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Kelly, Anne
Publications (5 of 5) Show all publications
Asfaw Idosa, B., Sahdo, B., Balcha, E., Kelly, A., Söderquist, B. & Särndahl, E. (2014). C10X polymorphism in the CARD8 gene is associated with bacteraemia. Immunity, inflammation and disease, 2(1), 13-20
Open this publication in new window or tab >>C10X polymorphism in the CARD8 gene is associated with bacteraemia
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2014 (English)In: Immunity, inflammation and disease, E-ISSN 2050-4527, Vol. 2, no 1, p. 13-20Article in journal (Refereed) Published
Abstract [en]

The NLRP3 inflammasome is an intracellular multi-protein complex that triggers caspase-1 mediated maturation of interleukin-1β (IL-1β); one of the most potent mediators of inflammation and a major cytokine produced during severe infections, like sepsis. However, the excessive cytokine levels seem to stage for tissue injury and organ failure, and high levels of IL-1β correlates with severity and mortality of sepsis. Instead, recent data suggest caspase-1 to function as a guardian against severe infections. CARD8 has been implied to regulate the synthesis of IL-1β via interaction to caspase-1. In recent years, polymorphism of CARD8 (C10X) per se or in combination with NLRP3 (Q705K) has been implicated with increased risk of inflammation. The aim was to investigate the correlation of these polymorphisms with severe blood stream infection. Human DNA was extracted from blood culture bottles that were found to be positive for microbial growth (i.e. patients with bacteraemia). Polymorphisms Q705K in the NLRP3 gene and C10X in the CARD8 gene were genotyped using TaqMan genotyping assay. The results were compared to healthy controls and to samples from patients with negative cultures. The polymorphism C10X was significantly over-represented among patients with bacteraemia as compared to healthy controls, whereas patients with negative blood culture were not associated with a higher prevalence. No association was observed with polymorphism Q705K of NLRP3 in either group of patients. Patients carrying polymorphism C10X in the CARD8 gene are at increased risk of developing bacteraemia and severe inflammation.

Place, publisher, year, edition, pages
West Sussex, UK: John Wiley & Sons, 2014
Keywords
Bacteraemia, blood culture, gene variants, infection, inflammasomes, inflammation, innate immunity, leukocytes, polymorphisims, sepsis
National Category
Clinical Laboratory Medicine Microbiology in the medical area Immunology in the medical area
Identifiers
urn:nbn:se:oru:diva-42421 (URN)10.1002/iid3.14 (DOI)25400921 (PubMedID)
Available from: 2015-02-05 Created: 2015-02-05 Last updated: 2018-11-30Bibliographically approved
Sahdo, B., Fransén, K., Asfaw Idosa, B., Eriksson, P., Söderquist, B., Kelly, A. & Särndahl, E. (2013). Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the NLRP3 inflammasome. PLoS ONE, 8(10)
Open this publication in new window or tab >>Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the NLRP3 inflammasome
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10Article in journal (Refereed) Published
Abstract [en]

Background: The NLRP3 inflammasome has been recognized as one of the key components of the innate immunity by sensing a diversity of insults. Inflammasome activation results in the maturation of the pro-inflammatory cytokines interleukin (IL)-1 beta and IL-18. Increased production of IL-1 beta is found in patients with gain-of-function polymorphisms in genes encoding the NLRP3 inflammasome. Since approximately 5% of the Swedish population are heterozygote carriers of these combined gene variants, their impact on inflammasome status and a relationship on disease development is therefore highly relevant to study. The present study investigates levels of inflammasome-produced cytokines as a measure of inflammasome activation in healthy individuals carrying Q705K polymorphism in the NLRP3 gene combined with C10X in the CARD8 gene.

Materials and Methods: Genotyping of 1006 healthy blood donors was performed for the polymorphisms Q705K in the NLRP3 and C10X in the CARD8 genes. IL-1 beta, IL-18, IL-33, as well as a number of other pro-inflammatory cytokines, were analyzed by Luminex or ELISA in plasma from individuals carrying the polymorphisms and in age and gender matched non-carrier controls.

Results & Discussion: The prevalence of the polymorphisms was in line with previous studies. Plasma levels of IL-1 beta and IL-33 were elevated among carriers of combined Q705K+C10X polymorphisms compared to controls, whereas no difference was found for IL-18 and the other cytokines measured. Moreover, carriers of C10X or Q705K per se had similar plasma levels of IL-1 beta as non-carriers. These data suggest that the combined polymorphisms create inflammasomes with increased basal activation state, which might provide a more favourable innate immune response. In spite of this, it could also represent the mechanisms by which the inflammatory loop is triggered into a long-term inflammatory phenotype.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2013
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-35447 (URN)10.1371/journal.pone.0075457 (DOI)000325483600018 ()24098386 (PubMedID)2-s2.0-84884894455 (Scopus ID)
Funder
Swedish Research Council, ES: K2010-57X-21435-01-3
Note

Funding Agencies:

Research committee of the County Council of Örebro

Nyckelfonden at Örebro University Hospital

Sund's Foundation for Rheumatic Research

King Gustaf V Memorial Foundation

Available from: 2014-06-19 Created: 2014-06-19 Last updated: 2019-06-14Bibliographically approved
Kelly, A., Jacobsson, S., Hussain, S., Olcen, P. & Mölling, P. (2013). Gene variability and degree of expression of vaccine candidate factor H binding protein in clinical isolates of Neisseria meningitidis. Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), 121(1), 56-63
Open this publication in new window or tab >>Gene variability and degree of expression of vaccine candidate factor H binding protein in clinical isolates of Neisseria meningitidis
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2013 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 121, no 1, p. 56-63Article in journal (Refereed) Published
Abstract [en]

