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Cedergren, Jan
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Nordin, J., Pettersson, M., Rosenberg, L. H., Mathioudaki, A., Karlsson, Å., Murén, E., . . . Meadows, J. R. S. (2021). Association of Protective HLA-A With HLA-B*27 Positive Ankylosing Spondylitis. Frontiers in Genetics, 12, Article ID 659042.
Öppna denna publikation i ny flik eller fönster >>Association of Protective HLA-A With HLA-B*27 Positive Ankylosing Spondylitis
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2021 (Engelska)Ingår i: Frontiers in Genetics, E-ISSN 1664-8021, Vol. 12, artikel-id 659042Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Objectives: To further elucidate the role of the MHC in ankylosing spondylitis by typing 17 genes, searching for HLA-B∗27 independent associations and assessing the impact of sex on this male biased disease.

Methods: High-confidence two-field resolution genotyping was performed on 310 cases and 2196 controls using an n-1 concordance method. Protein-coding variants were called from next-generation sequencing reads using up to four software programs and the consensus result recorded. Logistic regression tests were applied to the dataset as a whole, and also in stratified sets based on sex or HLA-B∗27 status. The amino acids driving association were also examined.

Results: Twenty-five HLA protein-coding variants were significantly associated to disease in the population. Three novel protective associations were found in a HLA-B∗27 positive population, HLA-A∗24:02 (OR = 0.4, CI = 0.2–0.7), and HLA-A amino acids Leu95 and Gln156. We identified a key set of seven loci that were common to both sexes, and robust to change in sample size. Stratifying by sex uncovered three novel risk variants restricted to the female population (HLA-DQA1∗04.01, -DQB1∗04:02, -DRB1∗08:01; OR = 2.4–3.1). We also uncovered a set of neutral variants in the female population, which in turn conferred strong effects in the male set, highlighting how population composition can lead to the masking of true associations.

Conclusion: Population stratification allowed for a nuanced investigation into the tightly linked MHC region, revealing novel HLA-B∗27 signals as well as replicating previous HLA-B∗27 dependent results. This dissection of signals may help to elucidate sex biased disease predisposition and clinical progression.

Ort, förlag, år, upplaga, sidor
Lausanne, Switzerland: Frontiers Research Foundation, 2021
Nyckelord
HLA allele typing; HLA-A*24:02; HLA-B*27 positive; ankylosing spondylitis; major histocompatibility complex; sex biased
Nationell ämneskategori
Endokrinologi och diabetes
Identifikatorer
urn:nbn:se:liu:diva-183696 (URN)10.3389/fgene.2021.659042 (DOI)000878867300001 ()34335681 (PubMedID)2-s2.0-85111581582 (Scopus ID)
Anmärkning

Funding agencies: Swedish Research Council, FORMAS (Dnr 2012-1531), Knut and Alice Wallenberg Foundation (Dnr 2012-0268), Swedish Research Council for Medicine and Health (D0283001 and Dnr 2018-02399), the Swedish Rheumatism Association, and King Gustaf V’s 80-year Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Tillgänglig från: 2022-05-15 Skapad: 2022-05-15 Senast uppdaterad: 2023-12-12Bibliografiskt granskad
Eloff, E., Martinsson, K., Ziegelasch, M., Cedergren, J., Reckner, Å., Skogh, T., . . . Kastbom, A. (2021). Autoantibodies are major predictors of arthritis development in patients with anti-citrullinated protein antibodies and musculoskeletal pain. Scandinavian Journal of Rheumatology, 50(3), 189-197
Öppna denna publikation i ny flik eller fönster >>Autoantibodies are major predictors of arthritis development in patients with anti-citrullinated protein antibodies and musculoskeletal pain
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2021 (Engelska)Ingår i: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 50, nr 3, s. 189-197Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Objectives: Predictors of arthritis development are highly warranted among patients with anti-citrullinated protein antibodies (ACPAs) and musculoskeletal symptoms to optimize clinical management. We aimed to identify clinical and laboratory predictors of arthritis development, including biochemically assessed alcohol consumption, among ACPA-positive patients with musculoskeletal pain.

