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Heterogeneity in tuberculosis pathology, microenvironments and therapeutic responses.

Lenaerts A, Barry CE, Dartois V - Immunol. Rev. (2015)

Bottom Line: Host-pathogen interactions within lesions are a dynamic process, driven by subtle and local differences in signaling pathways, resulting in diverging trajectories of lesions within a single host.The spectrum of TB lesions is a continuum with a large overlap in the lesion types found in latently infected and active TB patients.We hope this overview will guide TB researchers in the design, choice of read-outs, and interpretation of future studies in the search for predictive biomarkers and novel therapies.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Ft. Collins, CO, USA.

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Heterogeneity in lesion types observed in C3HeB/FeJ mice infected with M. tuberculosis Erdman. Type I lesions (A) in C3HeB/FeJ mice are defined as the caseous necrotic lesions composed of a neutrophil-dominated central core region that degenerates over time into an amorphous, acellular caseum surrounded by a band of intact neutrophils and a distinct rim of foamy macrophages at the peripheral margin. The foamy macrophages contain numerous intracellular bacilli, while large numbers of extracellular bacilli are dispersed within the acellular caseum. The core region is encapsulated by a collagen rim deposited by fibroblasts intermixed with epithelioid and activated macrophages, and few lymphocytes. Type II lesions (B) observed in C3HeB/FeJ mice closely resemble PMN alveolitis occasionally observed in human tuberculosis patients, as described by Canetti (2). These lesions are predominantly composed of necrotizing neutrophils, but lack the fibrotic encapsulation seen in the Type I lesions. Type II lesions present as fulminant granulocytic pneumonia, containing high bacterial numbers extracellular and intracellular within in neutrophils, and very few if any detectable lymphocytes, and negatively impact mouse survival. Type III lesions (C) in C3HeB/FeJ mice are similar to lesions observed in BALB/c mice following aerosol infection. These inflammatory lesions are composed predominantly of epithelioid and foamy macrophages with large numbers of lymphocytes present, only containing few bacteria which are primarily located within macrophages.
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fig03: Heterogeneity in lesion types observed in C3HeB/FeJ mice infected with M. tuberculosis Erdman. Type I lesions (A) in C3HeB/FeJ mice are defined as the caseous necrotic lesions composed of a neutrophil-dominated central core region that degenerates over time into an amorphous, acellular caseum surrounded by a band of intact neutrophils and a distinct rim of foamy macrophages at the peripheral margin. The foamy macrophages contain numerous intracellular bacilli, while large numbers of extracellular bacilli are dispersed within the acellular caseum. The core region is encapsulated by a collagen rim deposited by fibroblasts intermixed with epithelioid and activated macrophages, and few lymphocytes. Type II lesions (B) observed in C3HeB/FeJ mice closely resemble PMN alveolitis occasionally observed in human tuberculosis patients, as described by Canetti (2). These lesions are predominantly composed of necrotizing neutrophils, but lack the fibrotic encapsulation seen in the Type I lesions. Type II lesions present as fulminant granulocytic pneumonia, containing high bacterial numbers extracellular and intracellular within in neutrophils, and very few if any detectable lymphocytes, and negatively impact mouse survival. Type III lesions (C) in C3HeB/FeJ mice are similar to lesions observed in BALB/c mice following aerosol infection. These inflammatory lesions are composed predominantly of epithelioid and foamy macrophages with large numbers of lymphocytes present, only containing few bacteria which are primarily located within macrophages.

Mentions: In C3HeB/FeJ mice, subtle differences in the local immunological cascades may contribute to lesion type and fate. Several of the key immune features associated with lesion type are observed upon low dose aerosol M. tuberculosis infection. The polymorphic lung lesions found in C3HeB/FeJ mice could be categorized into three types based on cellular composition and subsequent differential immunological control (Fig. 3). Type I lesions are the fibrous encapsulated pulmonary lesions with central liquefactive necrosis, which show a layer of foamy macrophages around a core composed of neutrophilic debris surrounded by a collagen rim with interstitial functional macrophages. Type II lesions are less organized with a massive recruitment of neutrophils, resulting in large areas of cellular necrosis throughout the lung parenchyma, and Type III lesions develop as a result of the accumulation of lymphocytes, epithelioid and foamy macrophages, as well as small pockets of neutrophils. Importantly, these lesion types in C3HeB/FeJ mice do change and progress over time but do not appear to interconvert once established. This was clearly demonstrated in C3HeB/FeJ mice infected with a less virulent strain of M. tuberculosis, which initially produced only Type III lesions and never exhibited caseous necrosis, even 20 weeks after aerosol infection (A. Lenaerts, unpublished results). By comparing all three lesion types, the bacterial burden was found to be inversely proportional to the number of lymphocytes present in these pulmonary lesions. As a result, these three lesion types represent vastly different levels of host immunological control within the lung during infection. Type III lesions contained abundant lymphocytes and controlled bacterial replication more efficiently, and progressed at a rate slower than the other two lesion types (Table 1). These observations are consistent with the initiation of a strong adaptive immune response capable of controlling bacterial replication and limiting host immunopathology. It is the failing of the adaptive immune response that is ultimately responsible for the characteristic liquefactive necrotic lesions observed in the C3HeB/FeJ mice.


