: 99%

“…For instance, CD40L is expressed on alveolar macrophages of tuberculoid granulomas, and increased mRNA for CD40L is present in M. tuberculosis-infected macrophages. 52,53 CD40-CD40L interaction induces a cascade of events, including the production of cytokines and chemokines. The absence of CD40L impaired granuloma formation after BCG and M. avium infection, leading to increased necrosis and impaired control of bacterial growth; however, CD40L À/À mice survived M. tuberculosis infection despite impaired granuloma formation.…”

Section: Deletion Of Lta Removes Both Soluble and Membrane-bound Formmentioning

confidence: 99%

Life and death in the granuloma: immunopathology of tuberculosis

2007

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During tuberculosis (TB) infection, the granuloma provides the microenvironment in which antigen-specific T cells colocate with and activate infected macrophages to inhibit the growth of Mycobacterium tuberculosis. Although the granuloma is the site for mycobacterial killing, virulent mycobacteria have developed a variety of mechanisms to resist this macrophage-mediated killing. These surviving mycobacteria become dormant, however, if host cellular immunity or the signals maintaining granuloma structure wane, or if mycobacteria resume replication, leading to reactivation of TB. This balance of life and death applies not only to the mycobacterium but also to the host macrophages that may undergo apoptosis or necrosis, leading to the characteristic caseous necrosis within the granuloma, and the potential spread of TB infection. The immunological factors controlling the development and maintenance of the granuloma will be reviewed. Keywords: granuloma; tuberculosis; reactivation; cytokines; chemokinesThe formation and maintenance of granulomas are essential for the control of mycobacterial infections but, paradoxically, granulomas are also responsible for the typical immunopathology caused by these infections. There are over 70 species of Mycobacteria, but Mycobacterium tuberculosis and Mycobacterium leprae, the causative agents of tuberculosis (TB) and leprosy, are the major human pathogens. These slow-growing mycobacteria have adapted to survival within the macrophage, and this capacity for persistence of mycobacteria in the face of a potent cellular response underlies the chronic inflammatory reaction of the host. Mycobacterial infection of dendritic cells (DCs) stimulates CD4 and CD8 T cells, which on recruitment to the sites of infection activate infected macrophages. M. tuberculosis, however, blocks phago-lysosomal fusion and acidification of infected phagosomes, and also partially inhibits the activation of infected macrophages by interferon (IFN)-g, the major effector cytokine released by Th1-like CD4 T cells. As a result, some mycobacteria persist in the infected lung, leading to chronic antigenic stimulation and T-cell accumulation around macrophages. In the face of chronic cytokine stimulation, macrophages differentiate into epithelioid cells and fuse to form typical giant cells. Within the resulting granuloma, there is a balance between mycobacterial killing and survival. The local architecture results in the close apposition of lymphocytes and macrophages, and this is necessary for the activation of macrophages to kill M. tuberculosis. But the survival of some tuberculous bacilli leads to latent TB infection (LTBI), which is contained by the granulomatous process. Following acute M. tuberculosis infection, this process is adequate to control the infection in 95% of subjects, while the remainder progress to primary TB disease. There are currently two billion humans with LTBI, and reactivation of the infection occurs in 5-7% 1 of these subjects without, and in up to 50% with, human immunodeficiency virus...

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“…Activated macrophage products such as the L-arginine dependent pathway [4,7,8] may protect by generation of reactive nitrogen intermediates (RNI) of nitric oxide (NO). Such mechanisms of cytotoxic activity are influenced by cytokines such as interferon gamma (IFN-c) and tumor necrosis factor alpha (TNF-a), as demonstrated in several mouse studies [9][10][11]. It is important to mention that the mycobacterium has developed evolutionary survival mechanisms in which the antimicrobial activity has been evaded [7,8].…”

mentioning

confidence: 99%

Molecular signatures distinguishing active from latent tuberculosis in peripheral blood mononuclear cells, after in vitro antigenic stimulation with purified protein derivative of tuberculin (PPD) or Candida: a preliminary report

et al. 2008

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Purified protein derivative (PPD) or tuberculin skin testing is used to identify infected individuals with Mycobacterium tuberculosis (Mtb) and to assess cell-mediated immunity to Mtb. In the present study, we compared PBMC cultures in the presence of tuberculin or Candida antigens using cytokine bead arrays and RNA microarrays. Measurements of different cytokines and chemokines in supernatants of PMBC cultures in the presence of PPD showed increased levels of interferon (IFN)-gamma in active tuberculosis infection (ATBI) and latent TB infected (LTBI) compared to controls, and increased levels of TNF-alpha in ATBI compared with LTBI. Also, we found increase of IL-6 in cultures of PPD positive and controls but not in the cultures with Candida. We also report the molecular signature of tuberculosis infection, in ATBI patients, the following genes were found to be up-regulated and absent in LTBI individuals: two kinases (JAK3 and p38MAPK), four interleukins (IL-7, IL-2, IL-6, and IFNbeta1), a chemokine (HCC-4) a chemokine receptor (CxCR5), two interleukin receptors (IL-1R2 and IL-18R1), and three additional ones (TRAF5, Smad2, CIITA, and NOS2A). By contrast, IL-17 and IGFBP3 were significantly up-regulated in LTBI. And, STAT4, GATA3, Fra-1, and ICOS were down-regulated in ATBI but absent in LTBI. Conversely, TLR-10, IL-15, DORA, and IKK-beta were down-regulated in LTBI but not in ATBI. Interestingly, the majority of the up-regulated genes found in ATBI were found in cultures stimulated with tuberculin (PPD) or Candida antigens, suggesting that these pathogens stimulate similar immunological pathways. We believe that the molecular signature distinguishing active from latent tuberculosis infection may require using cytokine bead arrays along with RNA microarrays testing cell cultures at different times following in vitro proliferation assays using several bacterial antigens and PPD.

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In Situ Expression of CD40, CD40L (CD154), IL‐12, TNF‐α, IFN‐γ and TGF‐β1 in Murine Lungs during Slowly Progressive Primary Tuberculosis

Cited by 9 publications

References 46 publications

Pathology of post primary tuberculosis of the lung: An illustrated critical review

Pathology of post primary tuberculosis of the lung: An illustrated critical review

Life and death in the granuloma: immunopathology of tuberculosis

Molecular signatures distinguishing active from latent tuberculosis in peripheral blood mononuclear cells, after in vitro antigenic stimulation with purified protein derivative of tuberculin (PPD) or Candida: a preliminary report

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