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      Analysis of cytomegalovirus-specific T-cell responses in patients with hypertension: comparison of assay methods and antigens

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          Abstract

          Background

          Recent studies suggest an association between cytomegalovirus (CMV) infection and hypertension. In the present study, we used a variety of antigens and different assay methods to investigate the relationship between CMV-specific T-cell responses and arterial stiffness in patients with hypertension.

          Methods

          To evaluate arterial stiffness, pulse wave velocity (PWV) was measured in 207 hypertensive patients (average age, 63 ± 8 years). To measure CMV pp65 and IE-1-specific T-cell responses, we performed intracellular cytokine staining (ICS) and enzyme-linked immunospot (ELISPOT) assays. We also analyzed CMV-specific T-cell responses against 10 different CMV antigens using ELISPOT assays.

          Results

          In patients with hypertension, senescent CD8 + T-cell frequencies were significantly correlated with arterial stiffness. Moreover, arterial stiffness was independently associated with CMV pp65-specific CD8 + T-cell responses as measured by ICS. CMV-specific CD8 + T-cell responses measured by ICS and ELISPOT assays showed good agreement and significant correlation with each other. ELISPOT analyses against 10 different CMV antigens revealed a consistent response pattern irrespective of age, gender, and diabetes

          Conclusions

          CMV pp65-specific CD8 + T-cell responses were independently correlated with arterial stiffness in patients with hypertension. Additionally, the results of ICS and ELISPOT assays showed a significant correlation and good agreement with each other. These findings are important for guiding choices regarding the broad clinical application of CMV-specific T-cell response assays in this patient population.

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          Most cited references 17

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          Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections

          Key Points A decline in T-cell immunity is one of the most consistent and most profound deficiencies of the elderly. Therapeutic correction of this decline often restores immune responsiveness and immune defence. T-cell immune decline in the elderly has at least two underpinnings: a drop in the responsiveness of naive T cells to stimulation (cell-autonomous defects) and a reduction in naive T-cell numbers and diversity that leads to a dominant memory T-cell pool (T-cell population imbalance). This article discusses two key causes of age-related T-cell population imbalance: homeostatic cycling or proliferative expansion in the peripheral T-cell pool, and latent persistent infections, which repeatedly stimulate the T-cell pool over the lifetime of the individual. The reduction in production of naive T cells by the thymus forces the ageing organism to rely on compensatory homeostatic mechanisms to maintain the balance between naive and memory T-cell pools. Although this may be initially successful, recent evidence suggests that late in life these mechanisms exhaust their usefulness and actually contribute to a further demise of the remaining naive T cells. Latent persistent infections, particularly with herpesviruses, lead to life-long periodic restimulation of the immune system, here, evidence is presented for the role of viral reactivation in this restimulation using a mouse model of herpesvirus infection and ageing. Relative roles and the interplay between the homeostatic and viral factors are discussed, with the former having a surprisingly prominent role. Finally, modes of immune rejuvenation and anti-ageing intervention are debated in light of these advances in our knowledge.
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            Human T Cell Aging and the Impact of Persistent Viral Infections

            Aging is associated with a dysregulation of the immune response, loosely termed “immunosenescence.” Each part of the immune system is influenced to some extent by the aging process. However, adaptive immunity seems more extensively affected and among all participating cells it is the T cells that are most altered. There is a large body of experimental work devoted to the investigation of age-associated differences in T cell phenotypes and functions in young and old individuals, but few longitudinal studies in humans actually delineating changes at the level of the individual. In most studies, the number and proportion of late-differentiated T cells, especially CD8+ T cells, is reported to be higher in the elderly than in the young. Limited longitudinal studies suggest that accumulation of these cells is a dynamic process and does indeed represent an age-associated change. Accumulations of such late-stage cells may contribute to the enhanced systemic pro-inflammatory milieu commonly seen in older people. We do not know exactly what causes these observed changes, but an understanding of the possible causes is now beginning to emerge. A favored hypothesis is that these events are at least partly due to the effects of the maintenance of essential immune surveillance against persistent viral infections, notably Cytomegalovirus (CMV), which may exhaust the immune system over time. It is still a matter of debate as to whether these changes are compensatory and beneficial or pathological and detrimental to the proper functioning of the immune system and whether they impact longevity. Here, we will review present knowledge of T cell changes with aging and their relation to chronic viral and possibly other persistent infections.
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              Cytomegalovirus and human immunosenescence.

