Research Data - Cambridge Institute for Medical Research
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Item Open Access Research data supporting "The lipid transfer protein Saposin B does not directly bind CD1d for lipid antigen loading"Deane, Janet; Graham, Stephen; Shamin, Maria; Benedyk, Tomasz; Deane, Janet [0000-0002-4863-0330]; Graham, Stephen [0000-0003-4547-4034]Item Open Access Movies for Guy Pearson PhD ThesisPearson, GJ; Reid, Evan; Pearson, Guy [0000-0001-8623-9239]; Reid, Evan [0000-0003-1623-7304]Item Open Access Research data supporting "Capturing the systemic immune signature of a norovirus infection: an n-of-1 case study within a clinical trial": an adverse event case study from the "Adaptive study of IL-2 dose on regulatory T cells in Type 1 Diabetes (DILT1D) trial".Waldron-Lynch, F; Waldron-Lynch, Frank [0000-0002-0597-4328]Item Open Access Data record for the secondary endpoint analysis of regulatory T cell phenotypes from the "Adaptive study of IL-2 dose on regulatory T cells in Type 1 Diabetes (DILT1D)"Waldron-Lynch, F; Waldron-Lynch, Frank [0000-0002-0597-4328]Item Open Access Data record for adverse event case study: Adaptive study of IL-2 dose on regulatory T cells in Type 1 Diabetes (DILT1D)(University of Cambridge, 2016-01-11) Waldron-Lynch, Frank; TBCItem Open Access Data record for main results of: Adaptive study of IL-2 dose on regulatory T cells in Type 1 Diabetes (DILT1D)(University of Cambridge, 2016-01-06) Waldron-Lynch, Frank; Walker, Neil [0000-0001-9796-7688]Item Open Access Data record for article: Adaptive study of IL-2 dose frequency on regulatory T cells in type 1 diabetes (DILfrequency): a mechanistic, non-randomised, repeat dose,open label, response-adaptive study(2015-09-30) Truman, Lucy A.; Todd, John A.; Kareclas, Paula; Evangelou, Marina; Walker, Neil M.; Howlett, James; Mander, Adrian P.; Kennet, Jane; Wicker, Linda S.; Bond, Simon; Waldron-Lynch, Frank; Walker, Neil M. [0000-0001-9796-7688]Item Open Access Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability.(Hindawi Limited, 2015-12) Grozeva, Detelina; Carss, Keren; Spasic-Boskovic, Olivera; Tejada, Maria-Isabel; Gecz, Jozef; Shaw, Marie; Corbett, Mark; Haan, Eric; Thompson, Elizabeth; Friend, Kathryn; Hussain, Zaamin; Hackett, Anna; Field, Michael; Renieri, Alessandra; Stevenson, Roger; Schwartz, Charles; Floyd, James AB; Bentham, Jamie; Cosgrove, Catherine; Keavney, Bernard; Bhattacharya, Shoumo; Italian X-linked Mental Retardation Project; UK10K Consortium; GOLD Consortium; Hurles, Matthew; Raymond, F Lucy; Raymond, Lucy [0000-0003-2652-3355]To identify genetic causes of intellectual disability (ID), we screened a cohort of 986 individuals with moderate to severe ID for variants in 565 known or candidate ID-associated genes using targeted next-generation sequencing. Likely pathogenic rare variants were found in ∼11% of the cases (113 variants in 107/986 individuals: ∼8% of the individuals had a likely pathogenic loss-of-function [LoF] variant, whereas ∼3% had a known pathogenic missense variant). Variants in SETD5, ATRX, CUL4B, MECP2, and ARID1B were the most common causes of ID. This study assessed the value of sequencing a cohort of probands to provide a molecular diagnosis of ID, without the availability of DNA from both parents for de novo sequence analysis. This modeling is clinically relevant as 28% of all UK families with dependent children are single parent households. In conclusion, to diagnose patients with ID in the absence of parental DNA, we recommend investigation of all LoF variants in known genes that cause ID and assessment of a limited list of proven pathogenic missense variants in these genes. This will provide 11% additional diagnostic yield beyond the 10%-15% yield from array CGH alone.Item Open Access Lack of Neuronal IFN-β-IFNAR Causes Lewy Body- and Parkinson's Disease-like Dementia.