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Ossami Saidy RR, Eurich F, Globke B, Schöning W, Öllinger R, Raschzok N, Pratschke J, Eurich D, Dittrich L, Dobrindt EM. The Association Between Cytomegalovirus Infection and Kidney Damage in the Liver Transplant Setting. Viruses 2024; 16:1830. [PMID: 39772140 PMCID: PMC11680441 DOI: 10.3390/v16121830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 01/11/2025] Open
Abstract
INTRODUCTION The development of chronic kidney disease (CKD) is a common and significant complication, contributing to morbidity after liver transplantation (LT). Cytomegalovirus (CMV) infection is common in the overall population, and relevant reinfection after LT may occur. CMV-associated kidney damage has been discussed, but the clinical significance on CKD development after LT remains unclear. METHODS A total of 745 patients who underwent LT between 2006 and 2017 were included in this retrospective analysis. Clinical data, as well as laboratory parameters, were analyzed. Univariate and multivariate analysis were performed. RESULTS The univariate analysis revealed significantly impaired estimated glomerular filtration rates (eGFRs) in patients with histories of CMV infection (81.4 (8-137) mL/min vs. 90.0 (5-147) mL/min; p = 0.004). This effect was confirmed in the multivariate analysis. Post-LT, eGFR was impaired in patients with CMV (re)infection at 6, 12, 36, and 60 months, 10 years, and 15 years after LT. Immunosuppressive levels were comparable between groups. Overall survival was negatively affected by CMV infection (p = 0.001). DISCUSSION A clinically significant detrimental impact of CMV infection on renal function was observed, that could individualize clinical risk evaluation prior and after LT further. However, the pathophysiological mechanisms behind this observation are not yet understood.
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Affiliation(s)
- Ramin Raul Ossami Saidy
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité–Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (F.E.); (B.G.); (W.S.); (R.Ö.); (N.R.); (J.P.); (D.E.); (L.D.); (E.M.D.)
| | - Franziska Eurich
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité–Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (F.E.); (B.G.); (W.S.); (R.Ö.); (N.R.); (J.P.); (D.E.); (L.D.); (E.M.D.)
| | - Brigitta Globke
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité–Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (F.E.); (B.G.); (W.S.); (R.Ö.); (N.R.); (J.P.); (D.E.); (L.D.); (E.M.D.)
- Berlin Institute of Health at Charité—Universitätsmedizin Berlin, BIH Academy, Clinician Scientist Program, 10117 Berlin, Germany
| | - Wenzel Schöning
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité–Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (F.E.); (B.G.); (W.S.); (R.Ö.); (N.R.); (J.P.); (D.E.); (L.D.); (E.M.D.)
| | - Robert Öllinger
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité–Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (F.E.); (B.G.); (W.S.); (R.Ö.); (N.R.); (J.P.); (D.E.); (L.D.); (E.M.D.)
| | - Nathanael Raschzok
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité–Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (F.E.); (B.G.); (W.S.); (R.Ö.); (N.R.); (J.P.); (D.E.); (L.D.); (E.M.D.)
- Berlin Institute of Health at Charité—Universitätsmedizin Berlin, BIH Academy, Clinician Scientist Program, 10117 Berlin, Germany
| | - Johann Pratschke
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité–Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (F.E.); (B.G.); (W.S.); (R.Ö.); (N.R.); (J.P.); (D.E.); (L.D.); (E.M.D.)
| | - Dennis Eurich
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité–Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (F.E.); (B.G.); (W.S.); (R.Ö.); (N.R.); (J.P.); (D.E.); (L.D.); (E.M.D.)
| | - Luca Dittrich
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité–Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (F.E.); (B.G.); (W.S.); (R.Ö.); (N.R.); (J.P.); (D.E.); (L.D.); (E.M.D.)
| | - Eva Maria Dobrindt
- Department of Surgery, Campus Virchow Klinikum and Campus Charité Mitte, Charité–Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; (F.E.); (B.G.); (W.S.); (R.Ö.); (N.R.); (J.P.); (D.E.); (L.D.); (E.M.D.)
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Yao Z, Liang M, Zhu S. Infectious factors in myocarditis: a comprehensive review of common and rare pathogens. Egypt Heart J 2024; 76:64. [PMID: 38789885 PMCID: PMC11126555 DOI: 10.1186/s43044-024-00493-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 05/13/2024] [Indexed: 05/26/2024] Open
Abstract
BACKGROUND Myocarditis is a significant health threat today, with infectious agents being the most common cause. Accurate diagnosis of the etiology of infectious myocarditis is crucial for effective treatment. MAIN BODY Infectious myocarditis can be caused by viruses, prokaryotes, parasites, and fungi. Viral infections are typically the primary cause. However, some rare opportunistic pathogens can also damage heart muscle cells in patients with immunodeficiencies, neoplasms and those who have undergone heart surgery. CONCLUSIONS This article reviews research on common and rare pathogens of infectious myocarditis, emphasizing the complexity of its etiology, with the aim of helping clinicians make an accurate diagnosis of infectious myocarditis.
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Affiliation(s)
- Zongjie Yao
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qindao, China.
| | - Mingjun Liang
- Department of Intensive Care Medicine, Shanghai Six People's Hospital Affilicated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Simin Zhu
- Wuhan Third Hospital-Tongren Hospital of Wuhan University, Wuhan, China
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Ghamar Talepoor A, Doroudchi M. Immunosenescence in atherosclerosis: A role for chronic viral infections. Front Immunol 2022; 13:945016. [PMID: 36059478 PMCID: PMC9428721 DOI: 10.3389/fimmu.2022.945016] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/26/2022] [Indexed: 01/10/2023] Open
Abstract
Immune system is a versatile and dynamic body organ which offers survival and endurance of human beings in their hostile living environment. However, similar to other cells, immune cells are hijacked by senescence. The ageing immune cells lose their beneficial functions but continue to produce inflammatory mediators which draw other immune and non-immune cells to the senescence loop. Immunosenescence has been shown to be associated with different pathological conditions and diseases, among which atherosclerosis has recently come to light. There are common drivers of both immunosenescence and atherosclerosis; e.g. inflammation, reactive oxygen species (ROS), chronic viral infections, genomic damage, oxidized-LDL, hypertension, cigarette smoke, hyperglycaemia, and mitochondrial failure. Chronic viral infections induce inflammaging, sustained cytokine signaling, ROS generation and DNA damage which are associated with atherogenesis. Accumulating evidence shows that several DNA and RNA viruses are stimulators of immunosenescence and atherosclerosis in an interrelated network. DNA viruses such as CMV, EBV and HBV upregulate p16, p21 and p53 senescence-associated molecules; induce inflammaging, metabolic reprogramming of infected cells, replicative senescence and telomere shortening. RNA viruses such as HCV and HIV induce ROS generation, DNA damage, induction of senescence-associated secretory phenotype (SASP), metabolic reprogramming of infected cells, G1 cell cycle arrest, telomere shortening, as well as epigenetic modifications of DNA and histones. The newly emerged SARS-CoV-2 virus is also a potent inducer of cytokine storm and SASP. The spike protein of SARS-CoV-2 promotes senescence phenotype in endothelial cells by augmenting p16, p21, senescence-associated β-galactosidase (SA-β-Gal) and adhesion molecules expression. The impact of SARS-CoV-2 mega-inflammation on atherogenesis, however, remains to be investigated. In this review we focus on the common processes in immunosenescence and atherogenesis caused by chronic viral infections and discuss the current knowledge on this topic.
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Owen A, Patel JM, Parekh D, Bangash MN. Mechanisms of Post-critical Illness Cardiovascular Disease. Front Cardiovasc Med 2022; 9:854421. [PMID: 35911546 PMCID: PMC9334745 DOI: 10.3389/fcvm.2022.854421] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 06/22/2022] [Indexed: 11/13/2022] Open
Abstract
Prolonged critical care stays commonly follow trauma, severe burn injury, sepsis, ARDS, and complications of major surgery. Although patients leave critical care following homeostatic recovery, significant additional diseases affect these patients during and beyond the convalescent phase. New cardiovascular and renal disease is commonly seen and roughly one third of all deaths in the year following discharge from critical care may come from this cluster of diseases. During prolonged critical care stays, the immunometabolic, inflammatory and neurohumoral response to severe illness in conjunction with resuscitative treatments primes the immune system and parenchymal tissues to develop a long-lived pro-inflammatory and immunosenescent state. This state is perpetuated by persistent Toll-like receptor signaling, free radical mediated isolevuglandin protein adduct formation and presentation by antigen presenting cells, abnormal circulating HDL and LDL isoforms, redox and metabolite mediated epigenetic reprogramming of the innate immune arm (trained immunity), and the development of immunosenescence through T-cell exhaustion/anergy through epigenetic modification of the T-cell genome. Under this state, tissue remodeling in the vascular, cardiac, and renal parenchymal beds occurs through the activation of pro-fibrotic cellular signaling pathways, causing vascular dysfunction and atherosclerosis, adverse cardiac remodeling and dysfunction, and proteinuria and accelerated chronic kidney disease.
