Abstract:The etiology of autoinflammation in systemic juvenile idiopathic arthritis is unclear. Cepika et al. use integrated analysis of multidimensional blood stimulation data, applied to patients while off treatment and in complete remission, to reveal underlying cellular and molecular mechanisms that might predispose to disease.
“…For instance, whole-blood transcriptomics, serum proteomics and immune phenotyping was used in an attempt to quantitatively measure molecular remission in patients with rheumatoid arthritis [2]. In two other studies, transcriptome analysis, among other techniques, was harnessed to uncover the molecular networks underlying disease like juvenile idiopathic arthritis and juvenile systemic lupus erythematosus [3,4]. Finally, the clinical applicability of cell phenotyping in defining treatment strategies for patients with psoriatic arthritis is enticing [5].…”
Section: Rmds and Messages For The Futurementioning
Strategic treatment in which different bDMARDs were selected according to phenotypic differences in helper T cells showed significantly higher efficacy than standard bDMARD therapy, indicating the value of precision medicine.
“…For instance, whole-blood transcriptomics, serum proteomics and immune phenotyping was used in an attempt to quantitatively measure molecular remission in patients with rheumatoid arthritis [2]. In two other studies, transcriptome analysis, among other techniques, was harnessed to uncover the molecular networks underlying disease like juvenile idiopathic arthritis and juvenile systemic lupus erythematosus [3,4]. Finally, the clinical applicability of cell phenotyping in defining treatment strategies for patients with psoriatic arthritis is enticing [5].…”
Section: Rmds and Messages For The Futurementioning
Strategic treatment in which different bDMARDs were selected according to phenotypic differences in helper T cells showed significantly higher efficacy than standard bDMARD therapy, indicating the value of precision medicine.
“…But studies have also investigated changes in transcriptome abundance in isolated leukocyte populations as well as in single cells [5, 6]. Global changes in transcript abundance can also be observed upon stimulation of the cells in vitro with host or environmental derived immunogenic factors, such as pathogen-associated molecular pattern, antigenic peptides, as well as pro or anti-inflammatory cytokines or chemokines [7, 8].…”
SUMMARYAs the capacity for generating large scale data continues to grow the ability to extract meaningful biological knowledge from it remains a limitation. Here we describe the development of a new fixed repertoire of transcriptional modules. It is meant to serve as a stable reusable framework for the analysis and interpretation of blood transcriptome profiling data. It is supported by customized resources, which include analysis workflows, fingerprint grid plots data visualizations, interactive web applications providing access to a vast number of module-specific functional profiling reports, reference transcriptional profiles and give users the ability to visualize of changes in transcript abundance across the modular repertoire at different granularity levels. A use case focusing on a set of six modules comprising interferon-inducible genes is also provided. Altogether we hope that this resource will also serve as a framework for improving over time our collective understanding of the immunobiology underlying blood transcriptome profiling data.
“…Since some isoforms of adenylyl cyclase are Ca 2+ dependent it is possible that both of the agonists described in this paper could reduce fibrosis. Examination of this possibility and a number of others will be guided and accelerated by recent papers regarding the articular joint transciptome and proteome (Bhattacharjee et al., ; Cepika et al., )‐related systems biology methods and approaches (Distler et al., ; Groenendyk et al., ; Hui et al., ; Ogawa et al., ; Aitchison and Rout, ) and emerging knowledge of the cytokine profile in these joints under baseline conditions and as documented arthritis phenotypes are initiated and progress (Armaka et al., ).…”
In human articular joints, synovial fibroblasts (HSFs) have essential physiological functions that include synthesis and secretion of components of the extracellular matrix and essential articular joint lubricants, as well as release of paracrine substances such as ATP. Although the molecular and cellular processes that lead to a rheumatoid arthritis (RA) phenotype are not fully understood, HSF cells exhibit significant changes during this disease progression. The effects of ATP on HSFs were studied by monitoring changes in intracellular Ca ([Ca ] ), and measuring electrophysiological properties. ATP application to HSF cell populations that had been enzymatically released from 2-D cell culture revealed that ATP (10-100 μm), or its analogues UTP or ADP, consistently produced a large transient increase in [Ca ] . These changes (i) were initiated by activation of the P Y purinergic receptor family, (ii) required G -mediated signal transduction, (iii) did not involve a transmembrane Ca influx, but instead (iv) arose almost entirely from activation of endoplasmic reticulum (ER)-localized inositol 1,4,5-trisphosphate (IP ) receptors that triggered Ca release from the ER. Corresponding single cell electrophysiological studies revealed that these ATP effects (i) were insensitive to [Ca ] removal, (ii) involved an IP -mediated intracellular Ca release process, and (iii) strongly turned on Ca -activated K current(s) that significantly hyperpolarized these cells. Application of histamine produced very similar effects in these HSF cells. Since ATP is a known paracrine agonist and histamine is released early in the inflammatory response, these findings may contribute to identification of early steps/defects in the initiation and progression of RA.
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