Method: 82 ACPA-positive individuals with musculoskeletal pain but no clinical arthritis were followed for a median of 72 months (interquartile range 57–81 months). We evaluated the prognostic value of baseline clinical and laboratory factors including smoking, symptom duration, age, gender, shared epitope, rheumatoid factor (RF), anti-carbamylated protein antibodies, ACPA levels, erythrocyte sedimentation rate, C-reactive protein levels, tender joint count, patient-reported general well-being, 28-joint Disease Activity Score, and alcohol consumption as measured by phosphatidyl ethanol (PEth) levels in whole blood.

Results: During follow-up, 48% developed at least one arthritis. Multivariable analysis revealed an increased risk of arthritis development with RF positivity [hazard ratio (HR) = 2.3, 95% confidence interval (CI) 1.1–4.8, p = 0.028] and higher ACPA levels (HR = 1.0, 95% CI 1.000–1.001, p = 0.002). High levels of RF (HR = 4.4, 95% CI 1.7–11) entailed the highest HR in this ACPA-positive population. Neither clinical characteristics nor alcohol consumption measured by PEth conferred significant prognostic value.

Conclusions: ACPA levels and concurrent presence of RF are independent predictors of arthritis development among ACPA-positive patients with musculoskeletal pain. The results are compatible with a dose–response relationship between RA-related autoantibodies and risk of arthritis development. 

Ort, förlag, år, upplaga, sidor
Taylor & Francis Group, 2021
Nationell ämneskategori
Reumatologi och inflammation
Identifikatorer
urn:nbn:se:liu:diva-171943 (URN)10.1080/03009742.2020.1818820 (DOI)000592601600001 ()33243072 (PubMedID)2-s2.0-85096772948 (Scopus ID)
Anmärkning

Funding Agencies|Swedish Society of Medicine [SLS-682741]; King Gustaf Vs 80-year foundation [FAI-2017-0420]; Swedish Rheumatism Association [R-754141]; Ostergotland County Council [LIO-700501]

Tillgänglig från: 2020-12-16 Skapad: 2020-12-16 Senast uppdaterad: 2022-05-24Bibliografiskt granskad
Ziegelasch, M., Eloff, E., Hammer, H. B., Cedergren, J., Martinsson, K., Reckner, Å., . . . Kastbom, A. (2021). Bone Erosions Detected by Ultrasound Are Prognostic for Clinical Arthritis Development in Patients With ACPA and Musculoskeletal Pain. Frontiers in Medicine, 8, Article ID 653994.
Öppna denna publikation i ny flik eller fönster >>Bone Erosions Detected by Ultrasound Are Prognostic for Clinical Arthritis Development in Patients With ACPA and Musculoskeletal Pain
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2021 (Engelska)Ingår i: Frontiers in Medicine, E-ISSN 2296-858X, Vol. 8, artikel-id 653994Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Anti-citrullinated protein antibodies (ACPA) often precede onset of rheumatoid arthritis (RA) by years, and there is an urgent clinical need for predictors of arthritis development among such at-risk patients. This study assesses the prognostic value of ultrasound for arthritis development among ACPA-positive patients with musculoskeletal pain. We prospectively followed 82 ACPA-positive patients without clinical signs of arthritis at baseline. Ultrasound at baseline assessed synovial hypertrophy, inflammatory activity by power Doppler, and erosions in small joints of hands and feet. We applied Cox regression analyses to examine associations with clinical arthritis development during follow-up (median, 69 months; range, 24-90 months). We also compared the ultrasound findings among the patients to a control group of 100 blood donors without musculoskeletal pain. Clinical arthritis developed in 39/82 patients (48%) after a median of 6 months (range, 1-71 months). One or more ultrasound erosions occurred in 13/82 patients (16%), with none in control subjects (p < 0.001). Clinical arthritis development was more common among patients with baseline ultrasound erosions than those without (77 vs. 42%, p = 0.032), and remained significant in a multivariable Cox regression analysis that included previously described prognostic factors (HR 3.9, 95% CI 1.6-9.4, p = 0.003). Ultrasound-detected tenosynovitis was more frequent among the patients and associated with clinical arthritis development in a univariable analysis (HR 2.5, 95% CI 1.1-5.7, p = 0.031), but did not remain statistically significant in multivariable analysis. Thus, bone erosions detected by ultrasound are independent predictors of clinical arthritis development in an ACPA-positive at-risk population.

