Discrimination between CMV infection and Alzheimer's disease as driving forces for immune senescence

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URI: http://hdl.handle.net/10900/54817
Dokumentart: PhDThesis
Date: 2014-07
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biologie
Advisor: Pawelec, Graham (Prof. Dr.)
Day of Oral Examination: 2014-05-19
DDC Classifikation: 500 - Natural sciences and mathematics
570 - Life sciences; biology
610 - Medicine and health
Keywords: Durchflusscytometrie , Immunologie , Cytomegalie-Virus , Alzheimer-Krankheit
Other Keywords: Alzheimer Krankheit
Alzheimer's Disease
License: http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=de http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=en
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This study investigated the immune profiles of patients with dementia. The focus of this study was on leukocyte populations found in the blood. Initial experiments assessed the frequency of major leukocyte subsets in AD patients and healthy controls, but no differences were observed - the frequencies of B-cells, NK-cells and NKT-like cells were similar for all groups. The monocyte marker CD14 tended to be less frequently expressed in control subjects compared to AD patients, but the results differed across the cohorts that were studied. In the second phase of this study, the phenotype of different leukocyte populations was analysed. B-cells showed a tendency towards a lowered frequency of CD27-IgD+ naïve cells in AD patients compared to healthy controls. This trend was even more pronounced for T-cells, notably in the case of CD4+ T-cells. The frequencies of Naïve CD4+ T-cells were lower in AD patients than in controls in pilot studies as well as larger cohorts. Parallel to this, the percentages of late-differentiated CD4+ T-cells were found elevated in AD patients. In addition, the frequency of CD57- and KLRG-positive cells tended to be greater in patients than controls, but these differences were only statistically significant in some cohorts. Another observation, indicative of immune exhaustion, was an increased level of PD-1 in T-cells of AD patients compared with controls, although this was also not statistically significant. The question remains, which is the factor causing these immune changes in AD. One possible explanation is that Aβ is causing chronic antigenic stress and driving T-cell differentiation. Further studies investigated chemokine receptor expression. In AD, a compromised and potentially leaky blood-brain barrier results in an exchange between the periphery and the brain that does usually not occur. A consequence is that cytokines, Aβ protein and cells may migrate through the BBB contributing to systemic inflammation. One aspect of AD pathology is the potential recruitment of immune cells to the brain. To elucidate the mechanisms behind these processes, the frequency of peripheral leukocytes expressing CCR2, CCR4, CCR5 and CCR6 was determined. The results indicated that leukocytes from AD patients more frequently expressed these proteins, although the differences were not always statistically significant in all cohorts. In the case of CCR6, it was observed that this receptor was not only more often expressed on a single leukocyte subset, but expressed more frequently on B-cells, monocytes, CD4+ and CD8+ T-cells as well. In conclusion, this work provides evidence that hints toward a more differentiated and exhausted immune system in AD patients. What still remains unclear is whether the recruitment of immune cells to the brain is a consequence or cause of the disease. Experiments using in vitro models where the entry of immune cells to the brain can be blocked may provide insight into this lingering question. These experiments may also assist in determining if the migration of immune cells results in beneficial effects, for example by phagocytosing Aβ protein, or if they function to promote disease progression assuming that in vitro models accurately parallel human disease. A way of investigating this could be to enhance the chemokine gradient in vivo, as the immune cells examined in this study demonstrated increased CCR expression. In the event that immune cells are found to promote AD, it may be possible to treat patients with CCR-blockers in order to reduce immune cell migration to the brain. Using this approach, it may be possible to selectively block B-cell migration as they were observed to express CCR6, but not CCR4 or CCR5. After determining which leukocyte subset contributes to the promotion of disease, it may be possible to employ antibodies specific to CCRs that are predominately expressed on this subset. It is hypothesised that a rejuvenation of the immune system may be beneficial for AD patients. This might be achieved through improving Aβ clearance, possibly by enhancing monocyte migration from the periphery to the brain. Reduced Aβ load may result in reduced T-cell differentiation, i.e. fewer memory T-cells and more naïve T-cells. It is thought that in AD patients as in healthy elderly CMV is the driving force of CD8+ T-cell differentiation and Aβ may have a similar effect. Whether the effects of CMV and Aβ are additive remains to be determined. A larger cohort of study participants - as recruited here - including sufficient CMV- and CMV+ AD patients and controls would be necessary to investigate this. This question may be of particular importance given that CMV may contribute to inflammation in AD and thus provide another burden to the functioning of the immune system thereby decreasing the ability of the body to control the disease. The role that CMV may play in the functional decline of the immune system may also be related to cognitive decline, such as that in AD.

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