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Affiliation(s)
- Andrew Owen
- Department of Critical Care, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham, United Kingdom
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Jaimin M. Patel
- Department of Critical Care, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham, United Kingdom
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Dhruv Parekh
- Department of Critical Care, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham, United Kingdom
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Mansoor N. Bangash
- Department of Critical Care, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham, United Kingdom
- Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
- *Correspondence: Mansoor N. Bangash
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Seroprevalence of Cytomegalovirus in Haemodialysis Patients. JOURNAL OF PURE AND APPLIED MICROBIOLOGY 2022. [DOI: 10.22207/jpam.16.2.03] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Cytomegalovirus (CMV) is prevalent worldwide. It belongs to the β-herpesvirinae subfamily of Herpesviridae and comprises a double-stranded linear DNA genome and capsid, surrounded by an envelope. CMV infection is most prominently found in patients with kidney failure caused by various possible reasons such as urinary tract infection or systemic disease and are undergoing dialysis. The present study was conducted during the period of March 2020 to April 2021. It included 96 patients with chronic kidney disease undergoing hemodialysis (44 of patients were women and 52 men) within the age range of 11-70 years. Five-mL of the venous blood sample was drawn from each patient to conduct the rapid antibody test for the presence of CMV-specific antibodies (both IgG, and IgM). This study showed that the seroprevalence of CMV infection among haemodialysis patients was 75%. The seropositivity for CMV-IgG was 72.9% which was significantly higher than that for CMV-IgM (2.1%) for both sexes. The present study further demonstrated that the prevalence of positive CMV-IgG in males was higher than that in females (38.5% and 34.4%, respectively). In addition, the positivity of CMV-IgM was highest in the age group 61–70 years old (2.1%), while the positivity of CMV-IgG was highest in patients age groups 41–50 years (24%). The present study revealed a high seroprevalence of CMV infection among haemodialysis patients in Basrah City. The elevated seroprevalence could be related to many factors, including the endemicity of the virus, public health, patient immunity, environmental factors, and geographical location. CMV infection increases with age, and the infection rate in men was higher than that in women. The seroprevalence rate of CMV-IgG antibodies was higher than that of CMV-IgM antibodies, indicating a previous infection or reactivation of CMV virus among haemodialysis patients, leading to a high risk of CMV infection.
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Wall N, Godlee A, Geh D, Jones C, Faustini S, Harvey R, Penn R, Chanouzas D, Nightingale P, O’Shea M, Richter A, Moss P, Cunningham A, Harper L. Latent Cytomegalovirus Infection and Previous Capsular Polysaccharide Vaccination Predict Poor Vaccine Responses in Older Adults, Independent of Chronic Kidney Disease. Clin Infect Dis 2021; 73:e880-e889. [PMID: 33728434 PMCID: PMC8366832 DOI: 10.1093/cid/ciab078] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Patients with chronic kidney disease (CKD) are more prone to severe infection. Vaccination is a key strategy to reduce this risk. Some studies suggest vaccine efficacy may be reduced in patients with CKD, despite preserved maintenance of long-term responses to some pathogens and vaccines. Here, we investigated immune responses to 2 vaccines in patients with CKD to identify predictors of immunological responsiveness. METHODS Individuals >65 years old, with or without nondialysis CKD (n = 36 and 29, respectively), were vaccinated with a nonadjuvanted seasonal influenza vaccine (T-dependent) and Pneumovax23 (23-valent pneumococcal polysaccharide [PPV23], T-independent). Humoral responses were measured at baseline, day 28, and 6 months. Lymphocyte subset and plasma cell/blast analyses were performed using flow cytometry. Cytomegalovirus (CMV) serotyping was assessed by enzyme-linked immunosorbent assay. RESULTS Only modest responsiveness was observed to both vaccines, independent of CKD status (25% adequate response in controls vs. 12%-18% in the CKD group). Unexpectedly, previous immunization with PPV23 (median 10-year interval) and CMV seropositivity were associated with poor PPV23 responsiveness in both study groups (P < .001 and .003, respectively; multivariable linear regression model). Patients with CKD displayed expanded circulating populations of T helper 2 and regulatory T cells, which were unrelated to vaccine responses. Despite fewer circulating B cells, patients with CKD were able to mount a similar day 7 plasma cell/blast response to controls. CONCLUSION Patients with nondialysis CKD can respond similarly to vaccines as age- and sex-matched healthy individuals. CKD patients display an immune signature that is independent of vaccine responsiveness. Prior PPV23 immunization and CMV infection may influence responsiveness to vaccination. Clinical Trials Registration. NCT02535052.
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Affiliation(s)
- Nadezhda Wall
- Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK
| | - Alexandra Godlee
- Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK
| | - Daniel Geh
- Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK
| | - Charlotte Jones
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK
| | - Sian Faustini
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK
| | - Ruth Harvey
- National Institute for Biological Standards and Control, Potters Bar, UK
| | - Rebecca Penn
- National Institute for Biological Standards and Control, Potters Bar, UK
| | - Dimitrios Chanouzas
- Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK
| | - Peter Nightingale
- Institute Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, Edgbaston, Birmingham, UK
| | - Matthew O’Shea
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK
| | - Alex Richter
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK
| | - Paul Moss
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK
| | - Adam Cunningham
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK
| | - Lorraine Harper
- Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK
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Kirkham F, Pera A, Simanek AM, Bano A, Morrow G, Reus B, Caserta S, Smith HE, Davies KA, Rajkumar C, Kern F. Cytomegalovirus infection is associated with an increase in aortic stiffness in older men which may be mediated in part by CD4 memory T-cells. Theranostics 2021; 11:5728-5741. [PMID: 33897878 PMCID: PMC8058738 DOI: 10.7150/thno.58356] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 03/07/2021] [Indexed: 12/31/2022] Open
Abstract
Human Cytomegalovirus (CMV) infection is associated with atherosclerosis, higher cardiovascular disease (CVD) risk, and an increase in memory T-cells (Tmem). T-cells have also been implicated in CVD, independently of CMV infection. To better understand the CMV-associated CVD risk, we examined the association between CMV (IgG) serostatus and central aortic (carotid-to-femoral) pulse wave velocity (cfPWV), an early, independent predictor of CVD. We also investigated if such an association might be reflected by the distribution of Tmem and/or other T-cell subsets. Methods: Healthy older volunteers (60-93 years) underwent routine clinical and laboratory evaluation, including assessment of cfPWV in eligible participants. Flow-cytometry was used to assess proportions of memory T-cells, CD28null T-cells, and CMV-specific T-cells. The following associations were examined; CMV serostatus/cfPWV, CMV serostatus/proportion of Tmem, proportion of Tmem/cfPWV, CD28null T-cells/cfPWV, and CMV-specific T-cells/cfPWV. Linear regression models were used to adjust for age, sex, socioeconomic status, smoking, waist-to-hip ratio, cholesterol, and blood pressure as required. Results: Statistically significant positive associations were found (P-values for the fully adjusted models are given); CMV serostatus/cfPWV in men (P ≤ 0.01) but not in women, CMV serostatus/proportions of CD4 Tmem in men (P ≤ 0.05) but not in women; proportions of CD4 Tmem/cfPWV among CMV seropositive (CMV+) people (P ≤ 0.05) but not CMV seronegative (CMV-) people. Conclusion: CMV infection increases the CVD risk of older men by increasing cfPWV. This may be mediated in part by increased proportions of CD4 Tmem, higher numbers of which are found in CMV+ older people and more so among men than women. Given the high prevalence of CMV worldwide, our findings point to a significant global health issue. Novel strategies to mitigate the increased CVD risk associated with CMV may be required.
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Affandi JS, Lee S, Chih H, Brook E, Waters S, Howson P, Reid CM, Irish A, Price P. Cytomegalovirus burden improves a predictive model identifying measures of vascular risk in renal transplant recipients and healthy adults. J Med Virol 2020; 92:3650-3657. [PMID: 32017150 DOI: 10.1002/jmv.25697] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 01/31/2020] [Indexed: 12/20/2022]
Abstract
Cytomegalovirus (CMV) has been implicated in vascular pathologies and may warrant inclusion in cardiovascular predictive algorithms. We addressed this in healthy older adults and renal transplant recipients (RTR) as they retain a high burden of CMV. RTR (n = 45) stable more than 2 years after transplantation and 58 age-matched healthy adults were assessed. Plasma inflammatory biomarkers (soluble isoform of the interferon-β receptor [sIFNAR2], soluble tumour necrosis factorreceptor-1 [sTNFR1], soluble cluster of differentiation 14 [sCD14], C reactive protein, P-selectin, intracellular cell adhesion molecule-1, vascular cell adhesion molecule-1), and measures of CMV burden (antibodies, saliva CMV DNA, and interferon γ responses to CMV) were assessed in 2014 and evaluated in 2017 as predictors of vascular health-defined using flow-mediated dilatation (FMD), pulse wave velocity (PWV), and augmentation indices (Aix@ 75). Linear regression models adjusted for age, sex, and body mass index (BMI) were optimized to identify risk factors. In 2017, RTR had inferior vascular health marked by impaired FMD and PWV. Detectable CMV DNA (P = .02) was associated with impaired FMD, whilst CMV glycoprotein B (gB) antibody attenuated this effect (P = .03) (adjusted R2 = .42). In healthy adults, the optimal model for predicting FMD (R2 =.22) incorporated high P-selectin (P = .03) and low ICAM-1 (P = .03) levels with no significant impact of CMV. Elevated sIFNAR2 (P = .04) and gB antibody (P = .06) levels predicted increasing Aix@ 75 (poor vascular health) in healthy adults (R2 = .4), whilst optimal models for RTR (R2 = .37) linked low sIFNAR2 and CMV IE-1 antibody levels with lower Aix@ 75 (better vascular health). CMV IE-1 antibody was also protective in relation to PWV in healthy adults (R2 = .55). Overall, measures of active CMV replication were more predictive of impaired FMD in RTR than standard biomarkers, but increased CMV gB antibodies may be protective.