Ort, förlag, år, upplaga, sidor
FRONTIERS MEDIA SA, 2021
Nyckelord
anti-citrullinated protein antibodies; rheumatoid arthritis; ultrasound; musculoskeletal pain; erosions; clinical arthritis
Nationell ämneskategori
Reumatologi och inflammation
Identifikatorer
urn:nbn:se:liu:diva-175080 (URN)10.3389/fmed.2021.653994 (DOI)000636834400001 ()33834034 (PubMedID)
Anmärkning

Funding Agencies|Swedish Society of Medicine [SLS-682741]; King Gustaf Vs 80-year foundation [FAI-2017-0420]; Swedish Rheumatism Association [R-754141]; Ostergotland County Council [LIO-700501]

Tillgänglig från: 2021-04-20 Skapad: 2021-04-20 Senast uppdaterad: 2022-05-24Bibliografiskt granskad
Martinsson, K., Roos, K., Ziegelasch, M., Cedergren, J., Eriksson, P., Klimovich, V., . . . Kastbom, A. (2020). Elevated free secretory component in early rheumatoid arthritis and prior to arthritis development in patients at increased risk. Rheumatology, 59(5), 979-987
Öppna denna publikation i ny flik eller fönster >>Elevated free secretory component in early rheumatoid arthritis and prior to arthritis development in patients at increased risk
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2020 (Engelska)Ingår i: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 59, nr 5, s. 979-987Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Objectives. Considering growing evidence of mucosal involvement in RA induction, this study investigated circulating free secretory component (SC) in patients with either recent-onset RA or with ACPA and musculoskeletal pain. Methods. Two prospective cohorts were studied: TIRA-2 comprising 452 recent-onset RA patients with 3 years of clinical and radiological follow-up, and TIRx patients (n = 104) with ACPA IgG and musculoskeletal pain followed for 290 weeks (median). Blood donors and three different chronic inflammatory diseases served as controls. Free SC was analysed by sandwich ELISA. Results. Serum levels of free SC were significantly higher in TIRA-2 patients compared with TIRx and all control groups (P < 0.01). Among TIRx patients who subsequently developed arthritis, free SC levels were higher compared with all control groups (P < 0.05) except ankylosing spondylitis (P = 0.74). In TIRA-2, patients with ACPA had higher baseline levels of free SC compared with ACPA negative patients (P < 0.001). Free SC status at baseline did not predict radiographic joint damage or disease activity over time. In TIRx, elevated free SC at baseline trendwise associated with arthritis development during follow-up (P = 0.066) but this disappeared when adjusting for confounders (P = 0.72). Cigarette smoking was associated with higher levels of free SC in both cohorts. Conclusion. Serum free SC levels are increased in recent-onset RA compared with other inflammatory diseases, and associate with ACPA and smoking. Free SC is elevated before arthritis development among ACPA positive patients with musculoskeletal pain, but does not predict arthritis development. These findings support mucosal engagement in RA development.

Ort, förlag, år, upplaga, sidor
Oxford University Press, 2020
Nyckelord
rheumatoid arthritis (RA); free secretory component; cyclic citrullinated peptide antibodies (ACPA); musculoskeletal pain; clinical progress
Nationell ämneskategori
Reumatologi och inflammation
Identifikatorer
urn:nbn:se:liu:diva-166861 (URN)10.1093/rheumatology/kez348 (DOI)000537433000010 ()31504979 (PubMedID)2-s2.0-85084167837 (Scopus ID)
Anmärkning

Funding Agencies|Swedish Society of Medicine [SLS-682741]; Swedish Research CouncilSwedish Research Council [2011-02532]; Medical Research Council of Southeast Sweden [FORSS-37631]; King Gustaf Vs 80-year foundation [FAI-2017-0420]; Swedish Rheumatism association [R-754141]; Ostergotland County Council [LIO700501]