Heterogeneity in tuberculosis pathology, microenvironments and therapeutic responses.

Lenaerts A, Barry CE, Dartois V - Immunol. Rev. (2015)

Heterogeneity in lesion types observed in C3HeB/FeJ mice infected with M. tuberculosis Erdman. Type I lesions (A) in C3HeB/FeJ mice are defined as the caseous necrotic lesions composed of a neutrophil-dominated central core region that degenerates over time into an amorphous, acellular caseum surrounded by a band of intact neutrophils and a distinct rim of foamy macrophages at the peripheral margin. The foamy macrophages contain numerous intracellular bacilli, while large numbers of extracellular bacilli are dispersed within the acellular caseum. The core region is encapsulated by a collagen rim deposited by fibroblasts intermixed with epithelioid and activated macrophages, and few lymphocytes. Type II lesions (B) observed in C3HeB/FeJ mice closely resemble PMN alveolitis occasionally observed in human tuberculosis patients, as described by Canetti (2). These lesions are predominantly composed of necrotizing neutrophils, but lack the fibrotic encapsulation seen in the Type I lesions. Type II lesions present as fulminant granulocytic pneumonia, containing high bacterial numbers extracellular and intracellular within in neutrophils, and very few if any detectable lymphocytes, and negatively impact mouse survival. Type III lesions (C) in C3HeB/FeJ mice are similar to lesions observed in BALB/c mice following aerosol infection. These inflammatory lesions are composed predominantly of epithelioid and foamy macrophages with large numbers of lymphocytes present, only containing few bacteria which are primarily located within macrophages.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4368385&req=5

fig03: Heterogeneity in lesion types observed in C3HeB/FeJ mice infected with M. tuberculosis Erdman. Type I lesions (A) in C3HeB/FeJ mice are defined as the caseous necrotic lesions composed of a neutrophil-dominated central core region that degenerates over time into an amorphous, acellular caseum surrounded by a band of intact neutrophils and a distinct rim of foamy macrophages at the peripheral margin. The foamy macrophages contain numerous intracellular bacilli, while large numbers of extracellular bacilli are dispersed within the acellular caseum. The core region is encapsulated by a collagen rim deposited by fibroblasts intermixed with epithelioid and activated macrophages, and few lymphocytes. Type II lesions (B) observed in C3HeB/FeJ mice closely resemble PMN alveolitis occasionally observed in human tuberculosis patients, as described by Canetti (2). These lesions are predominantly composed of necrotizing neutrophils, but lack the fibrotic encapsulation seen in the Type I lesions. Type II lesions present as fulminant granulocytic pneumonia, containing high bacterial numbers extracellular and intracellular within in neutrophils, and very few if any detectable lymphocytes, and negatively impact mouse survival. Type III lesions (C) in C3HeB/FeJ mice are similar to lesions observed in BALB/c mice following aerosol infection. These inflammatory lesions are composed predominantly of epithelioid and foamy macrophages with large numbers of lymphocytes present, only containing few bacteria which are primarily located within macrophages.
Mentions: In C3HeB/FeJ mice, subtle differences in the local immunological cascades may contribute to lesion type and fate. Several of the key immune features associated with lesion type are observed upon low dose aerosol M. tuberculosis infection. The polymorphic lung lesions found in C3HeB/FeJ mice could be categorized into three types based on cellular composition and subsequent differential immunological control (Fig. 3). Type I lesions are the fibrous encapsulated pulmonary lesions with central liquefactive necrosis, which show a layer of foamy macrophages around a core composed of neutrophilic debris surrounded by a collagen rim with interstitial functional macrophages. Type II lesions are less organized with a massive recruitment of neutrophils, resulting in large areas of cellular necrosis throughout the lung parenchyma, and Type III lesions develop as a result of the accumulation of lymphocytes, epithelioid and foamy macrophages, as well as small pockets of neutrophils. Importantly, these lesion types in C3HeB/FeJ mice do change and progress over time but do not appear to interconvert once established. This was clearly demonstrated in C3HeB/FeJ mice infected with a less virulent strain of M. tuberculosis, which initially produced only Type III lesions and never exhibited caseous necrosis, even 20 weeks after aerosol infection (A. Lenaerts, unpublished results). By comparing all three lesion types, the bacterial burden was found to be inversely proportional to the number of lymphocytes present in these pulmonary lesions. As a result, these three lesion types represent vastly different levels of host immunological control within the lung during infection. Type III lesions contained abundant lymphocytes and controlled bacterial replication more efficiently, and progressed at a rate slower than the other two lesion types (Table 1). These observations are consistent with the initiation of a strong adaptive immune response capable of controlling bacterial replication and limiting host immunopathology. It is the failing of the adaptive immune response that is ultimately responsible for the characteristic liquefactive necrotic lesions observed in the C3HeB/FeJ mice.

Bottom Line: Host-pathogen interactions within lesions are a dynamic process, driven by subtle and local differences in signaling pathways, resulting in diverging trajectories of lesions within a single host.The spectrum of TB lesions is a continuum with a large overlap in the lesion types found in latently infected and active TB patients.We hope this overview will guide TB researchers in the design, choice of read-outs, and interpretation of future studies in the search for predictive biomarkers and novel therapies.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Ft. Collins, CO, USA.

Show MeSH
Related in: MedlinePlus