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Periodontitis Associates with a Type 1 IFN Signature in Peripheral Blood Neutrophils Helen J. Wright, John B. Matthews, Iain L. C. Chapple, Nic Ling-Mountford and Paul R. Cooper This information is current as of September 23, 2021. J Immunol 2008; 181:5775-5784; ; doi: 10.4049/jimmunol.181.8.5775 http://www.jimmunol.org/content/181/8/5775 Downloaded from References This article cites 72 articles, 11 of which you can access for free at: http://www.jimmunol.org/content/181/8/5775.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 23, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Periodontitis Associates with a Type 1 IFN Signature in Peripheral Blood Neutrophils1 Helen J. Wright, John B. Matthews, Iain L. C. Chapple, Nic Ling-Mountford, and Paul R. Cooper2 Peripheral blood neutrophils from periodontitis patients exhibit a hyperreactive and hyperactive phenotype (collectively termed hyperresponsivity) in terms of production of reactive oxygen species (ROS). The molecular basis for this phenomenon, however, has yet to be determined. Our objectives were to identify genes differentially expressed in hyperresponsive peripheral blood neutrophils from chronic periodontitis patients relative to periodontally healthy controls and use these data to identify potential contributory pathways to the hyperresponsive neutrophil phenotype. Using microarray technology we demonstrated differential expression of 163 genes (149 increased, 14 decreased) representing a range of ontological classes. There was increased expression of a significant number of IFN-stimulated genes (ISG). RT-PCR analysis of ISG transcripts in individual and pooled samples Downloaded from further corroborated these data, and indicated that levels decreased to near those of controls following successful therapy. Significantly enhanced Fc␥R-stimulated ROS production was subsequently achieved by priming control neutrophils with IFN- ␣/-␤/-␥, but not LPS, and gene expression analysis indicated that exposure to the type I IFN (in particular IFN-␣) better replicated the mRNA profile observed in vivo. Further studies demonstrated that plasma levels of IFN-␣ were significantly higher in samples from patients relative to unaffected controls. Following successful periodontitis treatment, plasma IFN-␣ levels, neutrophil ISG expression, and Fc␥R-stimulated neutrophil ROS output of patients, all decreased to levels comparable with those of controls. In conclusion, http://www.jimmunol.org/ although chronic periodontitis is a complex disease, raised IFN-␣ may be one determinant of the distinct molecular phenotype and hyperresponsivity exhibited by patients’ peripheral blood neutrophils. The Journal of Immunology, 2008, 181: 5775–5784. eripheral blood neutrophils (PBN)3 from patients with a lated ROS production (7–10). Although a host molecular defect in range of inflammatory disorders have been shown to have intracellular lipid signaling may explain peripheral neutrophil ROS P enhanced chemotactic and extracellular proteolytic activ- hyperreactivity in the relatively rare form of the disease, localized ity as well as the ability to produce increased amounts of reactive aggressive periodontitis (11), this mechanism does not explain the oxygen species (ROS; Refs. 1–3). It has been proposed that the patient predisposition observed in chronic periodontitis. The un- by guest on September 23, 2021 accumulation of these activated neutrophils at sites of tissue irritation, derlying mechanism(s) responsible for the hyperinflammatory neu- Ag localization, or bacterial infection subsequently leads to the tissue trophil phenotype seen in chronic periodontitis (the commonest damage that underpins the clinical course of these diseases. form of the disease) is currently unknown, although analyses in- Periodontitis is one of the most prevalent human inflammatory dicate that it is not a result of altered adhesion molecule (7) or diseases and is characterized by an aberrant and exaggerated neu- Phox gene (10) expression, polymorphisms in Fc␥R (8, 12), or in trophilic response to microbial plaque present at the gingival mar- vitro priming by cytokines or LPS (13, 14). Furthermore, the as- gin indicating dysregulation of the hosts’ innate immune response sociation of periodontitis with increased relative risk for cardio- (4, 5). The resultant collateral host