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Affiliation(s)
| | - Silvia Lee
- School of Biomedical Science and the Curtin Health Innovation Research Institute, Curtin University, Perth, Australia
- Department of Microbiology, Pathwest Laboratory Medicine, Perth, Australia
| | - HuiJun Chih
- School of Public Health, Curtin University, Perth, Australia
| | - Emily Brook
- School of Biomedical Science and the Curtin Health Innovation Research Institute, Curtin University, Perth, Australia
| | - Shelley Waters
- School of Biomedical Science and the Curtin Health Innovation Research Institute, Curtin University, Perth, Australia
| | - Prue Howson
- Renal Unit, Fiona Stanley Hospital, Perth, Australia
| | | | - Ashley Irish
- Renal Unit, Fiona Stanley Hospital, Perth, Australia
| | - Patricia Price
- School of Biomedical Science and the Curtin Health Innovation Research Institute, Curtin University, Perth, Australia
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Karangizi AHK, Chanouzas D, Fenton A, Moss P, Cockwell P, Ferro CJ, Harper L. Response to: Cytomegalovirus seropositivity is independently associated with cardiovascular disease in non-dialysis-dependent chronic kidney disease. QJM 2020; 113:702-703. [PMID: 32531065 DOI: 10.1093/qjmed/hcaa195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- A H K Karangizi
- Department of Renal Medicine, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK
- College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
| | - D Chanouzas
- Department of Renal Medicine, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK
- College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
| | - A Fenton
- Department of Renal Medicine, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK
| | - P Moss
- Department of Renal Medicine, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK
- College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
| | - P Cockwell
- Department of Renal Medicine, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK
| | - C J Ferro
- Department of Renal Medicine, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK
| | - L Harper
- Department of Renal Medicine, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK
- College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
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Moss P. "The ancient and the new": is there an interaction between cytomegalovirus and SARS-CoV-2 infection? IMMUNITY & AGEING 2020; 17:14. [PMID: 32501397 PMCID: PMC7251217 DOI: 10.1186/s12979-020-00185-x] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 05/18/2020] [Indexed: 02/01/2023]
Abstract
The SARS-CoV-2 pandemic represents one of the greatest infectious challenges to humanity in recent history. One of the striking features of infection is the heterogeneous clinical response with worse outcomes observed in older patients and those with underlying health conditions. To date the potential impact of previous infection history has been poorly investigated as a potential determinant of risk. Cytomegalovirus (CMV), a persistent herpesvirus infection whose prevalence increases with age, is a major modulator of immune function and several observations suggest that infection might act to influence clinical outcome following SARS-CoV-2 infection. In particular, CMV is associated with the acceleration of immune senescence and has been linked to a range of cardiovascular and metabolic disorders. This review addresses mechanisms by which cytomegalovirus infection may act to worsen the clinical outcome of SARS-CoV-2 infection, discusses how these potential links could be investigated, and assesses the potential significance of any findings that emerge.
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Affiliation(s)
- Paul Moss
- Institute of Immunology and Immunotherapy, University of Birmingham and Birmingham Health Partners, University Hospitals NHS Foundation Trust, Birmingham, UK
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11
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Bonavita CM, White TM, Francis J, Cardin RD. Heart Dysfunction Following Long-Term Murine Cytomegalovirus Infection: Fibrosis, Hypertrophy, and Tachycardia. Viral Immunol 2020; 33:237-245. [PMID: 32286167 PMCID: PMC7185328 DOI: 10.1089/vim.2020.0007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Human cytomegalovirus (HCMV) is associated with increased risk of chronic diseases of the heart and vasculature, including myocarditis, atherosclerosis, and transplant vasculopathy. To investigate CMV infection of the heart, murine cytomegalovirus (MCMV) was used to evaluate both acute and latent infection and the subsequent phenotypic and functional consequences of infection. Female BALB/c mice were intraperitoneally (i.p.) inoculated with 1 × 106 pfu of MCMV and evaluated at 14 and 50 days postinfection (dpi). At each time point, echocardiography was used to evaluate cardiac function and histology was conducted for phenotypic evaluation. MCMV replication in the heart was detected as early as 3 dpi and was no longer detectable at 14 dpi. Infected animals had significant cardiac pathology at 14 and 50 dpi when compared to uninfected controls. Histology revealed fibrosis of the heart as early as 14 dpi and the presence of white fibrous deposits on the surface of the heart. Functional evaluation showed significantly increased heart rate and muscle thickening in the latently infected animals when compared to the control animals. At 50 dpi, latent virus was measured by explant reactivation assay, demonstrating that MCMV establishes latency and is capable of reactivation from the heart, similar to other tissues such as spleen and salivary glands. Collectively, these studies illustrate that MCMV infection results in phenotypic alterations within the heart as early as 14 dpi, which progress to functional abnormalities during latency. These findings are similar to sinus tachycardia and hypertrophy of the heart muscle observed in cases of HCMV-induced acute myocarditis.
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Affiliation(s)
- Cassandra M. Bonavita
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana
| | - Timothy M. White
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana
| | - Joseph Francis
- Department of Comparative Biological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana
| | - Rhonda D. Cardin
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana
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Karangizi AHK, Chanouzas D, Fenton A, Moss P, Cockwell P, Ferro CJ, Harper L. Cytomegalovirus seropositivity is independently associated with cardiovascular disease in non-dialysis dependent chronic kidney disease. QJM 2020; 113:253-257. [PMID: 31613364 DOI: 10.1093/qjmed/hcz258] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 08/29/2019] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Cardiovascular disease (CVD) is the leading cause of early death in patients with chronic kidney disease (CKD). Previous work has described an association between Cytomegalovirus (CMV) seropositivity and CVD amongst patients with dialysis dependent end stage renal disease. Whether CMV seropositivity is associated with CVD in non-dialysis dependent CKD has not been established. AIM Investigate whether past CMV infection is associated with prevalent CVD in patients with non-dialysis dependent CKD. DESIGN A retrospective observational study using the Renal Impairment in Secondary Care cohort, a study evaluating bio-clinical determinants of outcomes in patients with progressive CKD. METHODS We assayed cryopreserved serum samples collected at inception for anti-CMV IgG antibodies from 764 patients with stages 2 to 5 CKD (pre-dialysis) and investigated its relationship with prevalent CVD. RESULTS Median estimated glomerular filtration was 24 ml/min/1.73 m2 (IQR 19-32). Sixty-eight percent of patients were CMV seropositive. CMV seropositivity was associated with older age, non-Caucasian ethnicity, diabetes and higher social deprivation index score. On univariable analysis, CMV seropositivity correlated with higher systolic blood pressure (P = 0.044), prevalent CVD (P < 0.001), ischaemic heart disease (P < 0.001) and cerebrovascular disease (P = 0.022). On multivariable analysis, CMV seropositive patients nearly twice as likely to have CVD compared to seronegative patients [Odds Ratio (OR) = 1.998, CI 1.231-3.242, P = 0.005]. CONCLUSIONS In patients with non-dialysis CKD, CMV seropositivity is independently associated with a higher prevalence of CVD.
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Affiliation(s)
- A H K Karangizi
- Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
- Renal Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK
| | - D Chanouzas
- Renal Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
| | - A Fenton
- Renal Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK
| | - P Moss
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
| | - P Cockwell
- Renal Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK
| | - C J Ferro
- Renal Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK
| | - L Harper
- Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
- Renal Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, B15 2TH, UK
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13
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Pickup L, Radhakrishnan A, Townend JN, Ferro CJ. Arterial stiffness in chronic kidney disease. Curr Opin Nephrol Hypertens 2019; 28:527-536. [DOI: 10.1097/mnh.0000000000000535] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Moss P. 'From immunosenescence to immune modulation': a re-appraisal of the role of cytomegalovirus as major regulator of human immune function. Med Microbiol Immunol 2019; 208:271-280. [PMID: 31053999 DOI: 10.1007/s00430-019-00612-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 04/09/2019] [Indexed: 12/29/2022]
Abstract
In the year 2000, cytomegalovirus was identified as a risk factor for mortality in a seminal study of octogenarian residents in Sweden. This finding triggered a wave of additional epidemiological investigations, some of which supported this association whilst others observed no such effect. In addition, this increased risk of death in CMV-seropositive people was correlated with observed changes within the T-cell repertoire such that accelerated 'immunosenescence' became a de facto explanation, without strong evidence to this effect. Recent years have seen a re-appraisal of these findings. Interestingly, many studies show that cytomegalovirus acts to improve immune function, most clearly in younger donors. In addition, the excess mortality in older people that is observed in CMV-seropositive cohorts appears to be related primarily to an excess of vascular disease rather than impairment of immune function. CMV is an important member of the natural 'virome' of Homo sapiens and has an important, and generally positive, modulatory influence on human immune function throughout most of life. However, within certain populations, this influence can become negative and age, co-morbidity and environment all act as determinants of this effect. As such, it is important that new interventions are developed that can mitigate the damaging influence of CMV on human health in populations at risk.
