Autosomal Recessive CD55 Deficiency
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ABSTRACT: We describe 11 patients from 8 families with homozygous LOF mutations in the complement regulatory protein CD55. Loss of CD55 is associated with increased complement activation, severe protein losing enteropathy accompanying a primary intestinal lymphangiectasia, and deep vein thrombotic events. We have named this disease CHAPLE after the principle components of the disease.
SECONDARY ACCESSION(S): PRJNA389488PRJNA389487
REPOSITORIES: dbGaP
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Project description:Primary objectives: This study aims at (further) revealing the pathophysiology of intestinal IR in man, with a specific interest for the role of proteases and protease-activated receptor-2 (PAR-2), cellular and inflammatory changes, barrier function and intestinal permeability, microscopic mucosal changes and gene expression patterns. An important element will be the determination of the effects of protease- and MMP inhibitors. By these means we hope to identify preventive and therapeutic strategies for patients with intestinal IR.
Primary endpoints: The primary endpoint in this study is inflammation (neutrophil influx, complement activation, interleukins, TNF-α, COX 1-2) and protease activity in tissue as well as in blood plasma.
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Project description:An increasing amount of studies integrate mRNA sequencing data into MS-based proteomics to complement the translation product search space. We present the generation of a protein synthesis-based database from deep sequencing of ribosome-protected mRNA fragments. This approach increases the overall protein identification rates with 3% and 11% (improved and new identifications) for human and mouse respectively and enables proteome-wide detection of 5’-extended proteoforms, uORF translation and near-cognate translation start sites.
2014-12-01 | GSE58207 | GEO
Project description:<p>We describe four patients from two unrelated families of different ethnicities who had primary immunodeficiency predominantly manifesting as susceptibility to EBV-related diseases. We performed whole exome sequencing (P1 and P2 from family 1) or whole genome sequencing (P4 and both parents from family 2) in those two families and identified homozygous frameshift or in-frame deletions in CD70 in these patients which abolished either CD70 surface expression or binding to its counter structure CD27. Sanger sequencing identified the same homozygous <i>CD70</i> mutation in P3, which is not included in the dbGaP submission. Autosomal recessive CD70 deficiency is a novel cause of combined immunodeficiency and EBV-associated diseases, reminiscent of CD27 deficiency.</p>
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Project description:Microglia repair injury and maintain homeostasis in the brain, but whether aberrant microglial activation can contribute to neurodegeneration remains unclear. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive up-regulation of lysosomal and innate immunity genes, increased complement production, and synaptic pruning activity in microglia. During aging, Grn-/- mice show profound accumulation of microglia and preferential elimination of inhibitory synapses in the ventral thalamus, which contribute to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, blocking complement activation by deleting C1qa gene significantly reduces synaptic pruning by Grn-/- microglia, and mitigates neurodegeneration, behavioral phenotypes and premature mortality in Grn-/- mice. These results uncover a previously unrecognized role of progranulin in suppressing microglia activation during aging, and support the idea that blocking complement activation is a promising therapeutic target for neurodegeneration caused by progranulin deficiency. Gene expression study in multiple brain regions from a mouse model of progranulin deficiency Please note that 9 outlier samples were excluded from data analysis. Therefore, there are 326 raw data columns (i.e. 163 samples) in the non_normalized data matrix while 154 samples are represented here.
2016-03-31 | E-GEOD-75083 | biostudies-arrayexpress
Project description:Tumorigenesis in different segments of the intestinal tract involves tissue-specific oncogenic drivers. In the colon, complement component 3 (C3) activation is a major contributor to inflammation and malignancies. By contrast, tumorigenesis in the small intestine involves fatty acid–binding protein 1. However, little is known of the upstream mechanisms driving their expressions in different segments of the intestinal tract. Here, we report that the RNA-binding protein DDX5 binds to the mRNA transcripts of C3 and fatty acid–binding protein 1 to augment their expressions posttranscriptionally. Knocking out DDX5 in epithelial cells protected mice from intestinal tumorigenesis and dextran sodium sulfate–induced col- itis. Identification of DDX5 as a common upstream regulator of tissue-specific oncogenic molecules provides an excellent therapeutic target for intestinal diseases.
