Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis

Publisher's version (útgefin grein)Asthma is one of the most common chronic diseases affecting both children and adults. We report a genome-wide association meta-analysis of 69,189 cases and 702,199 controls from Iceland and UK biobank. We find 88 asthma risk variants at 56 loci, 19 previously unreported, and evaluate their effect on other asthma and allergic phenotypes. Of special interest are two low frequency variants associated with protection against asthma; a missense variant in TNFRSF8 and 3‘ UTR variant in TGFBR1. Functional studies show that the TNFRSF8 variant reduces TNFRSF8 expression both on cell surface and in soluble form, acting as loss of function. eQTL analysis suggests that the TGFBR1 variant acts through gain of function and together with an intronic variant in a downstream gene, SMAD3, points to defective TGFβR1 signaling as one of the biological perturbations increasing asthma risk. Our results increase the number of asthma variants and implicate genes with known role in T cell regulation, inflammation and airway remodeling in asthma pathogenesis.We thank the individuals who participated in this study and the staff at the Icelandic Patient Recruitment Center and the deCODE genetics core facilities. Further to all our colleagues who contributed to the data collection and phenotypic characterization of clinical samples as well as to the genotyping and analysis of the whole-genome association data. This research has been conducted using the UK biobank Resource under Application Number ‘24711’.Peer Reviewe

A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease

Publisher's version (útgefin grein) Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Mutations in genes encoding subunits of the phagocyte NADPH oxidase complex are recognized to cause chronic granulomatous disease (CGD), a severe primary immunodeficiency. Here we describe how deficiency of CYBC1, a previously uncharacterized protein in humans (C17orf62), leads to reduced expression of NADPH oxidase’s main subunit (gp91phox) and results in CGD. Analyzing two brothers diagnosed with CGD we identify a homozygous loss-of-function mutation, p.Tyr2Ter, in CYBC1. Imputation of p.Tyr2Ter into 155K chipgenotyped Icelanders reveals six additional homozygotes, all with signs of CGD, manifesting as colitis, rare infections, or a severely impaired PMA-induced neutrophil oxidative burst. Homozygosity for p.Tyr2Ter consequently associates with inflammatory bowel disease (IBD) in Iceland (P = 8.3 × 10−8; OR = 67.6), as well as reduced height (P = 3.3 × 10−4; −8.5 cm). Overall, we find that CYBC1 deficiency results in CGD characterized by colitis and a distinct profile of infections indicative of macrophage dysfunction.We wish to thank the family of the two probands, as well as all the other individuals who participated in the study and whose contribution made this work possible.Peer Reviewe

Skólabyrjun grunnskólabarna

Verkefnið er lokað.Í þessu lokaverkefni til B.Ed.-gráðu við kennaraskor hug- og félagsvísindadeildar Háskólans á Akureyri vorið 2009 er leitast við að svara rannsóknarspurningunni: Hvað felst í skólabyrjun barna og hvernig er hægt að undirbúa þau sem best fyrir grunnskólann? Það er mikilvægt að börn upplifi jákvæða skólabyrjun og líði vel í skólanum. Tíðar heimsóknir leikskólabarna í grunnskóla undirbúa þau vel ásamt foreldrum sem eru mikilvægustu mótunaraðilar barnsins og geta undirbúið þau vel fyrir skólagöngu. Það þarf að stuðla að andlegri og líkamlegri velferð nemenda, þeim verður að finnast þau örugg. Taka þarf tillit til þroska nemenda í skólabyrjun, börn geta verið á mismunandi þroskastigi þó þau séu fædd á sama ári og skiptir máli hvort þau séu fædd í janúar eða desember. Niðurstöður ritgerðarinnar benda til að ef heimili og skóli vinna vel saman og gott upplýsingaflæði þar á milli geti það gert skólabyrjun barna jákvæðari. Þá skipta kennsluaðferðir miklu máli og að námsumhverfi sé notalegt og hvetjandi

Interferon-β induces hepatocyte growth factor in monocytes of multiple sclerosis patients.

