PD-1 Regulates Neural Damage in Oligodendroglia-Induced Inflammation

We investigated the impact of immune regulatory mechanisms involved in the modulation of the recently presented, CD8+ lymphocyte mediated immune response in a mouse model of oligodendropathy-induced inflammation (PLPtg-mutants). The focus was on the role of the co-inhibitory molecule PD-1, a CD28-related receptor expressed on activated T- and B-lymphocytes associated with immune homeostasis and autoimmunity. PLPtg/PD-1-deficient double mutants and the corresponding bone marrow chimeras were generated and analysed using immunohistochemistry, light- and electron microscopy, with particular emphasis on immune-cell number and neural damage. In addition, the immune cells in both the CNS and the peripheral immune system were investigated by IFN-gamma elispot assays and spectratype analysis. We found that mice with combined pathology exhibited significantly increased numbers of CD4+ and CD8+ T-lymphocytes in the CNS. Lack of PD-1 substantially aggravated the pathological phenotype of the PLPtg mutants compared to genuine PLPtg mutants, whereas the PD-1 deletion alone did not cause alterations in the CNS. CNS T-lymphocytes in PLPtg/PD-1-/- double mutants exhibited massive clonal expansions. Furthermore, PD-1 deficiency was associated with a significantly higher propensity of CNS but not peripheral CD8+ T-cells to secrete proinflammatory cytokines. PD-1 could be identified as a crucial player of tissue homeostasis and immune-mediated damage in a model of oligodendropathy-induced inflammation. Alterations of this regulatory pathway lead to overt neuroinflammation of high pathogenetic impact. Our finding may have implications for understanding the mechanisms leading to the high clinical variability of polygenic or even monogenic disorders of the nervous system

Physical Activity in Multiple Sclerosis: A Comparative Study of Vitamin D, Brain-Derived Neurotrophic Factor and Regulatory T Cell Populations

Background: Previous studies suggest beneficial effects of exercise in multiple sclerosis (MS). However, knowledge on the effects of physical activity on the immune system is limited. Objective: To assess potential relationships between cardiorespiratory fitness, cognitive function, and immune parameters in physically active and inactive MS patients. Methods: We identified 83 patients with relapsing-remitting disease, an unrestricted walking range, and stable interferon- � treatment from our data base. Based on the subjective report of physical activity, the lower/inactive (n = 21) and upper/ active quartiles (n = 21) of patients were selected. We assessed the frequency of T cells, B cells, NK cells, monocytes and regulatory T cell populations by flow cytometry, measured brain-derived neurotrophic factor and vitamin D serum levels by ELISA, and conducted spiroergometry and transcranial sonography. Results: Physical activity and cardiorespiratory fitness were not associated with brain-derived neurotrophic factor, frequency of T regulatory cells or any other immune cell subpopulation. However, we found a positive correlation of vitamin D serum levels with cardiorespiratory fitness. Conclusion: Overall, we found no negative effect of physical activity on the immune system. The association between vitamin D and cardiorespiratory fitness most likely reflects longer hours of sunlight exposure in active patients, suggesting a desirable ‘side- effect’ of physical activity

Hypermetabolism in the hippocampal formation of cognitively impaired patients indicates detrimental maladaptation

Structural deterioration and volume loss of the hippocampal formation is observed in many diseases associated with memory decline. Paradoxically, glucose metabolism of the hippocampal formation can be increased at the same time. This might be a consequence of compensatory (beneficial) or maladaptive (detrimental) mechanisms. Aim of this study was to differentiate between compensation and maladaptation by analyzing the association between glucose metabolism in the hippocampal formation measured by positron emission tomography with the glucose analogue 18F-fluorodeoxyglucose and cognitive performance as characterized by the extended Consortium to Establish a Registry for Alzheimer's Disease test battery in a sample of 87 patients (81.8 ± 5.4 years) with mild cognitive impairment or mild dementia and varying etiological diagnoses. Glucose metabolism in the hippocampal formation was negatively correlated with the performance in several cognitive subdomains, most pronounced for verbal semantic fluency, independent of overall neuronal dysfunction, presence of clinical Alzheimer's disease, and overall cognitive performance. This finding provides evidence that increased glucose metabolism in the hippocampal formation of cognitively impaired patients indicates detrimental maladaptation rather than a beneficial compensatory reaction. Excess glucose metabolism in the hippocampal formation might be a useful therapeutic target in these patients