Tillgänglig från: 2020-06-22 Skapad: 2020-06-22 Senast uppdaterad: 2022-04-19Bibliografiskt granskad
Kastbom, A., Klingberg, E., Verma, D., Carlsten, H., Forsblad-dElia, H., Wesamaa, J., . . . Söderkvist, P. (2013). Genetic variants in CARD8 but not in NLRP3 are associated with ankylosing spondylitis. Scandinavian Journal of Rheumatology, 42(6), 465-468
Öppna denna publikation i ny flik eller fönster >>Genetic variants in CARD8 but not in NLRP3 are associated with ankylosing spondylitis
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2013 (Engelska)Ingår i: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 42, nr 6, s. 465-468Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Objectives: The NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is important for interleukin-1beta (IL-1 beta) processing as part of an innate immune response. Caspase recruitment domain family, member 8 (CARD8) is an inhibitor of nuclear factor kappa B (NF-kappa B) and possibly also a part of the NLRP3 inflammasome. The objective of this study was to evaluate one single nucleotide polymorphism (SNP) in CARD8 and three SNPs in NLRP3 in ankylosing spondylitis (AS) susceptibility and disease phenotype. less thanbrgreater than less thanbrgreater thanMethod: We recruited 492 AS patients from Southern Sweden fulfilling the modified New York criteria for AS, and assessed phenotypic characteristics from medical records and questionnaires. Patients with psoriasis or clinically overt inflammatory bowel disease (IBD) were excluded, as were patients without human leucocyte antigen B27 (HLA-B27). Three NLRP3 SNPs (rs35829419, rs4353135, and rs10733113) and one SNP in CARD8 (rs2043211) were genotyped by commercially available TaqMan assays, and the results compared at genotype and allele levels to those of 793 population-based controls. In a subgroup of the patients (n = 169), faecal calprotectin was assessed as a marker of subclinical intestinal inflammation. less thanbrgreater than less thanbrgreater thanResults: The minor allele (A) of CARD8-C10X (rs2043211) was associated with a decreased risk of AS in a dominant model [odds ratio (OR) 0.74, 95% confidence interval (CI) 0.54-0.94, p = 0.012] and at the allelic level (OR 0.81, 95% CI 0.68-0.97, p = 0.02), but was not associated with levels of faecal calprotectin. There was no association regarding NLRP3 SNPs and AS susceptibility, and none of the investigated SNPs were associated with iritis, anti-tumour necrosis factor (anti-TNF) therapy, or peripheral joint involvement. less thanbrgreater than less thanbrgreater thanConclusion: In a Swedish population, the minor allele of CARD8-C10X is associated with a decreased risk of AS, but not with levels of faecal calprotectin or disease phenotype.

Ort, förlag, år, upplaga, sidor
Informa Healthcare, 2013
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-102509 (URN)10.3109/03009742.2013.779020 (DOI)000327259200007 ()
Anmärkning

Funding Agencies|Medical Research Council of Southeast Sweden (FORSS)|FORSS-88721|County Council of Ostergotland||

Tillgänglig från: 2013-12-12 Skapad: 2013-12-12 Senast uppdaterad: 2021-12-28
Cedergren, J., Forslund, T., Sundqvist, T. & Skogh, T. (2007). Intracellular oxidative activation in synovial fluid neutrophils from patients with rheumatoid arthritis but not from other arthritis patients. Journal of Rheumatology, 34(11), 2162-2170
Öppna denna publikation i ny flik eller fönster >>Intracellular oxidative activation in synovial fluid neutrophils from patients with rheumatoid arthritis but not from other arthritis patients
2007 (Engelska)Ingår i: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 34, nr 11, s. 2162-2170Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Objective: To compare total and intracellular oxidative activation of blood and synovial fluid (SF) neutrophils from patients with rheumatoid arthritis (RA) and other arthritides with blood donor neutrophils.

