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. 2014 May 7;9(5):e96779.
doi: 10.1371/journal.pone.0096779. eCollection 2014.

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

Gabriel Westman  1 , David Berglund  2 , Johan Widén  1 , Martin Ingelsson  3 , Olle Korsgren  2 , Lars Lannfelt  3 , Dag Sehlin  3 , Anna-Karin Lidehall  2 , Britt-Marie Eriksson  1
Affiliations

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

Gabriel Westman et al. PLoS One. .

Abstract

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-1β, 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 β (Aβ) protofibrils, respectively. CMV seropositive AD subjects presented with higher IFN-γ levels after anti-CD3/CD28 and CMV pp65 but not after Aβ 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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. AD vs. ND, negative control.
No significant differences in baseline cytokine secretion between AD and non demented (ND) subjects. Only CMV seropositive subjects were included.
Figure 2
Figure 2. AD vs. ND, anti-CD3/CD28 stimulation.
AD patients showed higher levels (p = 0.0056 or 0.056 with Bonferroni correction) of IFN-γ upon CD3/CD28 stimulation compared to non demented (ND) controls. Only CMV seropositive subjects were included.
Figure 3
Figure 3. AD vs. ND, CMV pp65 stimulation.
Higher levels (p = 0.016 or 0.16 with Bonferroni correction) of IFN-γ upon pp65 stimulation in AD patients compared to non demented (ND) controls. Only CMV seropositive subjects were included.
Figure 4
Figure 4. AD vs. ND, amyloid beta protofibril stimulation.
No significant differences in cytokine secretion between AD patients and non demented (ND) controls upon Aβ protofibril stimulation. Only CMV seropositive subjects were included.
Figure 5
Figure 5. CMV+ vs. CMV−, negative control.
No significant differences in baseline cytokine secretion between CMV seropositive and seronegative subjects. All subjects included regardless of dementia status.
Figure 6
Figure 6. CMV+ vs. CMV−, anti-CD3/CD28 stimulation.
Higher levels (p = 0.034 or 0.34 with Bonferroni correction) of IFN-γ in CMV seropositive subjects compared to seronegative subjects, upon CD3/CD28 stimulation. All subjects included regardless of dementia status.
Figure 7
Figure 7. CMV+ vs. CMV−, pp65 stimulation.
Higher levels of IFN-γ (p = 3.31E-5 or 0.00033 with Bonferroni correction), IL-2 (p = 0.00069 or 0.0069), IP-10 (p = 8.11E-5 or 0.00081) and TNF-α (p = 0.041 or 0.41) in CMV seropositive subjects compared to seronegative subjects. All subjects included regardless of dementia status.
Figure 8
Figure 8. CMV+ vs. CMV−, amyloid beta protofibril stimulation.
No significant differences in cytokine secretion between CMV seropositive and seronegative subjects upon Aβ protofibril stimulation. All subjects included regardless of dementia status.
Figure 9
Figure 9. Sub-group analysis of IFN-γ response upon anti-CD3/CD28 stimulation stratified by dementia and CMV status.
Significantly higher response in the AD CMV seropositive group, compared to both AD CMV seronegative subjects (p = 0.0142 or 0.14 with Bonferroni correction) and non-demented CMV seropositive subjects (p = 0.0056 or 0.056). Outliers excluded from plot, but included in the statistical analysis.
Figure 10
Figure 10. Dementia status and Apolipoprotein E genotype vs. plasma CRP.
a) No difference in plasma CRP levels between AD and ND groups. b) Hetero- and homozygote ApoE ε4 allele carriers present with lower plasma CRP compared to non-carriers (p = 0.017). Outliers excluded from plots, but included in statistical analysis. Both CMV seropositive and seronegative subjects included.
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