European Journal of Clinical Investigation, Jul 1, 1999
BackgroundIn a previous study, we demonstrated the presence of receptors for somatostatin, a neur... more BackgroundIn a previous study, we demonstrated the presence of receptors for somatostatin, a neuropeptide with immunoregulatory properties, in the inflammatory lesions of patients suffering from sarcoidosis and other granulomatous diseases by in vivo somatostatin receptor scintigraphy and in vitro autoradiography. However, it was not possible to identify exactly which cell types expressed the somatostatin receptors and which subtype was expressed. In this study we used a polyclonal antiserum directed against the sst2A receptor to identify more accurately the sst2A‐expressing cells in sarcoidosis and other granulomatous diseases.DesignTissue biopsies from 12 patients with sarcoidosis, one patient with giant cell arteritis and one patient with Wegener's granulomatosis were studied by immunohistochemistry with the sst2A‐specific antiserum. Two of the sarcoidosis patients were treated with the somatostatin analogue octreotide (100 μg t.i.d.).ResultsEpithelioid cells, multinucleated giant cells and a subset of CD68+ macrophages stained positive for sst2A in 9 out of 12 of the sarcoid biopsies and in both non‐sarcoid granuloma biopsies. Treatment with octreotide resulted in clinical improvement in one out of two treated patients.ConclusionThe identification of somatostatin receptors on granuloma macrophages, epithelioid cells and giant cells, and the successful treatment of one patient with sarcoidosis with a somatostatin analogue, may offer new possibilities for treatment of granulomatous diseases.
Objective: To identify the somatostatin receptor-expressing cells in rheumatoid synovium using a ... more Objective: To identify the somatostatin receptor-expressing cells in rheumatoid synovium using a recently developed antiserum directed against the somatostatin receptor subtype 2A (sst2A). Methods: We carried out immunohistochemical studies of synovial biopsies from 7 patients with rheumatoid arthritis (RA) and one non-RA patient, using a rabbit polyclonal antiserum directed against sst2A and monoclonal antibodies directed against phenotypic markers. Results: SSt2A was expressed by the endothelial cells of the synovial venules but also by a subset of synovial macrophages. Conclusion: The identification of somatostatin receptors on macrophages, which are thought to be important effector cells in RA, may offer mechanistic insights into the potential therapeutic effect of somatostatin (analogs) in RA.
In both cells and animals, cannibalism can transfer harmful substances from the consumed to the c... more In both cells and animals, cannibalism can transfer harmful substances from the consumed to the consumer. Macrophages are immune cells that consume their own dead via a process called cannibalistic efferocytosis. Macrophages that contain harmful substances are found at sites of chronic inflammation, yet the role of cannibalism in this context remains unexplored. Here we take mathematical and experimental approaches to study the relationship between cannibalistic efferocytosis and substance accumulation in macrophages. Through mathematical modelling, we deduce that substances which transfer between individuals through cannibalism will concentrate inside the population via a coalescence process. This prediction was confirmed for macrophage populations inside a closed system. We used image analysis of whole slide photomicrographs to measure both latex microbead and neutral lipid accumulation inside murine bone marrow-derived macrophages (104-105 cells) following their stimulation into an inflammatory state ex vivo. While the total number of phagocytosed beads remained constant, cell death reduced cell numbers and efferocytosis concentrated the beads among the surviving macrophages. % from small to large numbers per cell. Since lipids are also conserved during efferocytosis, these cells accumulated lipid derived from the membranes of dead and consumed macrophages (becoming macrophage foam cells). Consequently, enhanced macrophage cell death increased the rate and extent foam cell formation. Our results demonstrate that cannibalistic efferocytosis perpetuates exogenous (e.g. beads) and endogenous (e.g. lipids) substance accumulation inside macrophage populations. As such, cannibalism has similar detrimental consequences in both cells and animals
In both cells and animals, cannibalism can transfer harmful substances from the consumed to the c... more In both cells and animals, cannibalism can transfer harmful substances from the consumed to the consumer. Macrophages are immune cells that consume their own dead via a process called cannibalistic efferocytosis. Macrophages that contain harmful substances are found at sites of chronic inflammation, yet the role of cannibalism in this context remains unexplored. Here we take mathematical and experimental approaches to study the relationship between cannibalistic efferocytosis and substance accumulation in macrophages. Through mathematical modelling, we deduce that substances which transfer between individuals through cannibalism will concentrate inside the population via a coalescence process. This prediction was confirmed for macrophage populations inside a closed system. We used image analysis of whole slide photomicrographs to measure both latex microbead and neutral lipid accumulation inside murine bone marrow-derived macrophages (10<sup>4</sup>–10<sup>5</su...