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Affiliation(s)
- Paul Moss
- Haematology, University of Birmingham and Birmingham Health Partners, Birmingham, B15 2TA, UK.
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15
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Hoh BP, Abdul Rahman T, Yusoff K. Natural selection and local adaptation of blood pressure regulation and their perspectives on precision medicine in hypertension. Hereditas 2019; 156:1. [PMID: 30636949 PMCID: PMC6323824 DOI: 10.1186/s41065-019-0080-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2018] [Accepted: 01/01/2019] [Indexed: 01/09/2023] Open
Abstract
Prevalence of hypertension (HTN) varies substantially across different populations. HTN is not only common - affecting at least one third of the world's adult population - but is also the most important driver for cardiovascular diseases. Yet up to a third of hypertensive patients are resistant to therapy, contributed by secondary hypertension but more commonly the hitherto inability to precisely predict response to specific antihypertensive agents. Population and individual genomics information could be useful in guiding the selection and predicting the response to treatment - an approach known as precision medicine. However this cannot be achieved without the knowledge of genetic variations that influence blood pressure (BP). A number of evolutionary factors including population demographics and forces of natural selection may be involved. This article explores some ideas on how natural selection influences BP regulation in ethnically and geographically diverse populations that could lead to them being susceptible to HTN. We explore how such evolutionary factors could impact the implementation of precision medicine in HTN. Finally, in order to ensure the success of precision medicine in HTN, we call for more initiatives to understand the genetic architecture within and between diverse populations with ancestry from different parts of the world, and to precisely classify the intermediate phenotypes of HTN.
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Affiliation(s)
- Boon-Peng Hoh
- 1Faculty of Medicine and Health Sciences, UCSI University, Cheras, 56000 Kuala Lumpur, Malaysia.,2Chinese Academy of Sciences Key Laboratory of Computational Biology, Max Planck Independent Research Group on Population Genomics, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, CAS, Shanghai, 200031 China
| | - Thuhairah Abdul Rahman
- 3Clinical Pathology Diagnostic Centre Research Laboratory, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, 47000 Sungai Buloh, Selangor Malaysia
| | - Khalid Yusoff
- 1Faculty of Medicine and Health Sciences, UCSI University, Cheras, 56000 Kuala Lumpur, Malaysia
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16
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Chanouzas D, Sagmeister M, Faustini S, Nightingale P, Richter A, Ferro CJ, Morgan MD, Moss P, Harper L. Subclinical Reactivation of Cytomegalovirus Drives CD4+CD28null T-Cell Expansion and Impaired Immune Response to Pneumococcal Vaccination in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. J Infect Dis 2019; 219:234-244. [PMID: 30102389 PMCID: PMC6306020 DOI: 10.1093/infdis/jiy493] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 08/08/2018] [Indexed: 11/12/2022] Open
Abstract
Background Infection is the leading cause of death in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Expansion of CD4+CD28null T cells is associated with increased risk of infection and mortality, but is only present in cytomegalovirus (CMV)-seropositive individuals. We hypothesized that subclinical CMV reactivation drives CD4+CD28null T-cell expansion, that this is associated with impaired immune response to heterologous antigens, and that antiviral therapy may ameliorate this. Methods In a proof-of-concept open-label clinical trial, 38 CMV-seropositive AAV patients were randomized to receive valacyclovir for 6 months or no intervention. CMV reactivation was measured monthly in plasma and urine. CD4+CD28null T cells were enumerated at baseline and at 6 months. At 6 months, 36 patients were vaccinated with a 13-valent pneumococcal vaccine. Serotype-specific immunoglobulin G was assayed before and 4 weeks postvaccination to calculate the antibody response ratio. Results Valacyclovir treatment suppressed subclinical CMV reactivation and reduced CD4+CD28null T-cell proportion. CD4+CD28null T-cell reduction correlated with improved vaccine response, whereas CMV reactivation associated with reduced response to vaccination. Furthermore, expansion of CD4+CD28null T cells was associated with a reduction in the functional capacity of the CD4 compartment. Conclusions Suppression of CMV may improve the immune response to a T-cell-dependent pneumococcal vaccination in patients with AAV, thus offering potential clinical benefit. Clinical Trials Registration NCT01633476.
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Affiliation(s)
- Dimitrios Chanouzas
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, United Kingdom
- Department of Nephrology, University Hospitals Birmingham National Health Service Foundation Trust, United Kingdom
| | - Michael Sagmeister
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, United Kingdom
- Department of Nephrology, University Hospitals Birmingham National Health Service Foundation Trust, United Kingdom
| | - Sian Faustini
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, United Kingdom
| | | | - Alex Richter
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, United Kingdom
| | - Charles J Ferro
- Department of Nephrology, University Hospitals Birmingham National Health Service Foundation Trust, United Kingdom
- Institute of Translational Medicine Birmingham, United Kingdom
| | - Matthew David Morgan
- Department of Nephrology, University Hospitals Birmingham National Health Service Foundation Trust, United Kingdom
- Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, United Kingdom
| | - Paul Moss
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, United Kingdom
| | - Lorraine Harper
- Department of Nephrology, University Hospitals Birmingham National Health Service Foundation Trust, United Kingdom
- Institute of Translational Medicine Birmingham, United Kingdom
- Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, United Kingdom
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17
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Chanouzas D, Sagmeister M, Dyall L, Sharp P, Powley L, Johal S, Bowen J, Nightingale P, Ferro CJ, Morgan MD, Moss P, Harper L. The host cellular immune response to cytomegalovirus targets the endothelium and is associated with increased arterial stiffness in ANCA-associated vasculitis. Arthritis Res Ther 2018; 20:194. [PMID: 30157919 PMCID: PMC6116544 DOI: 10.1186/s13075-018-1695-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 08/01/2018] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND Cardiovascular disease is a leading cause of death in ANCA-associated vasculitis (AAV). An expansion of CD4+CD28null T cells is seen mainly in cytomegalovirus (CMV)-seropositive individuals and has been linked to increased cardiovascular disease risk in other conditions. The aims of this study were to phenotype CD4+CD28null T cells in AAV with respect to their pro-inflammatory capacity and ability to target and damage the endothelium and to investigate their relationship to arterial stiffness, a marker of cardiovascular mortality. METHODS CD4+CD28null T cells were phenotyped in 53 CMV-seropositive AAV patients in stable remission and 30 age-matched CMV-seropositive healthy volunteers by flow cytometry following stimulation with CMV lysate. The expression of endothelial homing markers and cytotoxic molecules was evaluated in unstimulated CD4+CD28null T cells. Arterial stiffness was measured by carotid-to-femoral pulse wave velocity (PWV) in patients with AAV. RESULTS CD4+CD28null T cells were CMV-specific and expressed a T helper 1 (Th1) phenotype with high levels of interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α) secretion. They also co-expressed the endothelial homing markers CX3CR1, CD49d and CD11b and cytotoxic molecules perforin and granzyme B. CD4+CD28null T cells were phenotypically similar in patients with AAV and healthy volunteers but their proportion was almost twice as high in patients with AAV (11.3% [3.7-19.7] versus 6.7 [2.4-8.8]; P = 0.022). The size of the CD4+CD28null T-cell subset was independently linked to increased PWV in AAV (0.66 m/s increase per 10% increase in CD4+CD28null cells, 95% confidence interval 0.13-1.19; P = 0.016). CONCLUSION The host cellular immune response to CMV leads to the expansion of cytotoxic CD4+CD28null T cells that express endothelial homing markers and are independently linked to increased arterial stiffness, a marker of cardiovascular mortality. Suppression of CMV in AAV may be of therapeutic value in reducing the risk of cardiovascular disease.
