8 research outputs found
Cytokine-induced changes in the gene expression profile of a human cerebral microvascular endothelial cell-line, hCMEC/D3.
- Author
- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 01/01/2013
- Field of study
Background: The human cerebral microvascular endothelial cell line, hCMEC/D3, has been used extensively to
model the blood–brain barrier (BBB) in vitro. Recently, we reported that cytokine-treatment induced loss of brain
endothelial barrier properties. In this study, we further determined the gene expression pattern of hCMEC/D3 cells
in response to activation with TNFα and IFNγ.
Findings: Using a microarray approach, we observed that expression of genes involved in the control of barrier
permeability, including inter-brain endothelial junctions (e.g. claudin-5, MARVELD-2), integrin-focal adhesions
complexes (e.g. integrin β1, ELMO-1) and transporter systems (e.g. ABCB1, SLC2A1), are altered by pro-inflammatory
cytokines.
Conclusions: Our study shows that previously-described cytokine-induced changes in the pattern of gene expression of endothelium are reproduced in hCMEC/D3 cells, suggesting that this model is suitable to study inflammation at the BBB, while at the same time it has provided insights into novel key molecular processes that are altered in brain endothelium during neuroinflammation, such as modulation of cell-to-matrix contacts
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EZH2 inhibition: a promising strategy to prevent cancer immune editing
- Author
- Publication venue
- 'Future Medicine Ltd'
- Publication date
- 01/08/2020
- Field of study
Immunotherapies are revolutionizing the clinical management of a wide range of cancers. However, intrinsic or acquired unresponsiveness to immunotherapies does occur due to the dynamic cancer immunoediting which ultimately leads to immune escape. The evolutionarily conserved histone modifier enhancer of zeste 2 (EZH2) is aberrantly overexpressed in a number of human cancers. Accumulating studies indicate that EZH2 is a main driver of cancer cells’ immunoediting and mediate immune escape through downregulating immune recognition and activation, upregulating immune checkpoints and creating an immunosuppressive tumor microenvironment. In this review, we overviewed the roles of EZH2 in cancer immunoediting, the preclinical and clinical studies of current pharmacologic EZH2 inhibitors and the prospects for EZH2 inhibitor and immunotherapy combination for cancer treatment
MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation.
- Author
- Publication venue
- 'FASEB'
- Publication date
- 01/01/2014
- Field of study
Blood-brain barrier (BBB) dysfunction is a hallmark of neurological conditions such as multiple sclerosis (MS) and stroke. However, the molecular mechanisms underlying neurovascular dysfunction during BBB breakdown remain elusive. MicroRNAs (miRNAs) have recently emerged as key regulators of pathogenic responses, although their role in central nervous system (CNS) microvascular disorders is largely unknown. We have identified miR-155 as a critical miRNA in neuroinflammation at the BBB. miR-155 is expressed at the neurovascular unit of individuals with MS and of mice with experimental autoimmune encephalomyelitis (EAE). In mice, loss of miR-155 reduced CNS extravasation of systemic tracers, both in EAE and in an acute systemic inflammation model induced by lipopolysaccharide. In cultured human brain endothelium, miR-155 was strongly and rapidly upregulated by inflammatory cytokines. miR-155 up-regulation mimicked cytokine-induced alterations in junctional organization and permeability, whereas inhibition of endogenous miR-155 partially prevented a cytokine-induced increase in permeability. Furthermore, miR-155 modulated brain endothelial barrier function by targeting not only cell-cell complex molecules such as annexin-2 and claudin-1, but also focal adhesion components such as DOCK-1 and syntenin-1. We propose that brain endothelial miR-155 is a negative regulator of BBB function that may constitute a novel therapeutic target for CNS neuroinflammatory disorders
Whole-genome sequencing reveals host factors underlying critical COVID-19
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- Publication venue
- 'Springer Science and Business Media LLC'
- Publication date
- 01/01/2022
- Field of study
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
Whole-genome sequencing reveals host factors underlying critical COVID-19
- Author
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- Zöllner S.
- Åsvold B.O.
- Publication venue
- Springer Science and Business Media LLC
- Publication date
- 07/07/2022
- Field of study
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
Invited lecture: Lack of processing of some antigens by the immunoproteasome results in poor presentation by dendritic cells: implications for vaccine design
- Author
- Publication venue
- Publication date
- 01/01/2000
- Field of study
Background: Increased leukocyte adhesion to brain endothelial cells forming the blood–brain barrier (BBB) precedes extravasation into the central nervous system (CNS) in neuroinflammatory diseases such as multiple sclerosis (MS). Previously, we reported that microRNA-155 (miR-155) is up-regulated in MS and by inflammatory cytokines in human brain endothelium, with consequent modulation of endothelial paracellular permeability. Here, we investigated the role of endothelial miR-155 in leukocyte adhesion to the human cerebral microvascular endothelial cell line, hCMEC/D3, under shear forces mimicking blood flow in vivo.