<b>Copyright information:</b>Taken from "Quantification of global transcription ... more <b>Copyright information:</b>Taken from "Quantification of global transcription patterns in prokaryotes using spotted microarrays"http://genomebiology.com/2007/8/12/R265Genome Biology 2007;8(12):R265-R265.Published online 13 Dec 2007PMCID:PMC2246267. Proteins identified by two-dimensional PAGE/MS [24] correlates with the most highly expressed genes (Chi-squared test for trend in proportions = 251.9, df = 1, value &lt; 0.0001). Similarly, there is a significant relationship between expression level and essentiality as determined by TraSH [7,26,27] (Chi-squared test for trend in proportions = 161.2, df = 1, value &lt; 0.0001).
<b>Copyright information:</b>Taken from "Quantification of global transcription ... more <b>Copyright information:</b>Taken from "Quantification of global transcription patterns in prokaryotes using spotted microarrays"http://genomebiology.com/2007/8/12/R265Genome Biology 2007;8(12):R265-R265.Published online 13 Dec 2007PMCID:PMC2246267. There is a strong correlation (0.86, Spearman's rank, &lt; 0.0001) between mRNA levels as predicted by our microarray analysis and mRNA copy number as determined by RTq-PCR.
<b>Copyright information:</b>Taken from "Quantification of global transcription ... more <b>Copyright information:</b>Taken from "Quantification of global transcription patterns in prokaryotes using spotted microarrays"http://genomebiology.com/2007/8/12/R265Genome Biology 2007;8(12):R265-R265.Published online 13 Dec 2007PMCID:PMC2246267. We found that longer probes correlated with increased fluorescent intensities, which then biased the ppm values we obtained. We are able to remove this bias using a model of linear regression. The three distinct groupings visible in the figure are an artifact of the probe lengths targeted during their synthesis by PCR. The level of expression for each gene in the genome, as determined by our analysis from chemostat grown wild-type H37Rv, is shown ordered as they appear in the chromosome. The log frequency distribution of mRNA abundances from (c). A clear skew to the right, containing a subset of very highly expressed genes, is typical of the distributions we have found.
Tregs can adopt a catabolic metabolic program with increased capacity for fatty acid oxidation-fu... more Tregs can adopt a catabolic metabolic program with increased capacity for fatty acid oxidation-fueled oxidative phosphorylation (OXPHOS). It is unclear why this form of metabolism is favored in Tregs and, more specifically, whether this program represents an adaptation to the environment and developmental cues or is "hardwired" by Foxp3. Here we show, using metabolic analysis and an unbiased mass spectroscopy-based proteomics approach, that Foxp3 is both necessary and sufficient to program Treg-increased respiratory capacity and Tregs' increased ability to utilize fatty acids to fuel oxidative phosphorylation. Foxp3 drives upregulation of components of all the electron transport complexes, increasing their activity and ATP generation by oxidative phosphorylation. Increased fatty acid β-oxidation also results in selective protection of Foxp3(+) cells from fatty acid-induced cell death. This observation may provide novel targets for modulating Treg function or selection ...
