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Gene expression profile in human monocytes treated with IgG from APS patients or IgG from controls

ABSTRACT: The antiphospholipid syndrome (APS) is an autoimmune disease in which antiphospholipid antibodies (aPL) cause vascular thrombosis (VT+) and/or pregnancy morbidity (PM+). The experiment aimed at determining whether specific aPL are associated with thrombotic or obstetric manifestations. In the present study we carried out microarray analysis comparing patterns of mRNA expression in monocytes from a healthy volunteer exposed to IgG from patients with a history of vascular thrombosis (VT+/PM-) or pregnancy morbidity (VT-/PM+) or to IgG from healthy controls (HC).

ORGANISM(S): Homo sapiens

SUBMITTER: Francesca Pregnolato

PROVIDER: E-MTAB-6671 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Whole blood transcriptome identifies interferon-regulated genes as key drivers in thrombotic primary antiphospholipid syndrome

Project description:Objective: Pathogenesis of antiphospholipid syndrome (APS) isn't fully elucidated. We aimed to identify gene signatures characterizing thrombotic primary APS (thrPAPS) and subgroups at high risk for worse outcomes. Methods: We performed whole blood next-generation RNA-sequencing in 62 patients with thrPAPS and 29 age-/sex-matched healthy controls (HCs), followed by differential gene expression analysis (DGEA) and enrichment analysis. We trained models on transcriptomics data using machine learning. Results: DGEA of 12.306 genes revealed 34 deregulated genes in thrPAPS versus HCs; 33 were upregulated by at least 2-fold, and 14/33 were type I and II interferon-regulated genes (IRGs) as determined by interferome database. Machine learning applied to deregulated genes returned 79% accuracy to discriminate thrPAPS from HCs, which increased to 82% when only the most informative IRGs were analyzed. Comparison of thrPAPS subgroups versus HCs showed an increased presence of IRGs among upregulated genes in venous thrombosis (21/23, 91%), triple-antiphospholipid antibody (aPL) positive (30/50, 60%), and recurrent thrombosis (19/42, 45%) subgroups. Enrichment analysis of upregulated genes in triple-aPL positive patients revealed terms related to 'type I interferon signaling pathway' and 'innate immune response'. DGEA among thrPAPS subgroups revealed upregulated genes, including IRGs, in patients with venous versus arterial thrombosis (n = 11, 9 IRGs), triple-aPL versus non-triple aPL (n = 10, 9 IRGs), and recurrent versus non-recurrent thrombosis (n = 10, 3 IRGs). Conclusion: Upregulated IRGs may better discriminate thrPAPS from HCs than all deregulated genes in peripheral blood. Taken together with DGEA data, IRGs are highly expressed in thrPAPS and high-risk subgroups of triple-aPL and recurrent thrombosis, with potential treatment implications.

2023-12-15 | GSE205465 | GEO

High titers and low fucosylation of early anti-SARS-CoV-2 IgG promote hyper-inflammation by anti-inflammatory macrophages (MIL10)

Project description:Patients diagnosed with coronavirus disease 2019 (COVID-19) mostly become critically ill around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific IgG in serum of critically ill COVID-19 patients induces hyper-inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more pro-inflammatory because of different glycosylation, particularly low fucosylation, of the Fc tail. Notably, low anti-spike IgG fucosylation normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion. We identified Fcγ Receptor (FcγR) IIa and FcγRIII as the two primary IgG receptors that are responsible for the induction of key COVID-19-associated cytokines such as interleukin-6 and tumor necrosis factor. In addition, we show that anti-spike IgG-activated macrophages can subsequently break pulmonary endothelial barrier integrity and induce microvascular thrombosis in vitro. Finally, we demonstrate that the hyper-inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of the kinase, Syk.

2021-04-30 | E-MTAB-10431 | biostudies-arrayexpress

Targeting the tissue factor coagulation initiation complex prevents antiphospholipid antibody development

Project description:Antiphospholipid antibodies (aPL) in primary or secondary antiphospholipid syndrome (APS) areis a major cause for acquired thrombophilia. Here we test the effect of specific inhibition of the TF coagulation initiation complex with nematode anticoagulant protein c2 (NAPc2) on the activation of monocytes by aPL. NGS data show that aPL-induced proinflammatory and prothrombotic activation of monocytes, but not interferon regulated gene induction is prevent by NAPc2.

2024-03-21 | GSE252972 | GEO

Targeting the tissue factor coagulation initiation complex prevents antiphospholipid antibody development.

Project description:Antiphospholipid antibodies (aPL) in primary or secondary antiphospholipid syndrome (APS) are a major cause for acquired thrombophilia. Here we show that specific inhibition of the TF coagulation initiation complex with nematode anticoagulant protein c2 (NAPc2) prevents the the development of persistent aPL and circulating phospholipid-reactive B1 cells in latent viral infection and lupus prone MRL-lpr mice. NGS mRNA profiling of splenic DC in lupus mice treated with NAPc2 versus saline control uncovered a suppression of dendritic cell activation in the spleen.

