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Acute v. baseline PBMC gene expression in patients with Systemic Capillary Leak Syndrome

ABSTRACT: The Systemic Capillary Leak Syndrome (SCLS) is an extremely rare and potentially life-treating vascular disorder of unknown etiology. SCLS is characterized by dramatic and transient episodes of hypotensive shock and edema due to plasma leakage into peripheral tissues. The disorder has garnered increased attention during the last several years because of the resemblance of its initial presentation to more common disorders such as systemic anaphylaxis, sepsis, and acute infections with the Ebola/Marburg family of filoviruses. Although approximately 70-80% of patients with SCLS have a concurrent monoclonal gammopathy of unknown significance (MGUS), any contribution of the paraprotein to acute flares is unknown. To identify circulating factors that contribute to the onset of acute SCLS crises, we performed transcriptomic profiling of paired peripheral blood mononuclear cell fractions obtained from patients during acute attacks and convalescent intervals using microarray. 61 genes were significantly up- or downregulated more than 2.5 fold in acute samples relative to baseline. One of the most upregulated genes was ADM, which encodes the vasoactive peptide adrenomedullin. The ADM surrogate pro-ADM was markedly elevated in SCLS acute sera compared to remission samples or sera from healthy controls. Monocytes and endothelial cells (ECs) from SCLS subjects expressed significantly more ADM in response to proinflammatory stimuli compared to healthy control cells. Application of ADM to ECs exerted protective effects on vascular barrier function. These results suggest a pathogenic contribution of ADM to the profound pressor-resistant hypotension that characterizes the initial stages of SCLS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE97287 | GEO | 2018/03/31

REPOSITORIES: GEO

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Project description:The Systemic Capillary Leak Syndrome (SCLS) is an extremely rare, orphan disease that resembles systemic anaphylaxis. The disorder is characterized by repeated, transient, and seemingly unprovoked episodes of hypotensive shock and peripheral edema due to transient endothelial hyperpermeability. SCLS is often accompanied by a monoclonal gammopathy of unknown significance (MGUS). Using Affymetrix Single Nucleotide Polymorphism (SNP) microarrays, we performed the first genome-wide SNP analysis of SCLS in a cohort of 12 disease subjects and 18 controls. Exome capture sequencing was performed on genomic DNA from nine of these patients as validation for the SNP-chip discoveries and de novo data generation. We identified candidate susceptibility loci for SCLS, which included a region flanking CAV3 (3p25.3) as well as SNP clusters in PON1 (7q21.3), PSORS1C1 (6p21.3), and CHCHD3 (7q33). Among the most highly ranked discoveries were gene-associated SNPs in the uncharacterized LOC100130480 gene (rs6417039, rs2004296). Top case-associated SNPs were observed in BTRC (rs1235580, 3rs4436485), ARHGEF18 (rs11668246), CDH13 (rs4782779), and EDG2 (rs12552348), which encode proteins with known or suspected roles in B cell function and/or vascular integrity. SNPs that were significantly associated with SCLS by microarray analysis were also detected and validated by exome deep sequencing. Functional annotation of highly ranked SNPs revealed enrichment of cell projections, cell junctions and adhesion, and molecules containing pleckstrin homology, Ras/Rho regulatory, and immunoglobulin Ig-like C2/fibronectin type III domains, all of which involve mechanistic functions that correlate with the SCLS phenotype. These results highlight SNPs with potential relevance to SCLS. Our study cohort included 12 patients with SCLS. The control group included 17 age, sex and ethnicity-matched healthy donors (including two relatives of SCLS patients), and a reference sample supplied by the SNP-chip manufacturer (Affymetrix), for which age information was not available. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from purified B lymphocytes.

Project description:Rationale Electroconvulsive seizure (ECS) therapy is a nonchemical treatment for depression. Since ECS up-regulates expression of c-Fos in the paraventricular nucleus of hypothalamus (PVN), the function of which is frequently influenced in depression, we hypothesized that ECS modulates functions of the PVN and contributes to its antidepressant effects. Objectives To identify gene expression changes in the mouse PVN by ECS treatment Material and methods First, we established a method to amplify nucleotides from small quantities of RNA. Mice received one shock of ECS and their brains were collected at 2 or 6 h after shock. The PVN was microdissected from dehydrated brain sections, its total RNA was extracted and microarray analysis was applied. Results At 2 h after ECS, 2.6% (589 genes) of the probes showed more than 2-fold decrease, and 0.9% (205 genes) showed more than 2-fold increase. To confirm the expression changes, genes showing differential expression with a wide range in the microarray were analyzed by qPCR. Among the genes with more than 2-fold change by ECS, down-regulated 94 genes and up-regulated 24 genes have been reported the association with anxiety, bipolar disorder or mood disorder by the Ingenuity knowledge database. The groups of down-regulated genes, which are suggested to modulate the function of the PVN or associate to psychiatric disorders, include neuropeptides (Cck), kinases (Prkcb, Prkcc, Camk2a), transcription factors (Bcl6, Tbr1), transporters (Aqp4) and others (Fmr1). Conclusion The present results indicate that ECS treatment can modulate the functions of PVN via a series of gene expression changes, and may contribute to its antidepressant effects at least in part. Mice received one shock of ECS and their brains were collected at 2 h (PVN_ECS2h_1, PVN_ECS2h_2) or 6 h after shock (PVN_ECS6h_1, PVN_ECS6h_2). The brains of sham-treated animals were collected at 2 h after treatment (PVN_sham_1, PVN_sham_2). The PVN was microdissected from dehydrated brain sections, and its total RNA was extracted. RNA samples from two or three animals were pooled to minimize the impact of biological variance. After nucleotide amplification by the ovation amplification, the gene expression profiles were obtained by the Affymetrix microarray analysis. The microarray analysis was performed twice using different sets of animals.

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Acute v. baseline PBMC gene expression in patients with Systemic Capillary Leak Syndrome

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