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Affiliation(s)
- Dimitrios Chanouzas
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT UK
- Renal Unit, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham, B15 2TH UK
| | - Michael Sagmeister
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT UK
- Renal Unit, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham, B15 2TH UK
| | - Lovesh Dyall
- Renal Unit, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham, B15 2TH UK
| | - Phoebe Sharp
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT UK
- Renal Unit, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham, B15 2TH UK
| | - Lucy Powley
- Renal Unit, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham, B15 2TH UK
| | - Serena Johal
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT UK
- Renal Unit, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham, B15 2TH UK
| | - Jessica Bowen
- Renal Unit, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham, B15 2TH UK
| | - Peter Nightingale
- Institute of Translational Medicine Birmingham, Heritage Building, Mindelsohn Way, Edgbaston, Birmingham, B15 2TH UK
| | - Charles J. Ferro
- Renal Unit, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham, B15 2TH UK
- Institute of Translational Medicine Birmingham, Heritage Building, Mindelsohn Way, Edgbaston, Birmingham, B15 2TH UK
| | - Matthew D. Morgan
- Renal Unit, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham, B15 2TH UK
- Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT UK
| | - Paul Moss
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT UK
| | - Lorraine Harper
- Renal Unit, University Hospitals Birmingham NHS Foundation Trust, Mindelsohn Way, Edgbaston, Birmingham, B15 2TH UK
- Institute of Translational Medicine Birmingham, Heritage Building, Mindelsohn Way, Edgbaston, Birmingham, B15 2TH UK
- Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT UK
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18
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Humoral immunity to memory antigens and pathogens is maintained in patients with chronic kidney disease. PLoS One 2018; 13:e0195730. [PMID: 29659606 PMCID: PMC5901993 DOI: 10.1371/journal.pone.0195730] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 03/28/2018] [Indexed: 01/29/2023] Open
Abstract
Patients with chronic kidney disease (CKD) have an increased risk of infection and poorer responses to vaccination. This suggests that CKD patients have an impaired responsiveness to all antigens, even those first encountered before CKD onset. To examine this we evaluated antibody responses against two childhood vaccine antigens, tetanus (TT) and diphtheria toxoids (DT) and two common pathogens, cytomegalovirus (CMV) and Salmonella enterica serovar Enteritidis (SEn) in two independent cohorts consisting of age-matched individuals with and without CKD. Sera were evaluated for antigen-specific IgG titres and the functionality of antibody to SEn was assessed in a serum bactericidal assay. Surprisingly, patients with CKD and control subjects had comparable levels of IgG against TT and DT, suggesting preserved humoral memory responses to antigens encountered early in life. Lipopolysaccharide-specific IgG titres and serum bactericidal activity in patients with CKD were also not inferior to controls. CMV-specific IgG titres in seropositive CKD patients were similar or even increased compared to controls. Therefore, whilst responses to new vaccines in CKD are typically lower than expected, antibody responses to antigens commonly encountered prior to CKD onset are not. The immunodeficiency of CKD is likely characterised by failure to respond to new antigenic challenges and efforts to improve patient outcomes should be focussed here.
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Georgianos PI, Pikilidou MI, Liakopoulos V, Balaskas EV, Zebekakis PE. Arterial stiffness in end-stage renal disease-pathogenesis, clinical epidemiology, and therapeutic potentials. Hypertens Res 2018. [PMID: 29531291 DOI: 10.1038/s41440-018-0025-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Arterial stiffness is an important risk factor for cardiovascular morbidity and mortality in patients with end-stage renal disease (ESRD). Arterial stiffness aggravates cardiovascular risk via multiple pathways, such as augmentation of aortic systolic pressure, subendocardial hypoperfusion, and excess pulsatile energy transmission from macro- to microcirculation. Pathogenesis of the arteriosclerotic process in ESRD is complex and not yet fully understood. Several factors unique to ESRD, such as mineral metabolism disturbances, vascular calcifications, formation of advanced glycation end-products, and acute and chronic volume overload, are proposed to play a particular role in the progression of arteriosclerosis in ESRD. As these and other mechanistic pathways of arterial stiffening in ESRD are elucidated, there is hope that this knowledge will be translated into novel therapeutic interventions targeting arterial stiffness. In the meantime, blood pressure (BP) lowering via strict volume control and appropriate use of antihypertensive drugs is a fundamental step in reversing accelerated arterial stiffening and modifying the cardiovascular risk profile of ESRD patients. In this article, we review the pathogenesis, clinical epidemiology, and therapies targeting arterial stiffness in ESRD, discussing recent advances and high-priority goals of future research in these important areas.
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Affiliation(s)
- Panagiotis I Georgianos
- Section of Nephrology and Hypertension, 1st Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
| | - Maria I Pikilidou
- Section of Nephrology and Hypertension, 1st Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Vassilios Liakopoulos
- Section of Nephrology and Hypertension, 1st Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Elias V Balaskas
- Section of Nephrology and Hypertension, 1st Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Pantelis E Zebekakis
- Section of Nephrology and Hypertension, 1st Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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20
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Stockdale L, Nash S, Nalwoga A, Painter H, Asiki G, Fletcher H, Newton R. Human cytomegalovirus epidemiology and relationship to tuberculosis and cardiovascular disease risk factors in a rural Ugandan cohort. PLoS One 2018; 13:e0192086. [PMID: 29408860 PMCID: PMC5800673 DOI: 10.1371/journal.pone.0192086] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 01/16/2018] [Indexed: 12/11/2022] Open
Abstract
Human cytomegalovirus (HCMV) infection has been associated with increased mortality, specifically cardiovascular disease (CVD), in high-income countries (HICs). There is a paucity of data in low- and middle-income countries (LMICs) where HCMV seropositivity is higher. Serum samples from 2,174 Ugandan individuals were investigated for HCMV antibodies and data linked to demographic information, co-infections and a variety of CVD measurements. HCMV seropositivity was 83% by one year of age, increasing to 95% by five years. Female sex, HIV positivity and active pulmonary tuberculosis (TB) were associated with an increase in HCMV IgG levels in adjusted analyses. There was no evidence of any associations with risk factors for CVD after adjusting for age and sex. HCMV infection is ubiquitous in this rural Ugandan cohort from a young age. The association between TB disease and high HCMV IgG levels merits further research. Known CVD risk factors do not appear to be associated with higher HCMV antibody levels in this Ugandan cohort.
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Affiliation(s)
- Lisa Stockdale
- London School of Hygiene and Tropical Medicine, Faculty of Infectious and Tropical Diseases, London, United Kingdom
| | - Stephen Nash
- London School of Hygiene and Tropical Medicine, Faculty of Epidemiology and Population Health, London, United Kingdom
| | - Angela Nalwoga
- London School of Hygiene and Tropical Medicine, Faculty of Infectious and Tropical Diseases, London, United Kingdom
- Medical Research Council/Uganda Virus Research Institute, Entebbe, Uganda
| | - Hannah Painter
- London School of Hygiene and Tropical Medicine, Faculty of Infectious and Tropical Diseases, London, United Kingdom
| | - Gershim Asiki
- Medical Research Council/Uganda Virus Research Institute, Entebbe, Uganda
| | - Helen Fletcher
- London School of Hygiene and Tropical Medicine, Faculty of Infectious and Tropical Diseases, London, United Kingdom
| | - Robert Newton
- Medical Research Council/Uganda Virus Research Institute, Entebbe, Uganda
- University of York, Department of Health Sciences, York, United Kingdom
- International Agency for Research on Cancer, Lyon, France
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21
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Abana CO, Pilkinton MA, Gaudieri S, Chopra A, McDonnell WJ, Wanjalla C, Barnett L, Gangula R, Hager C, Jung DK, Engelhardt BG, Jagasia MH, Klenerman P, Phillips EJ, Koelle DM, Kalams SA, Mallal SA. Cytomegalovirus (CMV) Epitope-Specific CD4 + T Cells Are Inflated in HIV + CMV + Subjects. THE JOURNAL OF IMMUNOLOGY 2017; 199:3187-3201. [PMID: 28972094 DOI: 10.4049/jimmunol.1700851] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 08/28/2017] [Indexed: 01/24/2023]
Abstract
Select CMV epitopes drive life-long CD8+ T cell memory inflation, but the extent of CD4 memory inflation is poorly studied. CD4+ T cells specific for human CMV (HCMV) are elevated in HIV+ HCMV+ subjects. To determine whether HCMV epitope-specific CD4+ T cell memory inflation occurs during HIV infection, we used HLA-DR7 (DRB1*07:01) tetramers loaded with the glycoprotein B DYSNTHSTRYV (DYS) epitope to characterize circulating CD4+ T cells in coinfected HLA-DR7+ long-term nonprogressor HIV subjects with undetectable HCMV plasma viremia. DYS-specific CD4+ T cells were inflated among these HIV+ subjects compared with those from an HIV- HCMV+ HLA-DR7+ cohort or with HLA-DR7-restricted CD4+ T cells from the HIV-coinfected cohort that were specific for epitopes of HCMV phosphoprotein-65, tetanus toxoid precursor, EBV nuclear Ag 2, or HIV gag protein. Inflated DYS-specific CD4+ T cells consisted of effector memory or effector memory-RA+ subsets with restricted TCRβ usage and nearly monoclonal CDR3 containing novel conserved amino acids. Expression of this near-monoclonal TCR in a Jurkat cell-transfection system validated fine DYS specificity. Inflated cells were polyfunctional, not senescent, and displayed high ex vivo levels of granzyme B, CX3CR1, CD38, or HLA-DR but less often coexpressed CD38+ and HLA-DR+ The inflation mechanism did not involve apoptosis suppression, increased proliferation, or HIV gag cross-reactivity. Instead, the findings suggest that intermittent or chronic expression of epitopes, such as DYS, drive inflation of activated CD4+ T cells that home to endothelial cells and have the potential to mediate cytotoxicity and vascular disease.
