DTH-Associated Pathology

Ehlers, Stefan; Hölscher, Christoph

doi:10.1002/9780470688618.taw0116

Cited by 8 publications

(10 citation statements)

References 176 publications

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“…Because l -ornithine, a product of arginase activity, is a necessary metabolite for the production of proline, which in turn controls collagen production, arginase activity has also been linked to tissue remodelling and fibrosis 29 . In human TB, peripheral blood mononuclear cells from patients with pulmonary disease display higher arginase activity 34 and progressive necrotic lesions are walled off by fibrotic tissue 2 , suggesting that arginase activity may contribute to pathology. We therefore analysed collagen deposition in lungs from Mtb -infected mice.…”

Section: Resultsmentioning

confidence: 99%

TheIL‐13/IL‐4Rαaxis is involved in tuberculosis‐associated pathology

et al. 2014

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Human tuberculosis (TB) is a leading global health threat and still constitutes a major medical challenge. However, mechanisms governing tissue pathology during post-primary TB remain elusive, partly because genetically or immunologically tractable animal models are lacking. In human TB, the demonstration of a large relative increase in interleukin (IL)-4 and IL-13 expression, which correlates with lung damage, indicates that a subversive T helper (TH)2 component in the response to Mycobacterium tuberculosis (Mtb) may undermine protective immunity and contribute to reactivation and tissue pathology. Up to now, there has been no clear evidence regarding whether IL-4/IL-13-IL-4 receptor-α (Rα)-mediated mechanisms may in fact cause reactivation and pathology. Unfortunately, the virtual absence of centrally necrotizing granulomas in experimental murine TB is associated with a poor induction of a TH2 immune response. We therefore hypothesize that, in mice, an increased production of IL-13 may lead to a pathology similar to human post-primary TB. In our study, aerosol Mtb infection of IL-13-over-expressing mice in fact resulted in pulmonary centrally necrotizing granulomas with multinucleated giant cells, a hypoxic rim and a perinecrotic collagen capsule, with an adjacent zone of lipid-rich, acid-fast bacilli-containing foamy macrophages, thus strongly resembling the pathology in human post-primary TB. Granuloma necrosis (GN) in Mtb-infected IL-13-over-expressing mice was associated with the induction of arginase-1-expressing macrophages. Indirect blockade of the endogenous arginase inhibitor l-hydroxyarginine in Mtb-infected wild-type mice resulted in a strong arginase expression and precipitated a similar pathology of GN. Together, we here introduce an experimental TB model that displays many features of centrally necrotizing granulomas in human post-primary TB and demonstrate that IL-13/IL-4Rα-dependent mechanisms leading to arginase-1 expression are involved in TB-associated tissue pathology. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Resultsmentioning

confidence: 99%

TheIL‐13/IL‐4Rαaxis is involved in tuberculosis‐associated pathology

et al. 2014

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“…TB is a systemic disease that becomes manifest most prominently in the lung (24). Progressive primary TB occurs when the initial inflammatory focus is unable to contain mycobacterial replication and the disease spreads to other parts of the lung.…”

Section: Discussionmentioning

confidence: 99%

“…Humans infected with Mtb typically have a strong DTH response, as measured by the PPD skin test (24). This holds also true for patients suffering from post-primary TB.…”

Section: Discussionmentioning

confidence: 99%

“…We were interested in analyzing the consequences of a macrophage-specific overexpression of IL-10 during experimental TB for the following reasons: first, macrophages rather than T cells were reported to be the major source of IL-10 in TB patients (18) and second, reactivation disease in patients is typically associated with a strong, rather than diminished, TH1 immune response (24). In this study, infection of mice expressing an epitope-tagged IL-10 under control of the human CD68 promoter specifically in macrophages (macIL-10 tg mice) (25) resulted in a very different immunological phenotype than reported for Mtb -infected tIL-10 tg mice.…”

Section: Introductionmentioning

confidence: 99%

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Autocrine IL-10 Induces Hallmarks of Alternative Activation in Macrophages and Suppresses Antituberculosis Effector Mechanisms without Compromising T Cell Immunity

Schreiber

Ehlers²,

Heitmann³

et al. 2009

The Journal of Immunology

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Elevated IL-10 has been implicated in reactivation tuberculosis (TB). Since macrophages rather than T cells were reported to be the major source of IL-10 in TB, we analyzed the consequences of a macrophage-specific overexpression of IL-10 in transgenic mice (macIL-10-transgenic) after aerosol infection with Mycobacterium tuberculosis (Mtb). MacIL-10 transgenic mice were more susceptible to chronic Mtb infection than nontransgenic littermates, exhibiting higher bacterial loads in the lung after 12 wk of infection and dying significantly earlier than controls. The differentiation, recruitment, and activation of Th1 cells as well as the induction of IFN-γ-dependent effector genes against Mtb were not affected by macrophage-derived IL-10. However, microarray analysis of pulmonary gene expression revealed patterns characteristic of alternative macrophage activation that were overrepresented in Mtb-infected macIL-10 transgenic mice. Importantly, arginase-1 gene expression and activity were strikingly enhanced in transgenic mice accompanied by a reduced production of reactive nitrogen intermediates. Moreover, IL-10-dependent arginase-1 induction diminished antimycobacterial effector mechanisms in macrophages. Taken together, macrophage-derived IL-10 triggers aspects of alternative macrophage activation and promotes Mtb recrudescence independent of overt effects on anti-TB T cell immunity.

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“…On the one hand, it is necessary to guarantee the cellular turnover within the granuloma to provide optimal juxtaposition of antigen-specific effector T cells and activated macrophages, resulting in the control of Mycobacterium tuberculosis (Mtb) replication (Kaufmann et al 2006). On the other hand, the inflammatory response itself can displace and destroy parenchymal tissue, leading to organ malfunction and premature death (Ehlers and Hölscher 2005). Homeostasis of inflammatory feedback loops is therefore key to long-term tissue integrity and overall survival during chronic granulomatous inflammation caused by Mtb.…”

Section: Introductionmentioning

confidence: 99%