Methods: Peripheral blood and SF samples were obtained from 26 gonarthritis patients (13 RA, 13 non-RA) attending the rheumatology unit for therapeutic joint aspiration. Isolated neutrophils were stimulated by a formylated tripeptide (fMLF) or by microbeads coated with collagen-I. Formation of superoxide-anion-derived reactive oxygen species (ROS) was studied by luminol-enhanced chemiluminescence. Paired samples of blood and SF neutrophils from patients with active arthritis were compared with blood neutrophils from patients in remission and from 47 healthy blood donors.

Results: SF neutrophils from patients with RA, but not from non-RA patients, showed high baseline intracellular ROS production. Blood neutrophils from arthritis patients in remission existed in a primed state as revealed by more rapid oxidative response after collagen-bead challenge and a more pronounced response after fMLF stimulation compared to healthy blood donors. Blood neutrophils from RA patients with ongoing gonarthritis, however, did not differ from healthy blood donors concerning oxidative activation, whereas blood neutrophils from non-RA patients with gonarthritis showed a significantly lower peak ROS production.

Conclusions: A novel finding with pathogenetic implications in our study is that SF neutrophils from patients with RA, but not other arthritides, are activated and produce ROS intracellularly. This implies that synovial neutrophils in RA are engaged in the processing of endocytosed material.

Nyckelord
Neutrophils, Arthritis, Reactive oxygen species, Superoxide anion
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-14585 (URN)
Tillgänglig från: 2007-08-27 Skapad: 2007-08-27 Senast uppdaterad: 2017-12-13
Cedergren, J., Forslund, T., Sundqvist, T. & Skogh, T. (2007). Oxidative activation of human neutrophils by type-1-collagen-coated particles is influenced by nitric oxide production and modulated by endogenous arginase. Journal of Leukocyte Biology
Öppna denna publikation i ny flik eller fönster >>Oxidative activation of human neutrophils by type-1-collagen-coated particles is influenced by nitric oxide production and modulated by endogenous arginase
2007 (Engelska)Ingår i: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673Artikel i tidskrift (Refereegranskat) Submitted
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-14588 (URN)
Tillgänglig från: 2007-08-27 Skapad: 2007-08-27 Senast uppdaterad: 2017-12-13
Cedergren, J. (2007). Radical aspects on arthritis: the role of neutrophil generation of nitric oxide and superoxide in inflammatory conditions. (Doctoral dissertation). Institutionen för molekylär och klinisk medicin
Öppna denna publikation i ny flik eller fönster >>Radical aspects on arthritis: the role of neutrophil generation of nitric oxide and superoxide in inflammatory conditions
2007 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The polymorphonuclear neutrophil granulocytes (neutrophils) are gaining renewed interest regarding their involvement in chronic inflammatory disorders, including rheumatoid arthritis (RA). Besides phagocytic and destructive capabilities, neutrophils have regulatory roles, e.g. by influencing responses from dendritic cells and lymphocytes. Several animal models have revealed that neutrophils are crucial for the initiation and maintenance of chronic inflammatory diseases. Neutrophil function is highly dependent on their ability to produce superoxide, an oxygen radical which can be further metabolized to other free radicals. Whether or not neutrophils are capable of producing the oxygen radical nitric oxide (NO˙) has been a matter of debate.

In this thesis it was shown that freshly isolated neutrophils from the joint cavity of patients with RA, but not from other arthritis patients, had ongoing intracellular production of superoxide, indicating the processing of ingested material.

The finding that joint neutrophils, but seemingly not circulating cells, expressed the NO-inducing enzyme iNOS, led to a series of experiments aimed to elucidate where in the exudative process this enzyme could first be detected. We could finally, for the first time, present evidence that human neutrophils actually express iNOS constitutively. Our data also suggest that neutrophil iNOS may be membrane associated, thus differing from the cytosolic location in other cell types. Since NOS activity was not demonstrated in isolated cells, the notion that neutrophil iNOS is regulated primarily at the transcriptional level must be questioned. NO production from iNOS requires the presence of its substrate, L-arginine. To test the hypothesis that neutrophil arginase prevents neutrophil NO-production, we investigated whether arginase inhibition affects neutrophil NO-dependent oxidative function. Initial data revealed a difference in the effect of arginase inhibition comparing neutrophil stimulus with a soluble formylated tri-peptide (fMLF) and integrin-mediated stimulation with particle-bound collagen type-1. This led to the hypothesis that integrin-ligation on neutrophils induces extracellular liberation of arginase, which was confirmed both by measuring arginase and its enzyme activity. The findings in this thesis may be important not only regarding the role of neutrophils in chronic joint inflammation, but also as a link in the accelerated atherosclerosis observed in chronic inflammatory disorders, e.g. RA.