(Elsevier BV, 2015-10-08) Ejlerskov, Patrick; Hultberg, Jeanette Göransdotter; Wang, JunYang; Carlsson, Robert; Ambjørn, Malene; Kuss, Martin; Liu, Yawei; Porcu, Giovanna; Kolkova, Kateryna; Friis Rundsten, Carsten; Ruscher, Karsten; Pakkenberg, Bente; Goldmann, Tobias; Loreth, Desiree; Prinz, Marco; Rubinsztein, David C; Issazadeh-Navikas, Shohreh; Rubinsztein, David [0000-0001-5002-5263]Neurodegenerative diseases have been linked to inflammation, but whether altered immunomodulation plays a causative role in neurodegeneration is not clear. We show that lack of cytokine interferon-β (IFN-β) signaling causes spontaneous neurodegeneration in the absence of neurodegenerative disease-causing mutant proteins. Mice lacking Ifnb function exhibited motor and cognitive learning impairments with accompanying α-synuclein-containing Lewy bodies in the brain, as well as a reduction in dopaminergic neurons and defective dopamine signaling in the nigrostriatal region. Lack of IFN-β signaling caused defects in neuronal autophagy prior to α-synucleinopathy, which was associated with accumulation of senescent mitochondria. Recombinant IFN-β promoted neurite growth and branching, autophagy flux, and α-synuclein degradation in neurons. In addition, lentiviral IFN-β overexpression prevented dopaminergic neuron loss in a familial Parkinson's disease model. These results indicate a protective role for IFN-β in neuronal homeostasis and validate Ifnb mutant mice as a model for sporadic Lewy body and Parkinson's disease dementia.Item Embargo Genome-wide transcriptional analyses of islet-specific CD4+ T cells identify Idd9 genes controlling diabetogenic T cell function.(American Association of Immunologists, 2015-03-15) Berry, Gregory J; Frielle, Christine; Luu, Thaiphi; Salzberg, Anna C; Rainbow, Daniel B; Wicker, Linda S; Waldner, HanspeterType 1 diabetes (T1D) is a polygenic disease with multiple insulin-dependent diabetes (Idd) loci predisposing humans and NOD mice to disease. NOD.B10 Idd9 congenic mice, in which the NOD Idd9 chromosomal region is replaced by the Idd9 from T1D-resistant C57BL/10 mice, are significantly protected from T1D development. However, the genes and pathways conferring T1D development or protection by Idd9 remain to be fully elucidated. We have developed novel NOD.B10-Idd9 (line 905) congenic mice that predominantly harbor islet-reactive CD4(+) T cells expressing the BDC2.5 TCR (BDC-Idd9.905 mice). To establish functional links between the Idd9 genotype and its phenotype, we used microarray analyses to investigate the gene expression profiles of ex vivo and Ag-activated CD4(+) T cells from these mice and BDC2.5 (BDC) NOD controls. Among the differentially expressed genes, those located within the Idd9 region were greatly enriched in islet-specific CD4(+) T cells. Bioinformatics analyses of differentially expressed genes between BDC-Idd9.905 and BDC CD4(+) T cells identified Eno1, Rbbp4, and Mtor, all of which are encoded by Idd9 and part of gene networks involved in cellular growth and development. As predicted, proliferation and Th1/Th17 responses of islet-specific CD4(+) T cells from BDC-Idd9.905 mice following Ag stimulation in vitro were reduced compared with BDC mice. Furthermore, proliferative responses to endogenous autoantigen and diabetogenic function were impaired in BDC-Idd9.905 CD4(+) T cells. These findings suggest that differential expression of the identified Idd9 genes contributed to Idd9-dependent T1D susceptibility by controlling the diabetogenic function of islet-specific CD4(+) T cells.