Interferon-β is a first-line therapy used to prevent relapses in relapsing-remitting multiple sclerosis. The clinical benefit of interferon-β in relapsing-remitting multiple sclerosis is attributed to its immunomodulatory effects on inflammatory mediators and T cell reactivity. Here, we evaluated the production of hepatocyte growth factor, a neuroprotective and neuroinflammation-suppressive mediator, by peripheral blood mononuclear cells collected from interferon-β--treated relapsing-remitting multiple sclerosis patients, relapsing remitting multiple sclerosis patients not treated with interferon-β, and healthy volunteers. Using intracellular flow cytometry analysis, increased production of hepatocyte growth factor was observed in circulating CD14(+) monocytes from patients undergoing long-term treatment with interferon-β versus untreated patients. Complementary in vitro studies confirmed that treatment with interferon-β induced rapid and transient transcription of the hepatocyte growth factor gene in CD14(+) monocytes and that intracellular and secreted monocytic hepatocyte growth factor protein levels were markedly stimulated by interferon-β treatment. Additional exploration revealed that "pro-inflammatory" (CD14(+)CD16(+)) monocytes produced similar levels of hepatocyte growth factor in response to interferon-β as "classical" (CD14(+)CD16(-)) monocytes, and that CD14(+) monocytes but not CD4(+) T cells express the hepatocyte growth factor receptor c-Met. Our findings suggest that interferon-β may mediate some of its therapeutic effects in relapsing-remitting multiple sclerosis through the induction of hepatocyte growth factor by blood monocytes by coupling immune regulation and neuroprotection

Upplifun mæðra af þjónustu í kringum barneignarferlið : samanburður milli aldurshópa

Tilgangur rannsóknar var að kanna hvort munur sé á upplifun kvenna eftir aldri á þjónustu kringum barneignaferlið. Sú þjónusta sem konum er veitt kringum barneignarferlið er á vegum mæðra- og ungbarnaverndar. Áhersla og markmið þessarar þjónustu er að efla og gæta að heilsu, vexti og þroska móður, barns og fjölskyldu. Rannsóknin byggist á eigindlegri rannsóknaraðferð þar sem notast var við rýnihópa til að auka skilning og þekkingu á upplifun mæðra á áður nefndri þjónustu. Þýði rannsóknar eru konur sem eiga eitt barn og áttu það annað hvort á aldrinum 15 til 20 ára eða 25 ára til 30 ára og nýtt höfðu þá þjónustu sem veitt er í kringum barneignarferlið. Þátttakendum var skipt í hópa eftir aldri svo unnt væri að gera samanburð milli þessara tveggja aldurshópa. Notast var við snjóboltaúrtak og í úrtaki voru sjö einstaklingar sem uppfylltu skilyrði þýðisins, miðað var við að hafa átta í úrtaki. Gagnagreining fór fram samkvæmt reglum um gagnasöfnun í rannsóknum þar sem rýnihópar eru notaðir til að nálgast viðmælendur. Gögn voru greind í megin- og undirþemu og þau studd með beinum tilvitnunum úr viðtölum. Niðurstöður rannsóknar voru fjögur meginþemu sem eru; fræðsla, samskipti, stuðningur og eftirlit. Í báðum hópum kom fram að auka mætti almenna fræðslu varðandi umönnun barns og andlega líðan og jöfn áhersla hópanna var á fræðslunámskeið og einstaklingsmiðaða fræðslu. Varðandi samskipti við heilbrigðisstarfsfólk þótti eldri hópnum þau hafa verið betri í mæðravernd en ungbarnavernd, yngri mæður greindu ekki mun þar á. Munur reyndist vera á upplifun mæðra á því reglubundna eftirliti sem þeim stóð til boða, en báðir hópar lögðu áherslu á mikilvægi andlegs eftirlits. Mæður upplifðu almennt góðan stuðning frá heilbrigðisfólki en misjafnt var hvaðan mæður fengu mestan stuðning og fór það eftir aldri þeirra. Þekking á þeim þáttum sem hafa hvað mest áhrif á upplifun mæðra tengt aldri nýtist til að auka skilning heilbrigðisstarfsfólks á þörfum mæðra og endurskoða þá þjónustu sem þeim er veitt. Lykilhugtök: ungar mæður, ungbarnavernd, mæðravernd, eftirlit, stuðningur, fræðsla, samskipti, þjónusta

c–Met protein is expressed on CD14⁺ monocytes, CD19⁺ B lymphocytes, but not T lymphocytes.