Results: Using a gain- and loss-of-function approach, we show that miR-155 up-regulation increases leukocyte firm adhesion of both monocyte and T cells to hCMEC/D3 cells. Inhibition of endogenous endothelial miR-155 reduced monocytic and T cell firm adhesion to naïve and cytokines-induced human brain endothelium. Furthermore, this effect is partially associated with modulation of the endothelial cell adhesion molecules VCAM1 and ICAM1 by miR-155.
Conclusions: Our results suggest that endothelial miR-155 contribute to the regulation of leukocyte adhesion at the inflamed BBB. Taken together with previous observations, brain endothelial miR-155 may constitute a potential molecular target for treatment of neuroinflammation diseases
Whole-genome sequencing reveals host factors underlying critical COVID-19
- Author
- Abd Elghafar Mohamed S.
- Abdel-Aziz Mahmoud
- Abdelrazik Marwa
- Abdollahi Hamed
- Abdullah T.
- Abecasis Goncalo
- Abedalthagafi M.
- Abel Lynn
- Abernathy C.
- Abraheem Azmeralde
- Abul-Husn Noura S.
- Acquilini D.
- Adams C.
- Adams Emma L.
- Adams K.
- Adamsara Alireza
- Adanini Olurenke
- Adeleye O.
- Adra D.
- Afilalo J.
- Afilalo M.
- Afolabi D.
- Afrasiabi Z.
- Agasou A.
- Agrawal Shruti
- Agüero D.
- Ahmad N.
- Ahmadi Saeideh
- Ahmed A.
- Ahmed Cecilia
- Akeroyd L.
- Akhtar M.N.
- Akinkugbe O.
- Aksentijevich Alexandra
- Al-Afghani H.
- Al-Awdah L.
- Alaamery M.
- Alahmadey Z.Z.
- Alaverdian D.
- Alavere H.
- Albader A.
- Albaiceta G.M.
- Albakri J.K.
- AlBardis H.
- Albeladi M.
- Albesher N.
- Albrich W.
- AlDhawi N.
- Aldridge J.
- Aleagha Afshar Etemadi
- Alexander Peter.
- Alfonso J.
- Alghamdi B.
- Alghamdi J.
- Ali A.
- Ali Altaf
- Ali I.A.M.
- Ali Syamlan
- Aliannejad Rasoul
- Aljawini N.
- AlJohani S.
- Alkwai S.
- Allan A.
- Allan E.
- Allan J.
- Alldis Zoe
- Allen L.
- Allen Meryem
- Allen Schvearn
- Allibone S.
- Allison K.S.
- Allos R.
- Ally S.M.
- AlMalik A.
- Almalki F.
- Almohammed I.
- Almutairi M.
- Alotaibi S.
- Alowayn A.M.
- Alqahtani S.
- Alqubaishi F.
- Alrashed M.
- Alshareef A.
- Alsolm E.
- Alswailm M.
- Altabaibeh A.
- Alvaro A.
- AlZahrani D.
- Amin V.
- Amirsavadkouhi Ali
- Amitrano Sara
- Anastasescu E.
- Anderson F.
- Anderson J.
- Anderson Madeleine
- Anderson Peter
- Anderson S.
- Anderson S.
- Anderson T.
- Andolfo I.
- Andretta F.
- Andreucci E.
- Andrew Angela
- Andrew B.
- Andrew Gratrix
- Andrews E.
- Andrews Shea J.
- Anedda F.
- Anemoli V.
- Annis A.
- Antcliffe David
- Antinori Andrea
- Antoni M.D.
- Anumakonda V.
- Apetri E.
- Aquino Maia
- Arabi Y.M.
- Aravindan Latha
- Arbane Gill
- Archer Katie
- Arden T.
- Arias Sonia Sousa
- Arif S.
- Armstrong Jacob
- Armstrong Lisa
- Armstrong Ruth
- Arning N.
- Arnold Sophie
- Arranz María Jesús
- Arribas E.
- Artuso R.
- Arumugam Prabhu
- Ascolillo Steven
- Ashraf Saima
- Ashton L.
- Aslibekyan S.
- Astin-Chamberlain Raine
- Atkinson E.G.
