Increased inflammatory response in cytomegalovirus seropositive patients with Alzheimer's disease.

Alzheimer's disease (AD) has been associated with increased local inflammation in the affected brain regions, and in some studies also with elevated levels of proinflammatory cytokines in peripheral blood. Cytomegalovirus (CMV) is known to promote a more effector-oriented phenotype in the T-cell compartment, increasing with age. The aim of this study was to investigate the inflammatory response of peripheral blood mononuclear cells (PBMCs) from AD patients and non-demented (ND) controls. Using a multiplex Luminex xMAP assay targeting GM-CSF, IFN-γ, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IP-10 and TNF-α, cytokine profiles from PBMCs were analysed after stimulation with anti-CD3/CD28 beads, CMV pp65 peptide mix or amyloid ß (Aß) protofibrils, respectively. CMV seropositive AD subjects presented with higher IFN-γ levels after anti-CD3/CD28 and CMV pp65 but not after Aß stimulation, compared to CMV seropositive ND controls. When analysing IFN-γ response to anti-CD3/CD28 stimulation on a subgroup level, CMV seropositive AD subjects presented with higher levels compared to both CMV seronegative AD and CMV seropositive ND subjects. Taken together, our data from patients with clinically manifest AD suggest a possible role of CMV as an inflammatory promoter in AD immunology. Further studies of AD patients at earlier stages of disease, could provide better insight into the pathophysiology.

Decreased proportion of cytomegalovirus specific CD8 T-cells but no signs of general immunosenescence in Alzheimer's disease.

Cytomegalovirus (CMV) has been suggested as a contributing force behind the impaired immune responsiveness in the elderly, with decreased numbers of naïve T-cells and an increased proportion of effector T-cells. Immunological impairment is also implicated as a part of the pathogenesis in Alzheimer's disease (AD). The aim of this study was to investigate whether AD patients present with a different CMV-specific CD8 immune profile compared to non-demented controls. Blood samples from 50 AD patients and 50 age-matched controls were analysed for HLA-type, CMV serostatus and systemic inflammatory biomarkers. Using multi-colour flow cytometry, lymphocytes from peripheral blood mononuclear cells were analysed for CMV-specific CD8 immunity with MHC-I tetramers A01, A02, A24, B07, B08 and B35 and further classified using CD27, CD28, CD45RA and CCR7 antibodies. Among CMV seropositive subjects, patients with AD had significantly lower proportions of CMV-specific CD8 T-cells compared to controls, 1.16 % vs. 4.13 % (p=0.0057). Regardless of dementia status, CMV seropositive subjects presented with a lower proportion of naïve CD8 cells and a higher proportion of effector CD8 cells compared to seronegative subjects. Interestingly, patients with AD showed a decreased proportion of CMV-specific CD8 cells but no difference in general CD8 differentiation.

CMV-specific T-cell immunity, viral load, and clinical outcome in seropositive renal transplant recipients: a pilot study.

BACKGROUND: Cytomegalovirus (CMV) infection is still the leading opportunistic infection following solid organ transplantation. The aim of this prospective study of renal transplant recipients was to evaluate the dynamics of CMV-specific T-cells, viral load, and clinical symptoms of CMV infection. METHODS: Levels of tetramer-selected CD8(+) T-cells (TetraCD8), CMV-specific interferon-gamma producing CD8(+) T-cells (IFNgammaCD8), and CD4(+) T-cells (IFNgammaCD4), measured using major histocompatibility complex-tetramer and cytokine flow cytometry techniques, and CMV DNA were monitored monthly in 17 CMV-seropositive patients up to one yr (median 12 months, range 3-12) after transplantation and correlated to clinical outcome. RESULTS: CMV DNAemia was detected in 94% of the patients, but only one patient developed CMV disease. CMV DNAemia >1 million copies/mL was seen in asymptomatic patients. CMV-specific T-cells decreased rapidly after transplantation. TetraCD8 and IFNgammaCD8 regenerated within three months, whereas IFNgammaCD4 recovery was impaired up to one yr after transplantation. The proportion of IFNgammaCD4 at two months post-transplantation as compared with baseline, correlated strongly with the magnitude of the CMV DNAemia. CONCLUSIONS: Monitoring the reduction of IFNgammaCD4 compared with baseline during the first months after transplantation could be considered in predicting risk for high-grade CMV DNAemia and in deciding strategic approaches for pre-emptive and prophylactic therapy.