scholarly journals Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases

2020 ◽  
Author(s):  
Guillermo Barturen ◽  
Sepideh Babaei ◽  
Francesc Català-Moll ◽  
Manuel Martínez-Bueno ◽  
Zuzanna Makowska ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Healthy Controls ◽  
Inception Cohort ◽  
Cluster Assignment ◽  
Systemic Autoimmune Diseases ◽  
Cross Sectional ◽  
Molecular Stratification ◽  
Molecular Pattern ◽  
Clinical Diagnoses ◽  
Molecular Patterns

SUMMARYBackgroundClinical heterogeneity, a hallmark of systemic autoimmune diseases (SADs) impedes early diagnosis and effective treatment, issues that may be addressed if patients could be grouped into a molecular defined stratification.MethodsWith the aim of reclassifying SADs independently of the clinical diagnoses, unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data of 918 patients with 7 SADs and 263 healthy controls was undertaken. In addition, an inception cohort was prospectively followed for 6 and 14 months to validate the results and analyze if cluster assignment changed or not with time.ResultsFour clusters were identified. Three clusters were aberrant, representing ‘inflammatory’, ‘lymphoid’, and ‘interferon’ patterns each including all diagnoses and defined by genetic, clinical, serological and cellular features. A fourth cluster showed no specific molecular pattern and accumulated also healthy controls. An independent inception cohort showed that with time, the molecular clusters remain stable, showing that single aberrant molecular signatures characterize each individual patient.ConclusionsPatients with SADs can be jointly stratified into three stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of therapy non-responsiveness marking a paradigm shift in the view of SADs.

scholarly journals Toll-Like Receptors 1/2/4/6 and Nucleotide-Binding Oligomerization Domain-Like Receptor 2 Are Key Damage-Associated Molecular Patterns Sensors on Periodontal Resident Cells

2021 ◽  
Vol 11 (11) ◽  
pp. 4724
Author(s):  
Yu Chen ◽  
Xiaoxiao Wang ◽  
Corrie H. C. Ng ◽  
Saiwah Tsao ◽  
Waikeung Leung
Keyword(s):  
Nucleotide Binding ◽  
Cross Sectional Study ◽  
Periodontal Tissue ◽  
Toll Like Receptors ◽  
Cross Sectional ◽  
Molecular Pattern ◽  
Health And Disease ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Oligomerization Domain

Background: Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are innate, damage-associated molecular patterns (DAMP) sensors. Their expressions in human periodontal resident cells and reactions toward irritations, such as hypoxia and lipopolysaccharide (LPS), remain not well characterized. This cross-sectional study aimed to investigate and characterize TLRs, NOD1/2 and NLRP1/2 expressions at the dento-gingival junction. Methods: Immunohistochemistry screening was carried out on periodontal tissue biopsies sections, while selected DAMP sensors signal and protein expression under Escherichia coli LPS (2 µg/mL) and/or hypoxia (1% O2), 24 h, by human gingival keratinocytes (HGK) or fibroblasts (HGF) were investigated. Results: Positive TLR1/2/4/5/6, NOD1/2 and NLRP1/2 immunostaining were observed in healthy and periodontitis biopsies with apparently more pocket epithelial cells positive for TLR2, TLR4 and NOD1/2. TLR1-6, NOD1/2 and NLRP1/2 messengers were detected in gingival/periodontal biopsies as well as healthy HGK and HGF explants. LPS and/or hypoxia induced signals and protein upregulation of NOD2 in HGKs or TLR1/6 and NOD2 in HGFs. Conclusion: Transcripts and proteins of TLR1/2/4/5/6, NOD1/2 and NLRP1/2 were expressed in human periodontal tissue in health and disease. Putting all observations together, NOD2, perhaps with TLR1/2/4/6, might be considered key, damage-associated molecular pattern sensors on periodontal resident cells.

scholarly journals The interplay of DAMPs, TLR4, and proinflammatory cytokines in pulmonary fibrosis