<p>Surface expression of c–Met was evaluated on CD4, CD8, CD14, CD16, CD19, and CD56 PBMC subpopulations by six-color flow cytometry. Cells were labeled with monoclonal anti–human c–Met antibody or isotype control antibody and specific antibodies for CD4, CD8, CD14, CD16, CD19 and CD56. Histograms depict monoclonal anti-human c–Met antibody (unfilled histogram) and isotype control antibody (filled histogram).</p

IFN–β induces HGF production by PBMCs.

<p>Human PBMCs or T cells were treated with IFN–β for the indicated time and dose. Culture supernatants were collected and HGF levels were evaluated using ELISA. (A) IFN–β increased release of HGF by human PBMCs in a time– and dose–dependent manner. (B) IFN–β did not stimulate HGF production by MACS–sorted CD4⁺ T cells. Data are expressed as means and standard deviations for triplicate wells of one representative experiment. **, <i>p</i><0.01; ***, <i>p</i><0.001, as determined by Student’s <i>t</i> test). (C) IFN–β did not induce cell–associated HGF levels by peripheral CD4⁺ T cells, as determined by flow cytometry. Cells were labeled with monoclonal anti–human HGF antibody or isotype control antibody and anti–human CD4 antibody. Representative histograms depict monoclonal anti–human HGF antibody (unfilled histogram) and isotype control antibody (filled histogram). Data are representative of three independent experiments.</p

Clinical characteristics of healthy controls and MS patients.

<p>EDSS, Expanded Disability Status Score; RRMS, patients with relapsing-remitting multiple sclerosis; RRMS-IFN-β, RRMS patients treated with interferon- β1a.</p

IFN–β stimulates <i>in vitro</i> HGF expression and the release of mature bioactive HGF by monocytes.

<p>(A) IFN–β increased HGF secretion by human MACS–separated monocytes from PBMCs in a dose-dependent manner, as determined by ELISA analysis. ***The mean value was significantly different from the control (medium alone) as determined by Student’s <i>t</i> test (<i>p</i><0.0001). (B, C) HGF α–subunit (mature bioactive HGF protein) levels increased in monocytes in a time–dependent (B) and dose–dependent (C) manner in response to IFN–β treatment, as shown by Western Blot analysis. Cytosolic and plasma membrane proteins from MACS–separated monocytes were separated by SDS–PAGE and revealed using an anti–human HGF monoclonal antibody. The molecular mass of HGF is indicated. (D) IFN–β induces monocytic HGF gene expression, as determined by quantitative real–time PCR. Cytokine mRNA levels from MACS–separated monocytes were normalized with respect to the level of human β–actin. The results presented are representative of at least three different experiments.</p

IFN–β–treatment increased levels of cell–associated HGF in monocytes from RRMS patients.

<p>(A) Flow cytometry for HGF was performed on CD14⁺ monocytes from the three groups (healthy control, untreated RRMS patients, and IFN–β−treated RRMS patients). Monocytes were stained for surface CD14 antigen and cell–associated HGF. Data show representative histogram overlays of isotype (filled histogram) and HGF–stained cells (unfilled histogram). (B) Cell-associated HGF levels in CD14⁺ cells were higher in healthy controls and IFN–β–treated RRMS patients. Surface expression was measured by flow cytometry and calculated as the mean corrected fluorescence index (MFI) ratio. Background HGF expression was assessed by measuring the fluorescence of cells incubated with a nonspecific isotype control antibody similarly labeled. The MFI for control anti–HGF antibody isotype staining was divided with the HGF MFI of monocytes. (C) Median serum HGF levels were similar in all three groups. ELISA for HGF was performed on sera from the three groups (healthy control, untreated RRMS patients, and IFN–β−treated RRMS patients). For both monocyte and serum HGF level analysis, each circle represents a single individual and the lines show the medians. Difference in median levels between groups was examined by Kruskal-Wallis test followed by Mann-Whitney <i>U</i> test due to a non-Gaussian distribution of values. *, <i>p</i><0.05 and ***, <i>p</i><0.001.</p