European Journal of Clinical Investigation, Jul 1, 1999
BackgroundIn a previous study, we demonstrated the presence of receptors for somatostatin, a neur... more BackgroundIn a previous study, we demonstrated the presence of receptors for somatostatin, a neuropeptide with immunoregulatory properties, in the inflammatory lesions of patients suffering from sarcoidosis and other granulomatous diseases by in vivo somatostatin receptor scintigraphy and in vitro autoradiography. However, it was not possible to identify exactly which cell types expressed the somatostatin receptors and which subtype was expressed. In this study we used a polyclonal antiserum directed against the sst2A receptor to identify more accurately the sst2A‐expressing cells in sarcoidosis and other granulomatous diseases.DesignTissue biopsies from 12 patients with sarcoidosis, one patient with giant cell arteritis and one patient with Wegener's granulomatosis were studied by immunohistochemistry with the sst2A‐specific antiserum. Two of the sarcoidosis patients were treated with the somatostatin analogue octreotide (100 μg t.i.d.).ResultsEpithelioid cells, multinucleated giant cells and a subset of CD68+ macrophages stained positive for sst2A in 9 out of 12 of the sarcoid biopsies and in both non‐sarcoid granuloma biopsies. Treatment with octreotide resulted in clinical improvement in one out of two treated patients.ConclusionThe identification of somatostatin receptors on granuloma macrophages, epithelioid cells and giant cells, and the successful treatment of one patient with sarcoidosis with a somatostatin analogue, may offer new possibilities for treatment of granulomatous diseases.
Objective: To identify the somatostatin receptor-expressing cells in rheumatoid synovium using a ... more Objective: To identify the somatostatin receptor-expressing cells in rheumatoid synovium using a recently developed antiserum directed against the somatostatin receptor subtype 2A (sst2A). Methods: We carried out immunohistochemical studies of synovial biopsies from 7 patients with rheumatoid arthritis (RA) and one non-RA patient, using a rabbit polyclonal antiserum directed against sst2A and monoclonal antibodies directed against phenotypic markers. Results: SSt2A was expressed by the endothelial cells of the synovial venules but also by a subset of synovial macrophages. Conclusion: The identification of somatostatin receptors on macrophages, which are thought to be important effector cells in RA, may offer mechanistic insights into the potential therapeutic effect of somatostatin (analogs) in RA.
In both cells and animals, cannibalism can transfer harmful substances from the consumed to the c... more In both cells and animals, cannibalism can transfer harmful substances from the consumed to the consumer. Macrophages are immune cells that consume their own dead via a process called cannibalistic efferocytosis. Macrophages that contain harmful substances are found at sites of chronic inflammation, yet the role of cannibalism in this context remains unexplored. Here we take mathematical and experimental approaches to study the relationship between cannibalistic efferocytosis and substance accumulation in macrophages. Through mathematical modelling, we deduce that substances which transfer between individuals through cannibalism will concentrate inside the population via a coalescence process. This prediction was confirmed for macrophage populations inside a closed system. We used image analysis of whole slide photomicrographs to measure both latex microbead and neutral lipid accumulation inside murine bone marrow-derived macrophages (104-105 cells) following their stimulation into an inflammatory state ex vivo. While the total number of phagocytosed beads remained constant, cell death reduced cell numbers and efferocytosis concentrated the beads among the surviving macrophages. % from small to large numbers per cell. Since lipids are also conserved during efferocytosis, these cells accumulated lipid derived from the membranes of dead and consumed macrophages (becoming macrophage foam cells). Consequently, enhanced macrophage cell death increased the rate and extent foam cell formation. Our results demonstrate that cannibalistic efferocytosis perpetuates exogenous (e.g. beads) and endogenous (e.g. lipids) substance accumulation inside macrophage populations. As such, cannibalism has similar detrimental consequences in both cells and animals
In both cells and animals, cannibalism can transfer harmful substances from the consumed to the c... more In both cells and animals, cannibalism can transfer harmful substances from the consumed to the consumer. Macrophages are immune cells that consume their own dead via a process called cannibalistic efferocytosis. Macrophages that contain harmful substances are found at sites of chronic inflammation, yet the role of cannibalism in this context remains unexplored. Here we take mathematical and experimental approaches to study the relationship between cannibalistic efferocytosis and substance accumulation in macrophages. Through mathematical modelling, we deduce that substances which transfer between individuals through cannibalism will concentrate inside the population via a coalescence process. This prediction was confirmed for macrophage populations inside a closed system. We used image analysis of whole slide photomicrographs to measure both latex microbead and neutral lipid accumulation inside murine bone marrow-derived macrophages (10<sup>4</sup>–10<sup>5</su...