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Affiliation(s)
- Chike O Abana
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - Mark A Pilkinton
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Silvana Gaudieri
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.,School of Human Sciences, University of Western Australia, Perth, Western Australia 6009, Australia.,Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia 6150, Australia
| | - Abha Chopra
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia 6150, Australia
| | - Wyatt J McDonnell
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - Celestine Wanjalla
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Louise Barnett
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Rama Gangula
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Cindy Hager
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Dae K Jung
- Stem Cell Transplantation, Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Brian G Engelhardt
- Stem Cell Transplantation, Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Madan H Jagasia
- Stem Cell Transplantation, Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Paul Klenerman
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, United Kingdom; and
| | - Elizabeth J Phillips
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232.,Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.,Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia 6150, Australia
| | - David M Koelle
- Department of Medicine, Laboratory Medicine, and Global Health, University of Washington, Seattle, WA 98195
| | - Spyros A Kalams
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232.,Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232
| | - Simon A Mallal
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232; .,Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.,Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia 6150, Australia
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22
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Yu HT, Youn JC, Kim JH, Seong YJ, Park SH, Kim HC, Lee WW, Park S, Shin EC. Arterial Stiffness Is Associated With Cytomegalovirus-Specific Senescent CD8 + T Cells. J Am Heart Assoc 2017; 6:JAHA.117.006535. [PMID: 28847915 PMCID: PMC5634298 DOI: 10.1161/jaha.117.006535] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Background Arterial stiffness is a well‐known predictor of future cardiovascular events. Search for the underlying mechanism of arterial stiffening is still under way. We investigated the relationship between arterial stiffness and cytomegalovirus infection in terms of T‐cell senescence. Methods and Results Arterial stiffness was evaluated using pulse wave velocity measurements in 415 Koreans (age 59±12 years). We also investigated the frequency of CD57+ or CD28null senescent T cells in peripheral blood lymphocytes and analyzed which immune parameters were correlated with pulse wave velocity. Furthermore, cytomegalovirus‐specific T cells were stimulated with overlapping peptides covering pp65 protein, and T‐cell function was evaluated by intracellular cytokine staining of interferon‐γ, tumor necrosis factor‐α, and CD107a. In a multivariate analysis, it was found that the frequency of CD57+ cells in the CD8+ T‐cell subset was independently correlated with pulse wave velocity after adjusting for traditional cardiovascular risk factors such as age, sex, diabetes mellitus history, smoking history, body mass index, blood pressure, serum creatinine, high‐density lipoprotein cholesterol, and high‐sensitivity C‐reactive protein. Cytomegalovirus pp65‐specific T cells were more frequently observed in the CD8+CD57+ population than in the CD8+CD57− population, and multivariate analysis revealed that the frequency of cytomegalovirus pp65‐specific interferon‐γ+, tumor necrosis factor‐α+, or CD107a+ cells in the CD8+ T‐cell subset was independently correlated with pulse wave velocity as well. Conclusions We demonstrate that arterial stiffness is associated with senescent CD57+ T cells and CMV pp65‐specific T cells in the CD8+ T‐cell subset. The precise role of cytomegalovirus‐specific, senescent T cells in vascular aging needs to be further investigated.
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Affiliation(s)
- Hee Tae Yu
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.,Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jong-Chan Youn
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.,Division of Cardiology, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong, Korea
| | - Jong Hoon Kim
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea
| | - Yeon-Jae Seong
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea
| | - Su-Hyung Park
- Laboratory of Translational Immunology and Vaccinology, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea
| | - Hyeon Chang Kim
- Department of Preventive Medicine, Cardiovascular and Metabolic Diseases Etiology Research Center, Yonsei University College of Medicine, Seoul, Korea
| | - Won-Woo Lee
- Department of Microbiology and Immunology and Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
| | - Sungha Park
- Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Eui-Cheol Shin
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea
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Li Z, Tang Y, Tang N, Feng Q, Zhong H, Liu YM, Wang LM, He F. High anti-human cytomegalovirus antibody levels are associated with the progression of essential hypertension and target organ damage in Han Chinese population. PLoS One 2017; 12:e0181440. [PMID: 28837559 PMCID: PMC5570371 DOI: 10.1371/journal.pone.0181440] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Accepted: 07/02/2017] [Indexed: 02/06/2023] Open
Abstract
Human cytomegalovirus (CMV) infection is associated with hypertension and has been linked with the pathogenesis of increased arterial blood pressure (BP). Currently, whether CMV infection is associated with the progression of hypertension and hypertensive target organ damage (TOD) remains to be identified. We aimed to examine the relationship between CMV infection and the progression of hypertension and hypertensive TOD, which could provide clues on the possible mediating mechanisms, in the Han Chinese population. A total of 372 patients with hypertension and 191 healthy controls (Han participants from Xinjiang, China) were included in the study. Enzyme-linked immunosorbent assay (ELISA) and qPCR were used to detect CMV infection. C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) titers were also analyzed using an ELISA kit. Moreover, cardiovascular disease markers were evaluated by echocardiography, carotid ultrasonography, and tomographic scans. Essential hypertension (EH) patients exhibited a marked increase in CMV IgG antibody, CRP, TNF-α, and IL-6 levels. Higher grade of hypertension and hypertensive TOD had higher CMV IgG antibody and CRP levels. The CMV IgG antibody titers were positively correlated with arterial BP, greater grade of hypertension and hypertensive TOD, and CRP and IL-6 levels. The higher quartile of CMV IgG titer and CRP level were associated with the incidence of hypertension and the progression of hypertension and hypertensive TOD. In the Han Chinese population, high CMV IgG titers are associated with the progression of hypertension and hypertensive TOD. CMV IgG titer >4.25 U could be an independent predictor of hypertension and progression of hypertension, while that >4.85 U could be an independent risk factor for hypertensive TOD. The underlying mechanism may be largely mediated by chronic inflammation.
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Affiliation(s)
- Zhen Li
- Department of Pathophysiology/Key Laboratory of Education Ministry of Xinjiang Endemic and Ethnic Diseases, Medical College of Shihezi University, Shihezi, China
- Department of Emergency and critical care medicine, the First Affiliated Hospital of Medical College of Shihezi University, Shihezi, China
| | - Yan Tang
- Department of Geriatrics, the First Affiliated Hospital of Medical College of Shihezi University, Shihezi, China
| | - Na Tang
- Department of Pathophysiology/Key Laboratory of Education Ministry of Xinjiang Endemic and Ethnic Diseases, Medical College of Shihezi University, Shihezi, China
| | - Qian Feng
- Department of Pathophysiology/Key Laboratory of Education Ministry of Xinjiang Endemic and Ethnic Diseases, Medical College of Shihezi University, Shihezi, China
| | - Hua Zhong
- Department of Pathophysiology/Key Laboratory of Education Ministry of Xinjiang Endemic and Ethnic Diseases, Medical College of Shihezi University, Shihezi, China
| | - Yong-min Liu
- Department of Pathophysiology/Key Laboratory of Education Ministry of Xinjiang Endemic and Ethnic Diseases, Medical College of Shihezi University, Shihezi, China
| | - La-mei Wang
- Centre of Medical Functional Experiments, Medical College of Shihezi University, Shihezi, China
| | - Fang He
- Department of Pathophysiology/Key Laboratory of Education Ministry of Xinjiang Endemic and Ethnic Diseases, Medical College of Shihezi University, Shihezi, China
- * E-mail:
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Firth C, Harrison R, Ritchie S, Wardlaw J, Ferro C, Starr J, Deary I, Moss P. Cytomegalovirus infection is associated with an increase in systolic blood pressure in older individuals. QJM 2016; 109:595-600. [PMID: 27071749 PMCID: PMC5027953 DOI: 10.1093/qjmed/hcw026] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Cytomegalovirus (CMV) is a chronic infection that is widely distributed in the population. CMV infects a range of tissues, including endothelium, and viral replication is suppressed by the host immune system. Infection is associated with increased risk of mortality from vascular disease in older people, but the mechanisms behind this have not been determined. AIM We investigated the association between CMV infection and cardiovascular phenotype in a cohort of healthy elderly donors. DESIGN CMV serostatus and cardiovascular parameters were determined in the Lothian Birth cohort, which comprises 1091 individuals aged 70 years in whom many environmental, biochemical and radiological correlates of vascular function have been determined. METHODS CMV serostatus was determined by enzyme-linked immunosorbant assay and correlated with a range of biochemical and phenotypic measures. RESULTS Sixty-five percent of participants were CMV seropositive, which indicates chronic infection. The mean sitting systolic blood pressure (SBP) was 149.2 mmHg in CMV seropositive individuals compared with 146.2 mmHg in CMV seronegative subjects (SD 18.7 vs. 19.7; P < 0.017). This association between CMV infection and SBP was not attenuated after adjustment for a wide range of biological and socio-economic factors. CONCLUSIONS These data show that CMV infection is associated with an increase in SBP in individuals at age 70 years. The magnitude is comparable to environmental variables such as obesity, diabetes or high salt intake. This is the first evidence to show that a chronic infection may be an important determinant of blood pressure and could have significant implications for the future management of hypertension.