Abstract [sv]

Vid reumatiska ledinflammationer ansamlas mycket stora mängder polymorfkärniga neutrofila granulocyter (neutrofiler) inne i den vätskefyllda ledhålan. Neutrofiler har kraftfull destruktiv potential och anses kunna bidra till uppkomst av skada i leden. Då flera djurmodeller av ledinflammation har visat sig omöjliga att initiera i frånvaro av neutrofiler, har intresset för denna celltyp åter ökat efter att de under lång tid har stått i skuggan av andra typer av vita blodkroppar. En viktig del i avdödning av mikroorganismer och cellsignalering är förmågan att bilda fria syreradikaler, t.ex. superoxid (˙O2-) och kväveoxid (NO˙). Denna avhandling belyser aspekter kring produktionen av dessa reaktiva syreprodukter och mekanismer av potentiell betydelse vid ledinflammation.

I det första arbetet visas att neutrofiler isolerade ur ledvätska från patienter med ledgångsreumatism (RA) har ett unikt beteende avseende superoxidproduktion jämfört med motsvarande celler från patienter med andra reumatiska sjukdomar. RA-neutrofiler från ledvätska (men inte från blod) producerar superoxid intracellulärt redan i vila och stimulering via vidhäftningsmolekyler ger en snabb ytterligare ökning av denna aktivitet. Fyndet antyder att cellerna är engagerade med hantering av endocyterade partiklar och/eller immunkomplex/immunaggregat.

I de båda nästkommande arbetena undersöktes förekomst av det NO˙-producerande enzymet iNOS i neutrofiler. En rad tidigare publikationer har rapporterat motsägelsefulla resultat i denna fråga. Efter en serie experiment kunde vi konstatera att humana neutrofiler uttrycker iNOS konstitutivt, men att både dess cellulära lokalisation och reglering skiljer sig från andra celler.

Neutrofiler har nyligen även visats innehålla arginas, ett enzym som konkurrerar med iNOS om bindningen till L-arginin och som därmed kan hämma NO˙-produktion. I det fjärde arbetet undersökte vi därför om hämning av arginas påverkade neutrofilernas funktion och produktion av superoxid. Vi fann att effekterna av arginashämning var större hos celler som stimulerats genom vidhäftning av kollagenklädda partiklar jämfört med en löslig formylerad tri-peptid (fMLF). Vidare, kunde vi visa att vidhäftning av kollagenklädda partiklar medför större extracellulär frisättning av arginas. Med stöd av dessa fynd kunde vi i påföljande försök bekräfta hypotesen att extracellulär frisättning av arginas är större efter vidhäftning av kollagen-partiklar än med fMLF-stimulering. Fysiologiskt är fyndet logiskt då det skulle medföra ökade vidhäftningsmöjligheter för neutrofilen inne i blodbanan genom att begränsa blodkärlets egen NO˙ produktion. Fyndet är också förenligt med den ökade frekvensen hjärt- och kärlsjukdomar vid RA, då en intensiv kontinuerlig utvandring av neutrofiler skulle medföra ökad arginas frisättning, sänkta argininnivåer och endotelial dysfunktion.