- Attwood B.
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- Austin Pauline
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- Azarzar S.
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- Baikady R.R.
- Baillie John Kenneth
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- Baird Yolanda
- Bakthavatsalam Dhanalakshmi
- Balaconis Mary K.
- Baldassarri M.
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- Baltzell A.H.
- Bamford A.
- Bamford Peter
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- Bandla Nageswar
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- Barclay Lucy
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- Bastion V.
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- Beith C.M.
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- Bellamy Mary
- Belli M.A.
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- Bellwood R.
- Below Jennifer
- Bemand T.
- Benetti E.
- Benham Leonie
- Bennett D.
- Bennett Sara
- Bentley David
- Bentley M.
- Benyon S.
- Beranova E.
- Bercades G.
- Bergantini L.
- Bergomi P.
- Berkowitz Nathan
- Bernardo D.
- Bevan E.
- Bewley J.
- Bhatia Nikhil
- Bhatterjee Ravi
- Bhuie Parminder
- Bi R.
- Biagio A.D.
- Bianchi F.
- Bibert S.
- Bibi Fatima
- Biddle Jack
- Biggs Heather
- Birch J.
- Birch J.
- Birch Sophie.
- Birchall K.
- Birchall K.
- Bird S.
- Birkinshaw Isobel
- Birt M.
- Biscarini F.
- Black E.
- Black K.
- Blackledge B.
- Blackman H.
- Blakemore H.
- Blay Natalia
- Blow Sara
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- Board S.
- Bochud P.Y.
- Bociek Aneta
- Boezen M.
- Boillat N.
- Bokhari M.
- Bolton Matthew
- Bolton Rachel
- Bonner Stephen
- Booker L.
- Borislavova B.
- Borra Catherine
- Botello A.
- Botfield Liam
- Bottà G.
- Bouab M.
- Bough L.
- Boughton A.P.
- Bowes A.
- Bowles Ruth
- Boyle P.
- Boyle R.
- Boz Ceilia
- Bradford Y.
- Bradley C.
- Bradley P.
- Bradley-Potts Joanne
- Bradshaw Zena
- Brady A.
- Brady M.
- Brady R.
- Brandwood C.
- Branney D.
- Brantwood Craig
- Brassard N.
- Brayne A.
- Brealey D.
- Bremmer P.
- Brenner B.
- Bretherick Andrew D.
- Brett Michael
- Brett Stephen
- Brickell K.
- Bridgett V.
- Brimfield Lutece
- Brinkworth Elaine
- Briton Kate
- Britvan Bari
- Bromley M.
- Brooke Hollie
- Brooks S.
- Brown A.
- Brown Adam
- Brown C.W.
- Brown Ellen
- Brown Joanna
- Bruce M.
- Brumpton Ben M.
- Bruno Raffaele
- Brunton Mark
- Bruttini M.
- Bryant J.
- Bryant S.
- Buckley C.
- Buckley Sarah
- Bunni L.
- Burda D.
- Buring Julie E
- Burn I.
- Burnett C.
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- Burt K.
- Burtenshaw Andrew
- Burton Maudrian
- Busani S.
- Bussotti M.
- Butcher D.
- Butler Aaron
- Butler Joanna
- Butler S.
- Butler-Laporte G.
- Butterworth A.S.
- Butterworth-Cowin N.
- Button H.
- Buxbaum Joseph D
- Cabrelli Louise
- Cagova L.
- Caldarelli G.P.
- Callaghan Marie
- Callier S.
- Cameli Paolo
- Campbell Archie
- Campbell Archie
- Campbell Helen
- Campbell Rachael
- Campbell Suzanne
- Campos Sara
- Camsooksai J.
- Canaccini A.
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- Carella M.
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- Carnahan M.
- Carreras A.
- Carriero M.L.
- Carter A.
- Carter David
- Carter E.
- Carter Joseph
- Carter S.
- Carungcong J.
- Casey Matt
- Castaño-Vinyals G.
- Castelli F.
- Castle K.
- Castori M.
- Caswell Melanie
- Catena E.
- Caterson Jess
- Cathcart Susanne
- Catlow L.
- Caulfield Mark J.
- Cavazza Anna
- Cawley Kathryn
- Cawthron K.
- Ceri S.
- Chablani M.
- Chadbourn Indra
- Chamnanphon Monpat
- Chan Georgia
- Chan R.
- Chandler B.
- Chang Xiao
- Chapman Susan
- Chariyavilaskul Pajaree
- Charles B.
- Charlesworth Ruth
- Charney Alexander W.