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Affiliation(s)
- C. Firth
- From the Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, B15 2TT UK
| | - R. Harrison
- Geriatric Medicine Unit, University of Edinburgh, Edinburgh, EH16, 4SB UK
| | - S. Ritchie
- Geriatric Medicine Unit, University of Edinburgh, Edinburgh, EH16, 4SB UK
| | - J. Wardlaw
- Centre for Clinical Brain Sciences, Edinburgh, UK
| | - C.J. Ferro
- University Hospitals NHS Foundation Trust, Edgbaston, Birmingham, B15 2WB UK
| | - J.M. Starr
- Geriatric Medicine Unit, University of Edinburgh, Edinburgh, EH16, 4SB UK
- Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK
- Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, EH8 9JZ, UK
| | - I.J. Deary
- Department of Psychology, University of Edinburgh, Edinburgh, EH8 9JZ, UK
- Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, EH8 9JZ, UK
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK
| | - P. Moss
- From the Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, B15 2TT UK
- University Hospitals NHS Foundation Trust, Edgbaston, Birmingham, B15 2WB UK
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25
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Wu CF, Liu PY, Wu TJ, Hung Y, Yang SP, Lin GM. Therapeutic modification of arterial stiffness: An update and comprehensive review. World J Cardiol 2015; 7:742-753. [PMID: 26635922 PMCID: PMC4660469 DOI: 10.4330/wjc.v7.i11.742] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 09/09/2015] [Accepted: 09/25/2015] [Indexed: 02/06/2023] Open
Abstract
Arterial stiffness has been recognized as a marker of cardiovascular disease and associated with long-term worse clinical outcomes in several populations. Age, hypertension, smoking, and dyslipidemia, known as traditional vascular risk factors, as well as diabetes, obesity, and systemic inflammation lead to both atherosclerosis and arterial stiffness. Targeting multiple modifiable risk factors has become the main therapeutic strategy to improve arterial stiffness in patients at high cardiovascular risk. Additionally to life style modifications, long-term ω-3 fatty acids (fish oil) supplementation in diet may improve arterial stiffness in the population with hypertension or metabolic syndrome. Pharmacological treatment such as renin-angiotensin-aldosterone system antagonists, metformin, and 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors were useful in individuals with hypertension and diabetes. In obese population with obstructive sleep apnea, weight reduction, aerobic exercise, and continuous positive airway pressure treatment may also improve arterial stiffness. In the populations with chronic inflammatory disease such as rheumatoid arthritis, a use of antibodies against tumor necrosis factor-alpha could work effectively. Other therapeutic options such as renal sympathetic nerve denervation for patients with resistant hypertension are investigated in many ongoing clinical trials. Therefore our comprehensive review provides knowledge in detail regarding many aspects of pathogenesis, measurement, and management of arterial stiffness in several populations, which would be helpful for physicians to make clinical decision.
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Affiliation(s)
- Ching-Fen Wu
- Ching-Fen Wu, Department of Internal Medicine, Mennonite Christian Hospital, Hualien 97144, Taiwan
| | - Pang-Yen Liu
- Ching-Fen Wu, Department of Internal Medicine, Mennonite Christian Hospital, Hualien 97144, Taiwan
| | - Tsung-Jui Wu
- Ching-Fen Wu, Department of Internal Medicine, Mennonite Christian Hospital, Hualien 97144, Taiwan
| | - Yuan Hung
- Ching-Fen Wu, Department of Internal Medicine, Mennonite Christian Hospital, Hualien 97144, Taiwan
| | - Shih-Ping Yang
- Ching-Fen Wu, Department of Internal Medicine, Mennonite Christian Hospital, Hualien 97144, Taiwan
| | - Gen-Min Lin
- Ching-Fen Wu, Department of Internal Medicine, Mennonite Christian Hospital, Hualien 97144, Taiwan
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26
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Kim J, Kim AR, Shin EC. Cytomegalovirus Infection and Memory T Cell Inflation. Immune Netw 2015; 15:186-90. [PMID: 26330804 PMCID: PMC4553256 DOI: 10.4110/in.2015.15.4.186] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 08/08/2015] [Accepted: 08/10/2015] [Indexed: 12/24/2022] Open
Abstract
Cytomegalovirus (CMV) infection in healthy individuals is usually asymptomatic and results in latent infection. CMV reactivation occasionally occurs in healthy individuals according to their immune status over time. T cell responses to CMV are restricted to a limited number of immunodominant epitopes, as compared to responses to other chronic or persistent viruses. This response results in progressive, prolonged expansion of CMV-specific CD8+ T cells, termed 'memory inflation'. The expanded CMV-specific CD8+ T cell population is extraordinarily large and is more prominent in the elderly. CMV-specific CD8+ T cells possess rather similar phenotypic and functional features to those of replicative senescent T cells. In this review, we discuss the general features of CMV-specific inflationary memory T cells and the factors involved in memory inflation.
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Affiliation(s)
- Jihye Kim
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Korea
| | - A-Reum Kim
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Korea
| | - Eui-Cheol Shin
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Korea
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27
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Abstract
Age-related changes in the immune system, commonly termed "immunosenescence," contribute to deterioration of the immune response and fundamentally impact the health and survival of elderly individuals. Immunosenescence affects both the innate and adaptive immune systems; however, the most notable changes are in T cell immunity and include thymic involution, the collapse of T cell receptor (TCR) diversity, an imbalance in T cell populations, and the clonal expansion of senescent T cells. Senescent T cells have the ability to produce large quantities of proinflammatory cytokines and cytotoxic mediators; thus, they have been implicated in the pathogenesis of many chronic inflammatory diseases. Recently, an increasing body of evidence has suggested that senescent T cells also have pathogenic potential in cardiovascular diseases, such as hypertension, atherosclerosis, and myocardial infarction, underscoring the detrimental roles of these cells in various chronic inflammatory responses. Given that cardiovascular disease is the number one cause of death worldwide, there is great interest in understanding the contribution of age-related immunological changes to its pathogenesis. In this review, we discuss general features of age-related alterations in T cell immunity and the possible roles of senescent T cells in the pathogenesis of cardiovascular disease.
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28
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Abstract
PURPOSE OF REVIEW Epidemiological studies have established arterial stiffness as an important risk factor for cardiovascular events and mortality in people with chronic kidney disease (CKD) at all stages. Although much has been learned about the mechanisms that lead to arterial stiffening in CKD, many questions remain unanswered and the optimal interventions for attenuating arterial stiffness remain to be determined. RECENT FINDINGS Recent data have confirmed the value of arterial stiffness as a predictor of both cardiovascular and renal risk. Advanced glycation end-product accumulation and chronic cytomegalovirus infection have been identified as novel potential contributors to arterial stiffening, but fibroblast growth factor 23 has not. Genetic studies suggest that the association between chronic kidney and cardiovascular disease is a result of clinical and environmental rather than genetic factors. Treatment with angiotensin-converting enzyme inhibitor or aldosterone inhibitor improves arterial stiffness in association with lowering blood pressure, but several potential novel interventions for reducing arterial stiffness await further investigation. SUMMARY Arterial stiffness is increasingly recognized as an important potentially modifiable measure of subclinical vascular disease in people with CKD. The introduction of arterial stiffness into routine practice awaits research focussed on including pulse wave velocity in renal and cardiovascular risk prediction tools, as well as interventions for ameliorating arterial stiffness.
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29
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Terrazzini N, Bajwa M, Thomas D, Smith H, Kern F. WITHDRAWN: Gender differences and age-specific associations between Body Mass Index and other cardiovascular risk factors in CMV infected and uninfected people. Immunol Lett 2014:S0165-2478(14)00199-0. [PMID: 25251661 DOI: 10.1016/j.imlet.2014.09.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Accepted: 09/12/2014] [Indexed: 10/24/2022]
Abstract
The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.imlet.2014.09.010. The duplicate article has therefore been withdrawn.
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Affiliation(s)
- Nadia Terrazzini
- Division of Medicine, Brighton and Sussex Medical School, Brighton, United Kingdom; School of Health, Sport and Bioscience, University of East London, London, United Kingdom;(7)Division of Primary Care and Public Health, Brighton and Sussex Medical School, Brighton, United Kingdom.
| | - Martha Bajwa
- Division of Medicine, Brighton and Sussex Medical School, Brighton, United Kingdom
| | - David Thomas
- Division of Medicine, Brighton and Sussex Medical School, Brighton, United Kingdom
| | - Helen Smith
- School of Health, Sport and Bioscience, University of East London, London, United Kingdom;(7)Division of Primary Care and Public Health, Brighton and Sussex Medical School, Brighton, United Kingdom
| | - Florian Kern
- Division of Medicine, Brighton and Sussex Medical School, Brighton, United Kingdom
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30
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Terrazzini N, Bajwa M, Thomas D, Smith H, Kern F. Gender differences and age-specific associations between body mass index and other cardiovascular risk factors in CMV infected and uninfected people. Immunol Lett 2014; 162:316-22. [PMID: 25251663 DOI: 10.1016/j.imlet.2014.09.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2014] [Accepted: 09/12/2014] [Indexed: 01/21/2023]
Abstract
Body mass index (BMI) is a known risk factor for cardiovascular disease and cancer. It is also related to white blood count (WBC) and inflammation. The effects of age and gender on these associations have not been explored. Here we have examined the relationships between BMI and inflammatory parameters/cardiovascular risk factors including WBC/neutrophil count (NC), CRP and mean arterial blood pressure (MAP), in young (20-35 years) and older (60-85 years) healthy donors with respect to gender and CMV IgG serology. In young but not older people significant associations between BMI and WBC were observed, however, with opposite directions in the two genders. Only in CMV+ older women a positive trend was preserved. Across the population, there was no significant association between NC and MAP; however, among older men we saw a positive correlation between the two parameters. Linear regression confirmed that across the whole population, age group (young versus older) and also the interaction between gender and age group but not gender alone had significant effects on this association. When analysing CMV+ older people separately we established that both NC and its interaction with gender had a significant effect on MAP. This study reveals that the correlations between common inflammatory markers/cardiovascular risk factors depend on age, gender, and CMV status in a complex fashion. Our findings support the need to evaluate risk factors independently in men and women and to take into account CMV infection status. More focused studies will be required to shed light on these novel findings.