tissue damage to the supporting vascular disease, fatal coronary events (15), and ischemic stroke periodontal tissues leads to progressive periodontitis and ulti- (16), and the demonstrable medium-term reductions in vascular mately culminates in tooth loss (6). Several studies have demon- endothelial dysfunction following aggressive periodontal therapies strated that PBN from chronic periodontitis patients are not only (17), emphasize the potential impact of inflammatory periodontitis ␥ hyperreactive, in response to Fc R stimulation by periodontal on peripheral macrovascular disease. pathogens, but also hyperactive, with respect to baseline unstimu- To identify factors predisposing to, or biomarkers of disease activity, peripheral blood levels of several acute phase response (APR) proteins in periodontitis patients have been analyzed. Dur- Periodontal Research Group, School of Dentistry, University of Birmingham, Bir- mingham, United Kingdom ing the APR, following local release of factors such as TNF-␣, ␤ Received for publication November 27, 2007. Accepted for publication August IL-1 , and IL-6, systemic changes occur that include significant 6, 2008. hepatic release of plasma proteins (e.g., C-reactive protein and The costs of publication of this article were defrayed in part by the payment of page serum amyloid A), activation of complement proteins, and several charges. This article must therefore be hereby marked advertisement in accordance other metabolic events (18, 19). Thus far, whereas plasma C-re- with 18 U.S.C. Section 1734 solely to indicate this fact. active protein levels have generally been found to be higher in 1 This work was supported by the Medical Research Council (MRC UK-G0000797). periodontitis patients compared with healthy controls, findings for 2 Address correspondence and reprint requests to Dr. Paul R. Cooper, Oral Biology, ϳ School of Dentistry, University of Birmingham, St. Chad’s Queensway, Birmingham, any of the other 40 recognized APR proteins are inconsistent, B4 6NN, U.K. E-mail address: [email protected] mainly due to the biological heterogeneity of patients (20–22). 3 Abbreviations used in this paper: PBN, peripheral blood neutrophil; ROS, reactive Notably, analysis of circulating APR-associated cytokine levels, oxygen species; APR, acute phase response; ISG, IFN-stimulated gene; RLU, relative including TNF-␣, IL-1␤, IL-2, IL-4, and IL-10, has therefore yet light unit; CL, chemiluminescence; bDNA, bacterial DNA. to identify any useful biomarkers, nor has it been able to provide Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 a mechanistic explanation for disease pathogenesis (23–26). www.jimmunol.org 5776 ELEVATED IFN-␣ LEVELS IN PERIODONTITIS Table I. Details of primer sequences and semi-quantitative RT-PCR conditionsa Gene Symbol Sequence Product Size Cycle No. Myxovirus (influenza virus) resistance 1, MX1 F-AGCCACTGGACTGACGACTT 203 bp 30 IFN-inducible protein p78 R-GAGGGCTGAAAATCCCTTTC IFN induced with tetratricopeptide repeats 4 IFIT4 F-CCCTTCAGGCATAGGCAGTA 185 bp 30 R-CTCCTACCCGTCACAACCAC IFN-stimulated protein, 15 kDa (ISG15) G1P2 F-CGCAGATCACCCAGAAGATT 185 bp 33 R-GCCCTTGTTATTCCTCACCA IFN induced with tetratricopeptide repeats 1 IFIT1 F-GGTCGGTTTCAGGAATTTCA 236 bp 33 R-GCCCGCTCATAGTACTCCAG CMV-inducible gene 5/viperin cig5 F-TAGCTGGTTGGCCCTACATC 237 bp 33 R-TGCTTGCTTTCTCTGAGCTG IFN-induced protein 44-like IFI-44 like F-AGCGGTGGGCTAAGATAGGT 245 bp 33 R-TCCACGCTGTTTCTCAAAGA GAPDH GAPDH F-TCTAGACGGCAGGTCAGGTCC 391 bp 26 R-CCACCCATGGCAAATTCCATG a All DNA sequences are shown in the 5Ј to 3Ј orientation. F ϭ Forward primer; R ϭ Reverse primer. Downloaded from Nevertheless, it is hypothesized that the APR, which may arise determine the priming effects of IFN on Fc␥R-stimulated ROS production chronically in patients, is responsible for the association between and expression of IFN-stimulated genes (ISG). Ethical approval was periodontitis and other systemic disorders such as cardiovascular granted by South Birmingham Local Research Ethics Committee (LREC ␥ 5643). Informed consent to participate was initially obtained, followed by disease (20, 27). Although IFN- may be important in eliciting the the completion of a medical questionnaire. APR, and its levels have been shown to be higher in tissues, serum, and gingival crevicular fluid from periodontitis
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