              'Immunosenescence' is an imprecise term used to describe deleterious age-associated changes to immune parameters observed in all mammals studied so far. Primarily anecdotal evidence implies that failing immunity is responsible for the increased incidence and severity of infectious disease in old people. However, there is a serious dearth of accurate hard data concerning the actual cause of death in the elderly and the contribution thereto of the multitude of age-associated alterations measured in the immune system. Cross-sectional studies comparing those currently young with those currently old reveal a large number of differences in the distribution of immune cell types in the blood, and to some extent the functional integrity of those cells. Many of these parameters differ markedly between individuals infected with CMV and uninfected people, regardless of infection with other persistent herpesviruses. The adaptive arm of immunity appears to be more seriously affected than the innate arm, particularly the T lymphocytes. However, cross-sectional studies suffer the disadvantage that like is not being compared with like, because the conditions applied during the entire life course of the currently elderly were different from those applied now to the young. These differences in environment, nutrition, pathology and possibly genetics, rather than merely age, may be expected to influence the parameters studied. Moreover, pathogen exposure of the currently elderly was also different from contemporary exposure, probably including CMV. Some of the problems associated with cross-sectional studies can be overcome by performing longitudinal studies, as pointed out in an earlier analysis of the Baltimore Longitudinal Ageing study looking at lymphocyte numbers. However, longitudinal studies are challenging in humans. Nonetheless, the pioneering Swedish OCTO/NONA studies of the very elderly which for the first time included a range of immune parameters, have identified a set of immune parameters predicting mortality at 2, 4 and 6 year follow-up; CMV infection makes a material contribution to this so-called 'immune risk profile (IRP)'. Whether the IRP is informative in younger individuals and the mechanism of the CMV effect is discussed in this review.
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                Author and article information

                Contributors
                +82-31-8086-2530 , jong.chan.youn@gmail.com
                jy1064076@gmail.com
                jungmk@kaist.ac.kr
                HEETYU@yuhs.ac
                park3@kaist.ac.kr
                kimic@dsmc.or.kr
                galiard@hallym.or.kr
                swchoi97@hallym.or.kr
                hansw29@hanmail.net
                khryu@hallym.or.kr
                SHPARK0530@yuhs.ac
                +82-42-350-4236 , ecshin@kaist.ac.kr
                Journal
                Clin Hypertens
                Clin Hypertens
                Clinical Hypertension
                BioMed Central (London )
                2056-5909
                20 March 2018
                20 March 2018
                2018
                : 24
                Affiliations
                [1 ]ISNI 0000 0004 0470 5964, GRID grid.256753.0, Division of Cardiology, , Dongtan Sacred Heart Hospital, Hallym University College of Medicine, ; Keunjaebong-gil 7, Hwaseong-si, Gyeonggi-do 18450 Republic of Korea
                [2 ]ISNI 0000 0001 2292 0500, GRID grid.37172.30, Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, ; 291 Daehak-ro, Yuseong-gu, Daejeon, 34141 Republic of Korea
                [3 ]ISNI 0000 0004 0470 5454, GRID grid.15444.30, Division of Cardiology, , Severance Cardiovascular Hospital, Yonsei University College of Medicine, ; Seoul, Republic of Korea
                [4 ]ISNI 0000 0001 2292 0500, GRID grid.37172.30, Laboratory of Translational Immunology and Vaccinology, Graduate School of Medical Science and Engineering, KAIST, ; Daejeon, Republic of Korea
                [5 ]ISNI 0000 0004 0647 8419, GRID grid.414067.0, Division of Cardiology, , Keimyung University Dongsan Medical Center, ; Daegu, Republic of Korea
                Article
                90
                10.1186/s40885-018-0090-8
                5861653
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: The Korean Society of Hypertension
                Award ID: Hypertension Seoul 2016 Grant
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003725, National Research Foundation of Korea;
                Award ID: NRF-2015R1C1A1A02036645
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100007551, Hallym University Medical Center;
                Award ID: HURF-2017-73
                Award Recipient :
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                © The Author(s) 2018

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