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Affiliation(s)
- Nadia Terrazzini
- Division of Medicine, Brighton and Sussex Medical School, Brighton, United Kingdom; School of Pharmacy and Biomolecular Sciences, Brighton, United Kingdom.
| | - Martha Bajwa
- Division of Medicine, Brighton and Sussex Medical School, Brighton, United Kingdom
| | - David Thomas
- Division of Medicine, Brighton and Sussex Medical School, Brighton, United Kingdom
| | - Helen Smith
- School of Pharmacy and Biomolecular Sciences, Brighton, United Kingdom
| | - Florian Kern
- Division of Primary Care and Public Health, Brighton and Sussex Medical School, Brighton, United Kingdom
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31
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Sansoni P, Vescovini R, Fagnoni FF, Akbar A, Arens R, Chiu YL, Cičin-Šain L, Dechanet-Merville J, Derhovanessian E, Ferrando-Martinez S, Franceschi C, Frasca D, Fulöp T, Furman D, Gkrania-Klotsas E, Goodrum F, Grubeck-Loebenstein B, Hurme M, Kern F, Lilleri D, López-Botet M, Maier AB, Marandu T, Marchant A, Matheï C, Moss P, Muntasell A, Remmerswaal EBM, Riddell NE, Rothe K, Sauce D, Shin EC, Simanek AM, Smithey MJ, Söderberg-Nauclér C, Solana R, Thomas PG, van Lier R, Pawelec G, Nikolich-Zugich J. New advances in CMV and immunosenescence. Exp Gerontol 2014; 55:54-62. [PMID: 24703889 DOI: 10.1016/j.exger.2014.03.020] [Citation(s) in RCA: 90] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Revised: 03/21/2014] [Accepted: 03/24/2014] [Indexed: 12/16/2022]
Abstract
Immunosenescence, defined as the age-associated dysregulation and dysfunction of the immune system, is characterized by impaired protective immunity and decreased efficacy of vaccines. An increasing number of immunological, clinical and epidemiological studies suggest that persistent Cytomegalovirus (CMV) infection is associated with accelerated aging of the immune system and with several age-related diseases. However, current evidence on whether and how human CMV (HCMV) infection is implicated in immunosenescence and in age-related diseases remains incomplete and many aspects of CMV involvement in immune aging remain controversial. The attendees of the 4th International Workshop on "CMV & Immunosenescence", held in Parma, Italy, 25-27th March, 2013, presented and discussed data related to these open questions, which are reported in this commentary.
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Affiliation(s)
- Paolo Sansoni
- Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
| | - Rosanna Vescovini
- Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy
| | | | - Arne Akbar
- Division of Infection and Immunity, University College London, London, United Kingdom
| | - Ramon Arens
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands
| | - Yen-Ling Chiu
- Institute of Cell Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Luka Cičin-Šain
- Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Julie Dechanet-Merville
- Composantes Innées de la Response Immunitaire et Différenciation, University of Bordeaux, Bordeaux, France
| | - Evelyna Derhovanessian
- Department of Internal Medicine II, Center for Medical Research University of Tübingen, Tübingen, Germany
| | - Sara Ferrando-Martinez
- Laboratorio de InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón and Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain
| | - Claudio Franceschi
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Daniela Frasca
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Tamas Fulöp
- Division of Geriatrics and Research Center on Aging, Department of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - David Furman
- Composantes Innées de la Response Immunitaire et Différenciation, University of Bordeaux, Bordeaux, France; Department of Microbiology & Immunology, School of Medicine, Stanford University, CA, USA
| | | | - Felicia Goodrum
- Department of Immunobiology and the Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ, USA
| | | | - Mikko Hurme
- Department of Microbiology and Immunology, University of Tampere, Tampere, Finland
| | - Florian Kern
- Division of Medicine, Pathogen Host Interaction (PHI), Brighton and Sussex Medical School, Brighton, United Kingdom
| | - Daniele Lilleri
- Laboratori Sperimentali di Ricerca, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Miguel López-Botet
- Immunology Unity, University Pompeu Fabra and Hospital del Mar Medical Research Institute, Barcelona, Spain
| | - Andrea B Maier
- Section of Gerontology and Geriatrics, Department of Internal Medicine, VU University Medical Center, Amsterdam, Netherlands
| | - Thomas Marandu
- Department of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Arnaud Marchant
- Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium
| | - Catharina Matheï
- KU Leuven, Department of Public Health and Primary Care, Leuven, Belgium
| | - Paul Moss
- School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Aura Muntasell
- Immunology Unity, University Pompeu Fabra and Hospital del Mar Medical Research Institute, Barcelona, Spain
| | - Ester B M Remmerswaal
- Department of Experimental Immunology and Renal Transplant Unit, Department of Internal Medicine, Amsterdam, Netherlands
| | - Natalie E Riddell
- Division of Infection and Immunity, University College London, London, United Kingdom
| | - Kathrin Rothe
- Section of Rheumatology, University of Leipzig, Leipzig, Germany
| | - Delphine Sauce
- INSERM, Infections and Immunity, Université Pierre et Marie Curie, Hôpital Pitié-Salpêtrière, Paris, France
| | - Eui-Cheol Shin
- Laboratory of Immunology and Infectious Diseases (LIID), Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea
| | - Amanda M Simanek
- Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA
| | - Megan J Smithey
- Department of Immunobiology and the Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ, USA
| | - Cecilia Söderberg-Nauclér
- Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Rafael Solana
- Immunology Unit, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain
| | - Paul G Thomas
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Rene van Lier
- Division of Research, Sanquin Blood Supply Foundation, Amsterdam, Netherlands
| | - Graham Pawelec
- Department of Internal Medicine II, Center for Medical Research University of Tübingen, Tübingen, Germany
| | - Janko Nikolich-Zugich
- Department of Immunobiology and the Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ, USA.
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32
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Yu HT, Shin EC. T cell immunosenescence, hypertension, and arterial stiffness. Epidemiol Health 2014; 36:e2014005. [PMID: 24904754 PMCID: PMC4040631 DOI: 10.4178/epih/e2014005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Accepted: 05/12/2014] [Indexed: 11/09/2022] Open
Affiliation(s)
- Hee Tae Yu
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea
| | - Eui-Cheol Shin
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea
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Stowe RP, Ruiz RJ, Fagundes CP, Stowe RH, Chen M, Glaser R. An ELISA method to compute endpoint titers to Epstein-Barr virus and cytomegalovirus: application to population-based studies. J Immunol Methods 2014; 408:64-9. [PMID: 24859346 DOI: 10.1016/j.jim.2014.05.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 05/07/2014] [Accepted: 05/13/2014] [Indexed: 12/28/2022]
Abstract
Indirect fluorescence analysis (IFA), the gold standard for determining herpesvirus antibody titers, is labor-intensive and poorly suited for large population-based studies. The enzyme-linked immunosorbent assay (ELISA) is used widely for measuring antiviral antibodies but also suffers drawbacks such as reduced specificity and the qualitative nature of the results due to limited interpretation of the optical density (OD) units. This paper describes a method to titer herpesvirus antibodies using microplates coated with virally-infected cells in which a standard curve, derived from IFA-scored samples, allowed OD units to be converted into titers. A LOOKUP function was created in order to report the data as traditional IFA-based (i.e., 2-fold) titers. The modified ELISA correlated significantly with IFA and was subsequently used to compute endpoint antibody titers to Epstein-Barr virus (EBV)-virus capsid antigen (VCA) and cytomegalovirus (CMV) in blood samples taken from 398 pregnant Hispanic women. Four women were EBV negative (1%), while 58 women were CMV negative (14.6%). EBV VCA antibody titers were significantly higher than CMV antibody titers (p<0.001). This method allows titering of herpesvirus antibodies by ELISA suitable for large population-based studies. In addition, the LOOKUP table enables conversion from OD-derived titers into 2-fold titers for comparison of results with other studies.
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Affiliation(s)
| | - R Jeanne Ruiz
- Gayle Greve Hunt College of Nursing, Texas Tech University Health Sciences Center, El Paso, TX, United States
| | - Christopher P Fagundes
- Department of Health Disparities Research, The University of Texas MD Anderson Cancer Center, United States
| | | | - Min Chen
- Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, United States; Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, United States
| | - Ronald Glaser
- Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH, United States; Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, United States
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Vitlic A, Phillips AC, Gallagher S, Oliver C, Lord JM, Moss P. Anticytomegalovirus antibody titres are not associated with caregiving burden in younger caregivers. Br J Health Psychol 2014; 20:68-84. [DOI: 10.1111/bjhp.12092] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Revised: 12/02/2013] [Indexed: 12/31/2022]
Affiliation(s)
- Ana Vitlic
- School of Sport and Exercise Sciences; University of Birmingham; UK
- MRC-Arthritis Research UK Centre for Musculoskeletal Ageing Research; University of Birmingham; UK
| | - Anna C. Phillips
- School of Sport and Exercise Sciences; University of Birmingham; UK
- MRC-Arthritis Research UK Centre for Musculoskeletal Ageing Research; University of Birmingham; UK
| | | | - Chris Oliver
- School of Psychology; University of Birmingham; UK
| | - Janet M. Lord
- MRC-Arthritis Research UK Centre for Musculoskeletal Ageing Research; University of Birmingham; UK
- School of Immunity and Infection; University of Birmingham; UK
| | - Paul Moss
- School of Cancer Sciences; University of Birmingham; UK
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