Genome-wide association studies in multiple sclerosis (MS) identified a polymorphism (rs6897932) located in the coding region of the alpha chain of the cytokine receptor interleukin 7 receptor (IL7R) as a component that increases susceptibility to develop the disease. This single nucleotide polymorphism (SNP) affects the splicing of the primary transcript leading to genotype-defined transcript ratios encoding either a full length membrane spanning form or a soluble receptor chain. Genotyping at the IL7R locus reveals that the region can be described by four haplotypes. Interestingly, only one out of three haplotypes harbouring the associated SNP is positively associated with MS whereas the other two do not show association. The minor allele containing haplotype shows a reduced susceptibility to develop MS. We hypothesized that additional functional or phenotypic differences exist between individuals homozygous for haplotypes shown to have either positive, negative, or neutral effect, on susceptibility to develop MS. Gene expression profiles of CD4+ T cells from MS individuals before and after stimulation with IL7 were recorded. Haplotype-specific gene signatures were found indicating small alterations in IL7/IL7R signal processing/sensitivity through JAK/STAT and p38/MAPK14. We can not exclude that the obtained signatures result from differences within the CD4+ T cell compartment that, in fact, should be seen as a consequence of systemic haplotype-specific processing of homeostatic and proliferation signals transmitted through IL7/IL7R.
IL7RA haplotype-associated alterations in cellular immune function and gene expression patterns in multiple sclerosis.
Specimen part, Disease, Disease stage, Treatment, Subject
View SamplesResistance towards anti-angiogenic therapy (AAT) still represents a substantial clinical challenge. We report here that tumor-infiltrating mast cells (MC) are powerful mediators decreasing efficacy of AAT in mice and cancer patients. They act in a cell-extrinsic manner by secreting granzyme B, which liberates pro-angiogenic mediators from the extracellular matrix. In addition, MC also diminish efficacy of anti-angiogenic agents in a cell-autonomous way, which can be blocked by the mast cell degranulation inhibitor cromolyn. Our findings are relevant in humans because patients harboring higher numbers of MC in their tumors have an inferior outcome after anti-angiogenic treatment in the Gepar Quinto randomized Phase 3 clinical trial. Thus, MC-targeting might represent a novel promising approach to increase efficacy of AAT.
Mast cells decrease efficacy of anti-angiogenic therapy by secreting matrix-degrading granzyme B.
Specimen part
View SamplesLong-lasting activation of T cells requires up-regulation of many genes, for example of transcription factors, cytoskeletal proteins and cell surface proteins encluding ion channels. An increase of ion channel density at the cell surface reflects the needs to manage increased Ca2+ influx into the activated T cell. Using oligonucleotide-based arrays we have surveyed changes in ion channel mRNA expression that occur upon T cell activation. We used Affymetrix Analysis to confirmate our data achieved by self-designed glass array analysis.
A truncation variant of the cation channel P2RX5 is upregulated during T cell activation.
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View SamplesMutations in ClC-5 cause Dent's disease, a disorder associated with low molecular weight proteinuria, hyperphosphaturia and kidney stones. ClC-5 is a Cl /H+-exchanger predominantly expressed in the kidney, where it facilitates the acidification of proximal tubular endosomes. The reduction in proximal tubular endocytosis resulting from a lack of ClC-5 raises the luminal concentration of filtered proteins and peptides like PTH.<br></br><br></br> We used gene expression profiling to identify possible signaling pathways that might be changed in ClC-5 KO kidneys, bones and intestines. Mouse model described in Piwon et al, ClC-5 Cl--channel disruption impairs endocytosis in a mouse model for Dent's disease, Nature 408, 369-373 (16 November 2000),doi: 10.1038/35042597
Kidney-specific upregulation of vitamin D3 target genes in ClC-5 KO mice.
Sex, Age, Specimen part, Subject
View Samples3 pairs of wt and ClC-6 knockout mice, RNA from p14 hippocampus
Lysosomal storage disease upon disruption of the neuronal chloride transport protein ClC-6.
Sex, Age, Specimen part, Subject, Time
View SamplesWild-type and mouse mutants for FGF3, FGF10 and FGF3/FGF10 double mutants at embryonic day E10 were analysed by microarrays for downregulated genes. A tissue sample corresponding to an area containing the otic vesicle and surrounding mesenchyme and neighboring hindbrain were isolated from E10 embryos (See Figure 3A of manuscript). Five samples were pooled for RNA preparation. Samples were isolated from wild-type, FGF3, FGF10 and FGF3/FGF10 double mutants. Two RNA samples for each genotype were generated (corresponding to 8 tissue samples). RNA was labeled and hybridized with Affymetrix U74A V2 arrays.
FGF signalling controls expression of vomeronasal receptors during embryogenesis.
Age, Specimen part, Disease, Disease stage
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