2021 ◽  
Author(s):  
Siavash Bolourani ◽  
Max Brenner ◽  
Ping Wang
Keyword(s):  
Lung Function ◽  
Idiopathic Pulmonary Fibrosis ◽  
Connective Tissue ◽  
Pulmonary Fibrosis ◽  
Autoimmune Diseases ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Systemic Autoimmune Diseases ◽  
Molecular Pattern ◽  
Tnf Α

AbstractPulmonary fibrosis is a chronic debilitating condition characterized by progressive deposition of connective tissue, leading to a steady restriction of lung elasticity, a decline in lung function, and a median survival of 4.5 years. The leading causes of pulmonary fibrosis are inhalation of foreign particles (such as silicosis and pneumoconiosis), infections (such as post COVID-19), autoimmune diseases (such as systemic autoimmune diseases of the connective tissue), and idiopathic pulmonary fibrosis. The therapeutics currently available for pulmonary fibrosis only modestly slow the progression of the disease. This review is centered on the interplay of damage-associated molecular pattern (DAMP) molecules, Toll-like receptor 4 (TLR4), and inflammatory cytokines (such as TNF-α, IL-1β, and IL-17) as they contribute to the pathogenesis of pulmonary fibrosis, and the possible avenues to develop effective therapeutics that disrupt this interplay.

scholarly journals O31 Integrative analysis reveals a molecular stratification of systemic autoimmune diseases

2020 ◽  
Author(s):  
Guillermo Barturen ◽  
Sepideh Babaei ◽  
Francesc Català-Moll ◽  
Manuel Martínez-Bueno ◽  
Zuzanna Makowska ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Integrative Analysis ◽  
Systemic Autoimmune Diseases ◽  
Molecular Stratification

scholarly journals Common neural responses to narrative speech in disorders of consciousness

2017 ◽  
Author(s):  
Ivan Iotzov ◽  
Brian C Fidali ◽  
Agustin Petroni ◽  
Mary M Conte ◽  
Nicholas D Schiff ◽  
...  
Keyword(s):  
Motor Impairment ◽  
Disorders Of Consciousness ◽  
Auditory Attention ◽  
Healthy Controls ◽  
Neural Responses ◽  
Disorder Of Consciousness ◽  
Cross Sectional ◽  
Clinical Diagnoses ◽  
Healthy Control ◽  
Sectional Analysis

AbstractObjectiveClinical assessment of auditory attention in patients with disorders of consciousness is often limited by motor impairment. Here, we employ inter-subject correlations among electroencephalography responses to naturalistic speech in order to assay auditory attention among patients and healthy controls.MethodsElectroencephalographic data were recorded from 20 subjects with disorders of consciousness and 14 healthy controls during of two narrative audio stimuli, presented both forwards and time-reversed. Inter-subject correlation of evoked electroencephalography signals were calculated, comparing responses of both groups to those of the healthy control subjects. This analysis was performed blinded and subsequently compared to the diagnostic status of each patient based on the Coma Recovery Scale-Revised.ResultsSubjects with disorders of consciousness exhibit significantly lower inter-subject correlation than healthy controls during narrative speech. Additionally, while healthy subjects had higher inter-subject correlation values in forward vs. backwards presentation, neural responses did not vary significantly with the direction of playback in subjects with disorders of consciousness. Increased inter-subject correlation values in the backward speech condition were noted with improving disorder of consciousness diagnosis, both in cross-sectional analysis and in a subset of patients with longitudinal data.InterpretationInter-subject correlation of neural responses to narrative speech audition differentiates healthy controls from patients and appears to index clinical diagnoses in disorders of consciousness.

scholarly journals Immunoprofiling of active and inactive systemic juvenile idiopathic arthritis reveals distinct biomarkers: a single-center study

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Heshuang Qu ◽  
Erik Sundberg ◽  
Cecilia Aulin ◽  
Manoj Neog ◽  
Karin Palmblad ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Inflammatory Diseases ◽  
Systemic Juvenile Idiopathic Arthritis ◽  
High Mobility ◽  
Healthy Controls ◽  
Cellular Functions ◽  
Cross Sectional ◽  
Immune Mechanisms ◽  
Molecular Pattern ◽  
Canonical Pathways