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Project description:Background: Although a number of intestinal inflammatory conditions pertain to the ileum, whole-genome gene expression analyses on ileal inflammation in animal models are lacking to date. Therefore, we aimed to identify and characterize alterations in gene expression in the acutely inflamed ileum of two murine models of intestinal inflammation, namely intestinal schistosomiasis and TNBS-induced ileitis, using Agilent whole-genome microarrays followed by bioinformatics analysis to detect enrichment of Kyoto Encyclopedia of Genes and Genomes pathways and Gene Ontology categories. Results: When compared with healthy control mice, of almost all known mouse genes and transcripts represented on the array, intestinal schistosomiasis and TNBS-induced ileitis yielded 207 and 1417 differential genes respectively, with 48 overlapping genes (adj.p.value<0.1 and log2FC>1 or <1). Complement and coagulation cascades, extracellular matrix-receptor interaction, Fc epsilon receptor I signaling pathways and protein activation cascade, cell adhesion categories were enriched for differential genes in intestinal schistosomiasis. Antigen processing and presentation, cell adhesion molecules, ABC transporters, Toll-like receptor signaling pathways and response to chemical stimulus categories were enriched for differential genes in TNBS-induced ileitis. Although cytokine-cytokine receptor interaction, intestinal immune network for immunoglobulin A production, focal adhesion pathways and immune, inflammatory and defense response categories were enriched for differential genes in both inflammation models, the vast majority of the associated differential genes were unique to each model. Conclusions: This study characterized the two diverse models of ileal inflammation at a whole-genome level and outlined their underlying molecular heterogeneity. The results indicate that intestinal schistosomiasis involves Th2 responses, enhanced tissue repair and complement activation, while TNBS-induced ileitis involves Th17 responses, defective antigen processing and presentation and altered Toll-like receptor-mediated responses. Epithelial barrier impairment seems to occur in both inflammation models. Moreover, the comprehensive differential gene-list provided by this study would be helpful as a starting point to explore a specific novel pathway in more detail dealing with small bowel inflammation. A total of 9 biological samples containing 3 each of Control, S.mansoni-infected and TNBS-treated were included in the study. A reference design was used including a reference sample containing a pool of equimolar amounts of all Control samples. The design consisted totally of 11 arrays which included 3 biological replicates each of Control (labeled in Cy5), S.mansoni-infected (labeled in Cy3) and TNBS-treated tissue samples(labeled in Cy5) as well as two dye flipped technical replicates of a Control and a S.mansoni-infected tissue sample. The reference was labeled with either Cy5 or Cy3, depending on the labeling of the test sample.
2012-10-05 | E-GEOD-31265 | biostudies-arrayexpress
Project description:Intestinal ischemia-reperfusion (IR) injury is initiated when natural IgM antibodies recognize neo-epitopes that are revealed on ischemic cells. The target molecules and mechanisms whereby these neo-epitopes become accessible to recognition are not well understood. Proposing that isolated intestinal epithelial cells (IEC) may carry IR-related neo-epitopes, we used in vitro IEC binding assays to screen hybridomas created from B cells of unmanipulated wild type C57BL/6 mice. We identified a novel IgM monoclonal antibody (mAb B4) that reacted with the surface of IEC by flow cytometric analysis and was alone capable of causing complement activation, neutrophil recruitment and intestinal injury in otherwise IR-resistant Rag1-/- mice. Monoclonal Ab B4 was found to specifically recognize mouse annexin IV. Pre-injection of recombinant annexin IV blocked IR injury in wild type C57BL/6 mice, demonstrating the requirement for recognition of this protein in order to develop IR injury in the context of a complex natural antibody repertoire. Humans were also found to exhibit IgM natural antibodies that recognize annexin IV. These data in toto identify annexin IV as a key ischemia-related target antigen that is recognized by natural Abs in a pathologic process required in vivo to develop intestinal IR injury. Keywords: Natural antibodies, Annexin, Ischemia Reperfusion, Inflammation, Complement In the study presented here, a total of 4 custom spotted antigen slides were hybridized with known antibodies.
2010-05-05 | E-GEOD-14862 | biostudies-arrayexpress
Project description:Mucus produced by goblet cells in the gastrointestinal (GI) tract forms a biological barrier that protects the intestine from invasion by commensals and pathogens. However, the host-derived regulatory network that controls mucus secretion and thereby changing gut microbiota has not been well studied. We found Forkhead box protein O1 (Foxo1) regulates mucus secretion by goblet cells and determines intestinal homeostasis. Loss of Foxo1 in intestinal epithelial cells (IECs) results in a defect in goblet cell autophagy and mucus secretion, leading to impaired gut microenvironment and dysbiosis.
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Project description:Microglia repair injury and maintain homeostasis in the brain, but whether aberrant microglial activation can contribute to neurodegeneration remains unclear. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive up-regulation of lysosomal and innate immunity genes, increased complement production, and synaptic pruning activity in microglia. During aging, Grn-/- mice show profound accumulation of microglia and preferential elimination of inhibitory synapses in the ventral thalamus, which contribute to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, blocking complement activation by deleting C1qa gene significantly reduces synaptic pruning by Grn-/- microglia, and mitigates neurodegeneration, behavioral phenotypes and premature mortality in Grn-/- mice. These results uncover a previously unrecognized role of progranulin in suppressing microglia activation during aging, and support the idea that blocking complement activation is a promising therapeutic target for neurodegeneration caused by progranulin deficiency.
2016-03-31 | GSE75083 | GEO
Project description:Interventions: Administraion of CPT-11 is twice for 4 weeks on days 1 and 15. CPT-11 is reconstituted in >=250 mL of normal saline or 5% dextrose in water and infuse 90min on day 1 for pharmacokinetics, and 90min over on day15. CPT-11 adjusted dosage is determined from 50,75,100,125 or 150mg/sqm in the heterozygous group and the homozygous group by continual reassessment method. CPT-11 dosage is fixed at 150mg/sqm in the wild group.Definision of UGT1A1 polymorphisms groups: The homozygous group is patient with homozygous genotype of UGT1A1*28/*28 or UGT1A1*6/*6, with combined heterozygous genotypes of UGT1A1*28 and UGT1A1*6. The heterozygous group is patient with heterozygous genotype of either UGT1A1*28 or UGT1A1*6. The wild group is patients with no UGT1A1*28 and UGT1A1*6 mutation.
Primary outcome(s): Maximum tolerated dose for the heterozygous group and the homozygous group, respectively. Incidence rate of dose limiting toxicities for the wild group.
Study Design: Single arm Non-randomized
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