<b>Copyright information:</b>Taken from "Quantification of global transcription ... more <b>Copyright information:</b>Taken from "Quantification of global transcription patterns in prokaryotes using spotted microarrays"http://genomebiology.com/2007/8/12/R265Genome Biology 2007;8(12):R265-R265.Published online 13 Dec 2007PMCID:PMC2246267. Proteins identified by two-dimensional PAGE/MS [24] correlates with the most highly expressed genes (Chi-squared test for trend in proportions = 251.9, df = 1, value &lt; 0.0001). Similarly, there is a significant relationship between expression level and essentiality as determined by TraSH [7,26,27] (Chi-squared test for trend in proportions = 161.2, df = 1, value &lt; 0.0001).
<b>Copyright information:</b>Taken from "Quantification of global transcription ... more <b>Copyright information:</b>Taken from "Quantification of global transcription patterns in prokaryotes using spotted microarrays"http://genomebiology.com/2007/8/12/R265Genome Biology 2007;8(12):R265-R265.Published online 13 Dec 2007PMCID:PMC2246267. There is a strong correlation (0.86, Spearman's rank, &lt; 0.0001) between mRNA levels as predicted by our microarray analysis and mRNA copy number as determined by RTq-PCR.
<b>Copyright information:</b>Taken from "Quantification of global transcription ... more <b>Copyright information:</b>Taken from "Quantification of global transcription patterns in prokaryotes using spotted microarrays"http://genomebiology.com/2007/8/12/R265Genome Biology 2007;8(12):R265-R265.Published online 13 Dec 2007PMCID:PMC2246267. We found that longer probes correlated with increased fluorescent intensities, which then biased the ppm values we obtained. We are able to remove this bias using a model of linear regression. The three distinct groupings visible in the figure are an artifact of the probe lengths targeted during their synthesis by PCR. The level of expression for each gene in the genome, as determined by our analysis from chemostat grown wild-type H37Rv, is shown ordered as they appear in the chromosome. The log frequency distribution of mRNA abundances from (c). A clear skew to the right, containing a subset of very highly expressed genes, is typical of the distributions we have found.
Tregs can adopt a catabolic metabolic program with increased capacity for fatty acid oxidation-fu... more Tregs can adopt a catabolic metabolic program with increased capacity for fatty acid oxidation-fueled oxidative phosphorylation (OXPHOS). It is unclear why this form of metabolism is favored in Tregs and, more specifically, whether this program represents an adaptation to the environment and developmental cues or is "hardwired" by Foxp3. Here we show, using metabolic analysis and an unbiased mass spectroscopy-based proteomics approach, that Foxp3 is both necessary and sufficient to program Treg-increased respiratory capacity and Tregs' increased ability to utilize fatty acids to fuel oxidative phosphorylation. Foxp3 drives upregulation of components of all the electron transport complexes, increasing their activity and ATP generation by oxidative phosphorylation. Increased fatty acid β-oxidation also results in selective protection of Foxp3(+) cells from fatty acid-induced cell death. This observation may provide novel targets for modulating Treg function or selection ...
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