Abstract Background This study aimed to perform an immunoprofiling of systemic juvenile idiopathic arthritis (sJIA) in order to define biomarkers of clinical use as well as reveal new immune mechanisms. Methods Immunoprofiling of plasma samples from a clinically well-described cohort consisting of 21 sJIA patients as well as 60 age and sex matched healthy controls, was performed by a highly sensitive proteomic immunoassay. Based on the biomarkers being significantly up- or down-regulated in cross-sectional and paired analysis, related canonical pathways and cellular functions were explored by Ingenuity Pathway Analysis (IPA). Results The well-studied sJIA biomarkers, IL6, IL18 and S100A12, were confirmed to be increased during active sJIA as compared to healthy controls. IL18 was the only factor found to be increased during inactive sJIA as compared to healthy controls. Novel factors, including CASP8, CCL23, CD6, CXCL1, CXCL11, CXCL5, EIF4EBP1, KITLG, MMP1, OSM, SIRT2, SULT1A1 and TNFSF11, were found to be differentially expressed in active and/or inactive sJIA and healthy controls. No significant pathway activation could be predicted based on the limited factor input to the IPA. High Mobility Group Box 1 (HMGB1), a damage associated molecular pattern being involved in a series of inflammatory diseases, was determined to be higher in active sJIA than inactive sJIA. Conclusions We could identify a novel set of biomarkers distinguishing active sJIA from inactive sJIA or healthy controls. Our findings enable a better understanding of the immune mechanisms active in sJIA and aid the development of future diagnostic and therapeutic strategies.

scholarly journals Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases

2020 ◽  
Author(s):  
Guillermo Barturen ◽  
Sepideh Babaei ◽  
Francesc Català‐Moll ◽  
Manuel Martínez‐Bueno ◽  
Zuzanna Makowska ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Integrative Analysis ◽  
Systemic Autoimmune Diseases ◽  
Molecular Stratification

scholarly journals An MRI measure of degenerative and cerebrovascular pathology in Alzheimer disease

Neurology ◽  
2018 ◽  
Vol 91 (15) ◽  
pp. e1402-e1412 ◽  
Author(s):  
Adam M. Brickman ◽  
Giuseppe Tosto ◽  
Jose Gutierrez ◽  
Howard Andrews ◽  
Yian Gu ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Neuronal Loss ◽  
Quantitative Measure ◽  
Quantitative Mri ◽  
Csf Biomarkers ◽  
Amyloid Pet ◽  
Healthy Controls ◽  
Cross Sectional ◽  
Clinical Diagnoses ◽  
Csf Levels

ObjectiveTo develop, replicate, and validate an MRI-based quantitative measure of both cerebrovascular and neurodegeneration in Alzheimer disease (AD) for clinical and potentially research purposes.MethodsWe used data from a cross-sectional and longitudinal community-based study of Medicare-eligible residents in northern Manhattan followed every 18–24 months (n = 1,175, mean age 78 years). White matter hyperintensities, infarcts, hippocampal volumes, and cortical thicknesses were quantified from MRI and combined to generate an MRI measure associated with episodic memory. The combined MRI measure was replicated and validated using autopsy data, clinical diagnoses, and CSF biomarkers and amyloid PET from the Alzheimer's Disease Neuroimaging Initiative.ResultsThe quantitative MRI measure was developed in a group of community participants (n = 690) and replicated in a similar second group (n = 485). Compared with healthy controls, the quantitative MRI measure was lower in patients with mild cognitive impairment and lower still in those with clinically diagnosed AD. The quantitative MRI measure correlated with neurofibrillary tangles, neuronal loss, atrophy, and infarcts at postmortem in an autopsy subset and was also associated with PET amyloid imaging and CSF levels of total tau, phosphorylated tau, and β-amyloid 42. The MRI measure predicted conversion to MCI and clinical AD among healthy controls.ConclusionWe developed, replicated, and validated an MRI measure of cerebrovascular and neurodegenerative pathologies that are associated with clinical and neuropathologic diagnosis of AD and related to established biomarkers.

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