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Natural killer (NK) cell deficit in coronary artery disease: no aberrations in phenotype but sustained reduction of NK cells is associated with low-grade inflammation
Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
2014 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 175, no 1, 104-112 p.Article in journal (Refereed) Published
Abstract [en]

Although reduced natural killer (NK) cell levels have been reported consistently in patients with coronary artery disease (CAD), the clinical significance and persistence of this immune perturbation is not clarified. In this study we characterized the NK cell deficit further by determining (i) differentiation surface markers and cytokine profile of NK cell subsets and (ii) ability to reconstitute NK cell levels over time. Flow cytometry was used to analyse NK cell subsets and the intracellular cytokine profile in 31 patients with non-ST elevation myocardial infarction (non-STEMI), 34 patients with stable angina (SA) and 37 healthy controls. In blood collected prior to coronary angiography, the proportions of NK cells were reduced significantly in non-STEMI and SA patients compared with controls, whereas NK cell subset analyses or cytokine profile measurements did not reveal any differences across groups. During a 12-month follow-up, the proportions of NK cells increased, although not in all patients. Failure to reconstitute NK cell levels was associated with several components of metabolic syndrome. Moreover, interleukin (IL)-6 levels remained high in patients with sustained NK cell deficit, whereas a decline in IL-6 (P < 0·001) was seen in patients with a pronounced increase in NK cells. In conclusion, we found no evidence that reduction of NK cells in CAD patients was associated with aberrations in NK cell phenotype at any clinical stage of the disease. Conversely, failure to reconstitute NK cell levels was associated with a persistent low-grade inflammation, suggesting a protective role of NK cells in CAD.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2014. Vol. 175, no 1, 104-112 p.
Keyword [en]
coronary artery disease; cytokines; inflammation; leukocytes; natural killer cell
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-103363DOI: 10.1111/cei.12210ISI: 000329165400012PubMedID: 24298947OAI: oai:DiVA.org:liu-103363DiVA: diva2:688842
Available from: 2014-01-17 Created: 2014-01-17 Last updated: 2017-12-06Bibliographically approved
In thesis
1. T Cells and NK Cells in Coronary Artery Disease: Longitudinal and methodological studies in humans
Open this publication in new window or tab >>T Cells and NK Cells in Coronary Artery Disease: Longitudinal and methodological studies in humans
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Coronary artery disease (CAD) is the leading cause of death worldwide and most often due to atherosclerosis. Atherosclerosis is a chronic inflammatory process that involves the arteries, inclouding those that supply blood to the heart muscle. Although inflammation is an important contributing factor to atherosclerosis, the mechanisms are not fully understood. One mechanism contributing to atherogenesis may involve some infectious microorganisms such as cytomegalovirus (CMV). In atherosclerosis, the arterial wall becomes infiltrated with lipids followed by different types of leukocytes and inflammatory mediators (atherogenesis). Leukocytes recirculate continuously between the blood and lymphoid organs, such as lymph nodes, where the adaptive immune response is started and regulated.

The general aim of this thesis was to increase the understanding of associations between lymphocyte populations and different conditions of CAD (unstable and stable). To assess changes over time, a longitudinal follow up design was mostly used. Therefore, also perspectives of longitudinal variation were included in the thesis.

Paper I showed that flow cytometric evaluation of lymphocyte populations is a robust technique that can be used in longitudinal studies, both in clinical and research settings. It was also shown that the time of sampling over the year did not have a major impact on the findings.

In paper II, thoracic lymph nodes were investigated to assess whether CAD-associated changes were more prominent in comparison with blood. As expected, there were several major differences in lymphocyte composition between lymph nodes and blood. However, the analysis of thoracic lymph nodes did not reveal any further changes that were not detected in blood. Thus, blood is still the most reliable compartment for studies of lymphocyte populations in CAD since it is not possible to examine the local findings in the artery wall.

Natural killer (NK) cells are innate lymphocytes with both regulatory and effector functions. In paper II and III we confirmed previous findings that CAD patients have lower proportions of NK cells in blood. However, the NK subtype and cytokine profile (paper III, measured by subtype markers and intra-cellular cytokine staining) did not differ between patients and controls. During a 12-month follow-up, the proportions of NK cells increased, although not in all patients. Failure to reconstitute NK cell levels was associated with several components of the metabolic syndrome and with a persistent low-grade inflammation as measured by plasma IL-6 levels. The findings support the notion of a protective role for NK cells in inflammation.

CD4+ but not CD8+ T cells were significantly increased in patients with both unstable and stable conditions compared with healthy individuals (paper IV). Subpopulations of CD4+ T cells (CD4+CD28null) have previously been associated with CAD. However, we show that CD28null and CD28null57+ cells within the CD4+ and CD8+ T cell populations were similar in CAD patients and healthy controls. Instead, CMV seropositivity was the major determinant of expanded CD28null and CD57+ T cell fractions in both patients and healthy individuals. During the 1 year follow up the proportion of CD4+CD28null and CD8+CD28null cells increased in patients, which may reflect an accelerated immunological ageing occurring after the cardiac event.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. 85 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1409
National Category
Immunology Cell Biology
Identifiers
urn:nbn:se:liu:diva-111050 (URN)10.3384/diss.diva-111050 (DOI)978-91-7519-303-8 (ISBN)
Public defence
2014-11-07, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2014-10-06 Created: 2014-10-06 Last updated: 2014-10-06Bibliographically approved

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Backteman, KarinErnerudh, JanJonasson, Lena

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Division of Inflammation MedicineFaculty of Health SciencesDepartment of Clinical Immunology and Transfusion MedicineDivision of Cardiovascular MedicineDepartment of Cardiology in Linköping
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