- Charnock R.
- Chasman D.I.
- Chassé M.
- Chaudhary Kumardeep
- Chavan S.
- Cheema Yusuf
- Chen Hung-Hsin
- Chen Jiantao
- Cheng N.
- Cherian Shiney
- Chetam L.
- Chetruengchai Wanna
- Cheyne C.
- Childs D.
- Chittoor G.
- Cho Judy H.
- Cho K.
- Choi Sam
- Choudhury Yasmin
- Christine Almaden-Boyle None
- Chukkambotla Srikanth
- Churchhouse C.
- Chwialkowska Karolina
- Claassen S.
- Clamp Sarah
- Clapham M.
- Claringbould A.
- Clark Amy
- Clark M.
- Clark Martynn
- Clark Richard
- Clark Sarah
- Clark Victoria
- Clarke D.
- Clarke N.
- Clarkson M.
- Clayton Sarah
- Clement Ian
- Clements S.
- Coates Charlotte
- Cockrell Maeve
- Coetzee S.
- Coghlan Phoebe
- Coignet M.
- Coiro G.
- Coker D.
- Cole J.
- Cole J.
- Cole Stephen
- Coleman Dabheoc
- Coles Holly
- Colley Julie
- Collier D.
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- Åsvold Bjørn Olav
- Publication venue
- Publication date
- 01/01/2022
- Field of study
Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
A second update on mapping the human genetic architecture of COVID-19
- Author
- Abd Elghafar MS
- Abdel-Aziz M
- Abdelrazik M
- Abdullah MS
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- Kanellopoulou A
- Kaneyama Y
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- Sell C
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- Shivanathan I
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- Shoremekun A
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- Solomonson M
- Solomonson M
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- Sonobe K
- Soria JM
- Soriano A
- Souto JC
- Speight A
- Speirs S
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- Spinner CD
- Spivey M
- Springle P
- Sra S
- Sri-Chandana C
- Srikaran S
- St-Cyr J
- Stacey A
- Stagg C
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- Szabo D
- Szakmany T
- Szentpéteri JL
- Szoor-McElhinney H
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- Sækmose SG
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- Takahashi K
- Takahashi K
- Takahashi M
- Takahashi M
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- Takano K
- Takata T
- Takayanagi N
- Takeda Y
- Takeuchi M
- Taki R
- Tamayo E
- Tamayo-Velasco A
- Tampsett R
- Tanaka A
- Tanaka H
- Tanate A
- Tanck A
- Taneski F
- Tani M
- Tanigawa Y
- Tanino Y
- Taniyama D
- Tanudjaja F
- Taracido-Fernandez JC
- Tardif N
- Tariq A
- Tateishi T
- Tateno H
- Tatham K
- Tauekelova A
- Tauro S
- Tavares S
- Taylor B
- Taylor C
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- Teles A
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- Tenorio-Castaño JA
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- Terai H
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- Timpson NJ
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- Tivenan H
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- Tutt G
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- Verdugo RA
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- Wyllie DH
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- Xue X
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- Yamada Y
- Yamagata K
- Yamasaki M
- Yang J
- Yaspan B
- Yassen AM
- Yasui Y
- Yates B
- Yatomi M
- Ye C
- Yermakovich D
- Yeung RSM
- Yi X
- Yonekawa A
- Yoo S
- Yoon K
- Yoshida K
- Yoshida S
- Yoshida S
- Yoshida T
- Yoshihara T
- Yoshiya K
- Yoshiyama T
- Young M
- Yue F
- Yun N
- Yáñez CE
- Yáñez Z
- Zainulabid UA
- Zainy T
- Zak A
- Zaki A
- Zamikula J
- Zamudio IPM
- Zanella A
- Zapata-Contreras D
- Zapatamartinez M
- Zarate R
- Zarei N
- Zavaleta DAF
- Zawadzki P
- Zawati MH
- Zborowski AC
- Zeberg H
- Zechner M
- Zhang Q
- Zhao X
- Zheng C
- Zheng T
- Zhlawi HJ
- Zhlawi MWJ
- Zholdybayeva E
- Zhou W
- Zhu W
- Zitter L
- Zoller H
- Zongo O
- Zorloni C
- Zuñiga-Pacheco P
- Zárate RN
- Zúñiga-Ramos J
- Álvarez BG
- Ávila-Arcos MA
- Ávila-Arcos MC
- Özer O
- Überla K
- Þorsteinsdóttir U
- Publication venue
- Nature Research
- Publication date
- 21/06/2023
- Field of study