2024-03-21 | GSE252397 | GEO

A targetable pathway in neutrophils mitigates both arterial and venous thrombosis

Project description:Arterial and venous (A/V) thrombosis constitutes the greatest source of morbidity and mortality worldwide. Long considered as distinct entities, accumulating evidence indicates that A/V thrombosis can occur in the same populations suggesting that common mechanisms are likely operative. Although hyperactivation of the immune system is a common forerunner to the genesis of thrombotic events in both vascular systems, the key molecular control points remain poorly understood. Consequently, anti-thrombotic therapies targeting the immune system for therapeutic gain are lacking. Here we show that neutrophils are key effectors of both A/V thrombosis and can be targeted via novel immunoregulatory nanoparticles. Using antiphopholipid antibody syndrome (APS) as a model for devastating A/V thrombosis, we identified the transcription factor Krüppel-like factor 2 (KLF2) as a key regulator of neutrophil activation. Upon activation via genetic loss of KLF2 or administration of antiphospholipid antibodies, neutrophils cluster P-selectin glycoprotein ligand 1 (PSGL-1) via cortical actin remodeling, thereby increasing adhesion potential at thrombosis sites. Targeting clustered PSGL-1 using designer nanoparticles attenuates neutrophil-mediated A/V thrombosis in APS and KLF2 knockout models, illustrating the importance and feasibility of targeting activated neutrophils to prevent pathological thrombosis. Together, our results demosntrate a role for activated neutrophils to prevent pathological thrombosis. Together, our results demonstrate a role for activated neutorphils in both arterial and venous thrombosis and identify key molecular events that serve as potential targets for therapeutics against diverse causes of immunothrombosis.

2022-09-12 | GSE208336 | GEO

B cells in triple positive antiphospholipid syndrome

Project description:Peripheral B cell selection of autoreactive B cells is crucial for preventing autoimmunity. In this study, we identify that a significant proportion of antiphospholipid (aPL) B cells present in the naive compartment, exhibit polyreactivity and belong to the natural repertoire. We used scRNA Seq to follow B cells with aPL features throughout their development from naïve B cells to plasma cells in patients with PAPS.

2024-10-08 | GSE262240 | GEO

miRNAs screening in small extracellular vesicles (sEVs) from patients with primary antiphospholipid syndrome (PAPS)

Project description:To discover miRNAs implicate in PAPS pathogenesis, we isolated sEVs from plasma of PAPS patients, aPL patients (patients with positive antiphospholipid antibodies without thrombotic or obstretic complications) and control. Then, we extracted RNA total and we performed miRNA-sequencing.

2023-07-18 | GSE220791 | GEO

RNA-Seq in neutrophils from Antiphospholipid Syndrome

Project description:Antiphospholipid antibodies are a leading cause of thrombosis. To further elucidate the role of neutrophils in APS, we performed a comprehensive transcriptome analysis using the total RNA of neutrophils isolated from 9 patients with primary APS and 9 age, sex and ethnicity-matched healthy controls using next-generation RNA-seq.

2017-11-15 | GSE102215 | GEO

Antiphospholipid antibodies induce Proinflammatory and Procoagulant Pathways in Endothelial cells.

Project description:Antiphospholipid syndrome (APS) is an autoimmune thrombophillia characterized by recurrent thrombotic events and/or pregnancy morbidity in the presence of antiphospholipid antibodies detected either as anti-cardiolipin, anti-β2 Glycoprotein I (anti-β2GPI) or Lupus anticoagulant (LA). Endothelial deregulation characterizes the syndrome. To address the gene expression changes occurring in the endothelial cells in the context of APS, we performed transcriptome analysis of Human Umbilical Vein Endothelial cells (HUVECs) stimulated with anti-β2GPI-β2GPI complexes.

2023-05-24 | GSE143506 | GEO

Extensive proteomic approaches to identify glycosylphosphatidylinositol-anchored proteins in Arabidopsis reveal their diverse responses to cold acclimation

Project description:When plants are exposed to non-freezing low temperatures, they can increase their freezing tolerance (cold acclimation, CA). Changes of plasma membrane (PM) and sterol/sphingolipid-enriched microdomain proteins are thought to be crucial for acquisition of freezing tolerance. Particularly, glycosylphosphatidylinositol-anchored proteins (GPI-APs), which are lipid-modified proteins and potentially targeted to PM surface and apoplast, are deeply-involved in microdomain functions. However, GPI-AP functions in the CA mechanisms are not yet characterized. In present study, we conducted large-scale proteomics to investigate CA-induced GPI-APs in Arabidopsis leaves.

2016-07-29 | PXD002908 | Pride

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