Ort, förlag, år, upplaga, sidor
Institutionen för molekylär och klinisk medicin, 2007
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 984
Nyckelord
neutrophils, reactive oxygen species, arthritis, NOS, NO, arginase, integrins
Nationell ämneskategori
Klinisk medicin
Identifikatorer
urn:nbn:se:liu:diva-9505 (URN)978-91-85715-67-1 (ISBN)
Disputation
2007-03-16, Berzeliussalen, Hälsouniversitetet, Universitetssjukhuset, Linköping, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2007-08-27 Skapad: 2007-08-27 Senast uppdaterad: 2020-03-29
Cedergren, J., Follin, P., Forslund, T., Lindmark, M., Sundqvist, T. & Skogh, T. (2003). Inducible nitric oxide synthase (NOS II) is constitutive in human neutrophils. APMIS, 111(10), 963-968
Öppna denna publikation i ny flik eller fönster >>Inducible nitric oxide synthase (NOS II) is constitutive in human neutrophils
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2003 (Engelska)Ingår i: APMIS, ISSN 0903-4641, Vol. 111, nr 10, s. 963-968Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The objective was to study the expression of inducible nitric oxide synthase (NOS II) in and NO production by human blood neutrophils and in in vivo exudated neutrophils. Cellular expression of NOS II was evaluated by flow cytometry in whole blood, in isolated blood neutrophils, and in neutrophils obtained by exudation in vivo into skin chambers. Neutrophil NOS II was also demonstrated by Western blotting. Uptake of 3H-labelled L-arginine was studied in vitro and NOS activity measured in a whole cell assay by the conversion of 3H-arginine to 3H-citrulline. In contrast to unseparated blood cells, NOS II was demonstrable both in isolated blood neutrophils and exudated cells. The failure to detect NOS II by flow cytometry in whole blood cells thus proved to be due to the quenching effect of hemoglobin. Western blotting revealed a 130 kD band corresponding to NOS II in isolated blood neutrophils, but detection was dependent on diisopropylfluorophosphate for proteinase inhibition. L-arginine was taken up by neutrophils, but enzymatic activity could not be demonstrated. We conclude that human neutrophils constitutively express NOS II, but that its demonstration by FITC-labelling is inhibited by hemoglobin-mediated quenching in whole blood samples.

Nyckelord
Inflammation, nitric oxide, iNOS, granulocytes
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-14587 (URN)10.1034/j.1600-0463.2003.1111008.x (DOI)
Tillgänglig från: 2007-08-27 Skapad: 2007-08-27 Senast uppdaterad: 2015-08-31
Cedergren, J., Forslund, T., Sundqvist, T. & Skogh, T. (2002). Inducible nitric oxide synthase is expressed in synovial fluid granulocytes. Clinical Experimental Immunology, 130, 150-155
Öppna denna publikation i ny flik eller fönster >>Inducible nitric oxide synthase is expressed in synovial fluid granulocytes
2002 (Engelska)Ingår i: Clinical Experimental Immunology, ISSN 0009-9104, Vol. 130, s. 150-155Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The objective of the study was to evaluate the NO-producing potential of synovial fluid (SF) cells. SF from 15 patients with arthritis was compared with blood from the same individuals and with blood from 10 healthy controls. Cellular expression of inducible nitric oxide synthase (iNOS) was analysed by flow cytometry. High-performance liquid chromatography was used to measure L-arginine and L-citrulline. Nitrite and nitrate were measured colourimetrically utilizing the Griess' reaction. Compared to whole blood granulocytes in patients with chronic arthritis, a prominent iNOS expression was observed in SF granulocytes (P < 0.001). A slight, but statistically significant, increase in iNOS expression was also recorded in lymphocytes and monocytes from SF. L-arginine was elevated in SF compared to serum (257 ± 78 versus 176 ± 65 µmol/l, P = 0.008), whereas a slight increase in L-citrulline (33 ± 11 versus 26 ± 9 µmol/l), did not reach statistical significance. Great variations but no significant differences were observed comparing serum and SF levels of nitrite and nitrate, respectively, although the sum of nitrite and nitrate tended to be elevated in SF (19.2 ± 20.7 versus 8,6 ± 6.5 µmol/l,P = 0.054). Synovial fluid leucocytes, in particular granulocytes, express iNOS and may thus contribute to intra-articular NO production in arthritis.

Nyckelord
arthritis, granulocytes, iNOS, nitric oxide
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-14586 (URN)10.1046/j.1365-2249.2002.01959.x (DOI)
Tillgänglig från: 2007-08-27 Skapad: 2007-08-27 Senast uppdaterad: 2015-08-31
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