The factor H binding protein (fHbp) is currently being evaluated in clinical trials as a vaccine candidate for a meningococcal group B vaccine. We have previously described the prevalence and sequence variation of fHbp (Jacobsson et al., 2009) and here we investigate the expression of the antigen. The present study includes isolates from carriers (n = 62) and patients with invasive Neisseria meningitidis infections (n = 146), of which 62 had a fatal outcome. Among the invasive isolates from patients with fatal and non-fatal infections fHbp allele 1 was most common (42% and 29% respectively), but it was only identified in 3% of the carrier isolates, where allele 16 was most frequent (13%). The Fluorescence-activated cell sorting analysis identified fHbp expression in all except seven isolates and further analysis by Western blot showed that five of these seven samples were indeed negative using a polyclonal anti-fHbp serum. The negative isolates belonged to serogroup B fHbp allele 24, Y allele 104, and W-135 allele 16 (all invasive). Two were non-serogroupable carrier isolates (allele 21 and 101). An interesting finding is that isolates from invasive infections with fatal outcome had lower expression of fHbp or lower affinity for the fHbp antibody compared to isolates from non-fatal invasive infections and carriers.

Keywords
Neisseria meningitidis, vaccine, factor H binding protein, sequencing, fluorescence-activated cell sorting, Western blot
National Category
Immunology in the medical area
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-27749 (URN)10.1111/j.1600-0463.2012.02934.x (DOI)000313830600007 ()23030708 (PubMedID)
Available from: 2013-02-27 Created: 2013-02-27 Last updated: 2018-04-16Bibliographically approved
Idosa, B. A., Sahdo, B., Balcha, E., Kelly, A., Söderquist, B. & Särndahl, E.C10X polymorphism in the CARD8 gene is associated with bacteraemia.
Open this publication in new window or tab >>C10X polymorphism in the CARD8 gene is associated with bacteraemia
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction:: The NLRP3 inflammasome is an intracellular multi-protein complex that triggers caspase-1 mediated maturation of interleukin-1β (IL-1β); one of the most potent mediators of inflammation and a major cytokine produced during severe infections, like sepsis. However, the excessive cytokine levels seem to stage for tissue injury and organ failure, and high levels of IL-1β correlates with severity and mortality of sepsis. Instead, recent data suggest caspase- 1 to function as a guardian against severe infections. CARD8 has been implied to regulate the synthesis of IL-1β via interaction to caspase-1. In recent years, polymorphism of CARD8 (C10X) per se or in combination with NLRP3 (Q705K) has been implicated with increased risk of inflammation. The aim was to investigate the correlation of these polymorphisms with severe blood stream infection.

Methods:: Human DNA was extracted from blood culture bottles that were found to be positive for microbial growth (i.e. patients with bacteraemia). Polymorphisms Q705K in the NLRP3 gene and C10X in the CARD8 gene were genotyped using TaqMan genotyping assay. The results were compared to healthy controls and to samples from patients with negative cultures.

Results:: The polymorphism C10X was significantly over-represented among patients with bacteraemia as compared to healthy controls, whereas patients with negative blood culture were not associated with a higher prevalence. No association was observed with polymorphism Q705K of NLRP3 in eithergroup of patients.

Conclusions:: Patients carrying polymorphism C10X in the CARD8 gene are at increased risk of developing bacteraemia and severe inflammation.

Keywords
bacteraemia, blood culture, gene variants, infection, inflammasomes, inflammation, innate immunity, leukocytes, polymorphisms, sepsis
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-32015 (URN)
Available from: 2013-10-15 Created: 2013-10-15 Last updated: 2017-10-17Bibliographically approved
Sahdo, B., Fransén, K., Idosa, B. A., Eriksson, P., Söderquist, B., Kelly, A. & Särndahl, E.Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the nlrp3 inflammasome.
Open this publication in new window or tab >>Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the nlrp3 inflammasome
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: The NLRP3 inflammasome has been recognized as one of the key components of the innate immunity by sensing a diversity of insults. Inflammasome activation results in the maturation of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Increased production of IL-1β is found in patients with gain-of-function polymorphisms in genes encoding the NLRP3 inflammasome. Since approximately 5% of the Swedish population are heterozygote carriers of these combined gene variants, their impact on inflammasome status and a relationship on disease development is therefore highly relevant to study. The present study investigates levels of inflammasome-produced cytokines as a measure of inflammasome activation in healthy individuals carrying Q705K polymorphism in the NLRP3 gene combined with C10X in the CARD8 gene.

Materials and Methods: Genotyping of 1006 healthy blood donors was performed for the polymorphisms Q705K in the NLRP3 and C10X in the CARD8 genes. IL-1β, IL-18, IL-33, as well as a number of other pro-inflammatory cytokines, were analyzed by Luminex or ELISA in plasma from individuals carrying the polymorphisms and in age and gender matched noncarrier controls.

Results & Discussion: The prevalence of the polymorphisms was in line with previous studies. Plasma levels of IL-1β and IL-33 were elevated among carriers of combined Q705K/C10X polymorphisms compared to controls, whereas no difference was found for IL- 18 and the other cytokines measured. These data suggest that these combined polymorphisms creates inflammasomes with increased basal activation state, which might provide a more favourable innate immune response. In spite of this, it could also represent the mechanisms by which the inflammatory loop is triggered into a long-term inflammatory phenotype.

Keywords
Auto-inflammation, Cytokines, Inflammasome, Interleukin-1β, Leukocytes
National Category
Medical and Health Sciences Immunology
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-32006 (URN)
Available from: 2013-10-15 Created: 2013-10-14 Last updated: 2017-10-17Bibliographically approved
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