Validation of Immune Cell Modules in Multicellular Transcriptomic Data

Pollara, Gabriele; Murray, Matthew J; Heather, James; Byng-Maddick, Rachel; Guppy, Naomi; Ellis, Matthew; Turner, Chris; Chain, Benjamin M.; Noursadeghi, Mahdad

doi:10.1371/journal.pone.0169271

Cited by 27 publications

(35 citation statements)

References 27 publications

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“…All module score calculations were calculated in R v3.6.1 and RStudio v1.2.1335, using scripts generated and deposited in our previous publication (https://github.com/MJMurray1/MDIScoring) (13). Mann-Whitney tests, Spearman rank correlations and Kruskal-Wallis tests were calculated in GraphPad Prism v8.4.…”

Section: Discussionmentioning

confidence: 99%

“…The expression of transcriptional modules was derived by calculating the geometric mean expression of all constituent genes, as previously described (13). The scripts used allowed the absence of a constituent gene in the analysed dataset, a scenario that did not affect geometric mean calculation.…”

Section: Module Expression Assessmentmentioning

confidence: 99%

“…We have previously derived an IL-1 response module from cytokine stimulated fibroblasts (table 2) (16). As in our prior studies (12,13,16), we used the geometric mean of the constituent genes in a module as a summary statistic to describe the relative expression of the module. We demonstrate that in both MDM and PBMC (17,19), IL-1 stimulation induced greater expression of the IL-1 response module than either IL-6 or TNF stimulation where there was no increased expression above unstimulated cells ( Fig 1A + B).…”

Section: Identification and Validation Of Il-1 And Il-6 Transcriptionmentioning

confidence: 99%

“…The measurement of individual cytokines at the protein or RNA level may not reflect their biological activity accurately within multivariate immune systems that incorporate redundancy and feedback loops. To address this limitation, we have previously derived and validated gene expression signatures, or modules, representing the transcriptional response to cytokine stimulation, using them to measure functional cytokine activity within genome-wide transcriptomic data from clinical samples (12)(13)(14)(15). No such transcriptional modules have been published and tested for detection of human IL-1 or IL-6 bioactivity.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional response modules characterise IL-1β and IL-6 activity in COVID-19

Bell

Meydan

Kim

et al. 2020

Preprint

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Dysregulated IL-1 and IL-6 responses have been implicated in the pathogenesis of severe Coronavirus Disease 2019 (COVID-19). Innovative approaches for evaluating the biological activity of these cytokines in vivo are urgently needed to complement clinical trials of therapeutic targeting of IL-1 and IL-6 in COVID-19. We show that the expression of IL-1 or IL-6 inducible transcriptional signatures (modules) reflects the bioactivity of these cytokines in juvenile idiopathic arthritis (JIA) and rheumatoid arthritis, and discerns the effect of therapeutic cytokine blockade in JIA. In COVID-19, elevated expression of IL-1 and IL-6 response modules, but not these cytokines per se, is a feature of disease both in blood and in affected organs. We propose that IL-1 and IL-6 transcriptional response modules can provide a dynamic readout of the activity of these cytokine pathways in vivo, with potential applications for identifying COVID-19 patients who may benefit from IL-1 or IL-6 blocking therapy, and to aid quantification of the biological effects of these treatments.

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Section: Discussionmentioning

confidence: 99%

Section: Module Expression Assessmentmentioning

confidence: 99%

Section: Identification and Validation Of Il-1 And Il-6 Transcriptionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Transcriptional response modules characterise IL-1β and IL-6 activity in COVID-19

Bell

Meydan

Kim

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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“…Advanced analysis module includes a relative cellular abundance assay based on cell-type specific genes, utilizing a validated, published algorithm [18]. Similar algorithms have been developed and implemented independently, and are increasingly common for cell-type deconvolution (particularly for immune cells) in heterogeneous samples [19][20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Differential Gene Expression Associated with BMI, Gender, and IBS-subtype in Human White Blood Cells: Results from a Custom 250-plex Nanostring Probe Panel

Robinson¹

2019

Preprint

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Chronic gastro-abdominal pain with altered bowel habits are associated with pathologies including gastroenteritis, autoimmune and inflammatory bowel disease, and irritable bowel syndrome (IBS). In IBS, diagnostic evidence of infection or inflammation are absent, yet symptoms nonetheless include chronic abdominal pain and alterations of stool frequency and consistency, with most common subtypes including diarrhea-predominant (IBS-D) or constipation predominant (IBS-C). [1, 2] IBS is a common clinical complaint in westernized nations, with females more frequently diagnosed than males [3]. Obesity is also associated with increased likelihood of chronic pain [4], and is associated with intestinal dysbiosis, and systemic inflammatory signatures [5]. Improving personalized medicine therefore requires patient stratification based on a combination of biological factors contributing to the individual’s symptom and biomarker spectrum. The “buffy coat” method isolates leukocytes and PBMCs from whole blood, comprises the immune cell population in peripheral blood. These cells are relatively inactive but are primed to respond to generalized and localized immune activation signals; they are under active investigation as diagnostic biomarkers [6]. Collection of buffy coat is a standard method in clinical laboratories; detection of immune activation via RNA expression biomarkers will be informative of differential biological response, and be tractable to collect in clinical settings. Results of differential expression, pathway analysis, and cell-type abundance analysis from buffy coat RNA, is presented here using variables for BMI, Gender, and IBS-subtype from publicly available Nanostring RNA expression and phenotypic data from the NCBI GEO database.

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Parvimonas micra is associated with tumour immune profiles in molecular subtypes of colorectal cancer

Löwenmark

Löfgren-Burström

et al. 2022

Cancer Immunol Immunother

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The importance of the tumour microbiome in different aspects of colorectal cancer (CRC) has been increasingly recognised, but many questions remain. The aim of this study was to explore the effect of specific CRC associated microbes on the tumour immune response, which has a considerable prognostic value in CRC. We applied specific qPCR to detect Parvimonas micra and Fusobacterium nucleatum in tumour tissues from an immunologically well-characterised cohort of 69 CRC patients. This cohort included detailed analyses of immune profiles based on flow cytometry and transcriptomics in tumour tissue and blood, along with comprehensive analyses of molecular subtypes. P. micra and F. nucleatum were detected in 24% and 64% of tumour tissues, respectively. We found a significant association of P. micra with high-grade tumours and tumours of CMS1 subtype. F. nucleatum was significantly associated with right-sided tumours, microsatellite instability, and CMS1 tumours. The immunological analyses revealed significant associations of P. micra with activated CD69+ T lymphocytes and increased antigen-presenting HLA-DR+ B lymphocytes. P. micra was also positively associated with M1 and M2 macrophage traits. The impact of P. micra tumour colonisation on the immune response was further assessed using transcriptomics in validation of our findings. No associations were found between F. nucleatum and immune profiles in this study. Our findings support novel associations between P. micra and the immune response in CRC. A better understanding of these interactions might help to identify important predictive and prognostic tools as well as new targets for therapy.

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Validation of Immune Cell Modules in Multicellular Transcriptomic Data

Cited by 27 publications

References 27 publications

Transcriptional response modules characterise IL-1β and IL-6 activity in COVID-19

Transcriptional response modules characterise IL-1β and IL-6 activity in COVID-19

Differential Gene Expression Associated with BMI, Gender, and IBS-subtype in Human White Blood Cells: Results from a Custom 250-plex Nanostring Probe Panel

Parvimonas micra is associated with tumour immune profiles in molecular subtypes of colorectal cancer

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