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. 2023 Oct 7;5(5):fcad259.
doi: 10.1093/braincomms/fcad259. eCollection 2023.

A blunted TH17 cytokine signature in women with mild cognitive impairment: insights from inflammatory profiling of a community-based cohort of older adults

Affiliations

A blunted TH17 cytokine signature in women with mild cognitive impairment: insights from inflammatory profiling of a community-based cohort of older adults

Adam D Bachstetter et al. Brain Commun. .

Abstract

People with dementia have an increase in brain inflammation, caused in part by innate and adaptive immune cells. However, it remains unknown whether dementia-associated diseases alter neuro-immune reflex arcs to impact the systemic immune system. We examined peripheral immune cells from a community-based cohort of older adults to test if systemic inflammatory cytokine signatures associated with early stages of cognitive impairment. Human peripheral blood mononuclear cells were cultured with monocyte or T-cell-targeted stimuli, and multiplex assays quantitated cytokines in the conditioned media. Following T-cell-targeted stimulation, cells from women with cognitive impairment produced lower amounts of TH17 cytokines compared with cells from cognitively healthy women, while myeloid-targeted stimuli elicited similar amounts of cytokines from cells of both groups. This TH17 signature correlated with the proportion of circulating CD4+ and CD8+ T cells and plasma glial fibrillary acidic protein and neurofilament light concentrations. These results suggest that decreases in TH17 cytokines could be an early systemic change in women at risk for developing dementia. Amelioration of TH17s cytokines in early cognitive impairment could, in part, explain the compromised ability of older adults to respond to vaccines or defend against infection.

Keywords: Alzheimer’s disease; biomarker; immunity; neuroimmunology; sex differences.

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Conflict of interest statement

The authors report no competing interests.

Figures

Graphical Abstract
Graphical Abstract
Figure 1
Figure 1
TH17 cytokines from αCD3/αCD28-stimulated PBMC associate with cognitive impairment in women. (A) PBMCs were stimulated with LPS or αCD3/αCD28. Study participants were divided into healthy controls (CDR = 0) or cognitively impaired (CDR = 0.5–1). (B) Cognitive status had no effect on levels of cytokines produced by the LPS-stimulated PBMCs. The cytokines produced by αCD3/αCD28-stimulated PBMCs were clustered into functional categories, including (C) cytokines that promote growth and survival of T cells; (D) TH1-type cytokines that promote cellular immune and inflammatory responses to infection and injury, (E) TH2-type cytokines associated with allergy and anti-inflammatory activity; (F) IL-27 associated with polarization of T cells from TH1/TH2 to a TH17 response; and (G) TH17 cytokines associated with activating cellular immunity and autoimmune disease. (H) The TH17 cytokines (IL-17A, IL-17F, IL-21, IL-22, CCL20) were standardized and the average z-score was used to identify a TH17 signature. Cognitively impaired women had a lower TH17 signature than control women. Circles represent individual study participants. *FDR < 0.05, **FDR < 0.01, ***FDR < 0.001 for unadjusted t-test. See Supplemental Tables 4 and 5 for all statistical comparisons. Multiple comparisons corrected with the Benjamini–Hochberg FDR.
Figure 2
Figure 2
The association of age, apoE genotype, and CVD risk factors with cytokine production from stimulated PBMCs. (A) Increased age correlated with lower amounts of cytokines produced from αCD3/αCD28-stimulated PBMCs. The correlation was gender-dependent, particularly with the TH17-associated cytokines, where age correlated with lower cytokines in men but not women. (B) In men, ApoE4 carriers (one or two copies) had higher IL-1β, TNFα, and CCL20 from LPS-stimulated PBMCs compared with the E4− group. In women, stimulated E4+ PBMCs produced fewer cytokines (IFNγ, LTα, IL-22, and CCL20) than stimulated E4− PBMCs. Age was not different between the E4− or E4+ groups (t = −1.01, P = 0.32). (C) In men, a greater burden of CVD risk factors (2–3 versus 0–1) was associated with more cytokines produced from αCD3/αCD28-stimulated PBMCs. Women did not show the same pattern. Circles are individual participants. The dashed line shows the 95% confidence interval for the linear regression (A). *FDR < 0.05, **FDR < 0.01, ***FDR < 0.001, unadjusted t-test results (B and C). See Supplemental Tables 7–10 for all statistical comparisons. The Benjamini–Hochberg adjustment used for FDR values.
Figure 3
Figure 3
PBMCs from cognitively impaired subjects make lower amounts of TH17-associated cytokines than cognitively unimpaired subjects. (A) Individuals with cognitive impairment on the MMSE (score <25) had a low TH17 signature (mean Z-score of IL-17A, IL-17F, IL-21, IL-22, CCL20) compared with those within a normal MMSE range (score ≥25) (****P < 0.0001; corrected for age and education). (B) The MoCA correlated with the TH17 signature (age and education adjusted). The dashed line shows the 95% confidence interval for the linear regression. (C) Staging for dementia was based on CDR and MMSE results. The TH17 signature was lower in women with MCI and mild dementia. In men, the lower TH17 signature was only seen in individuals with mild dementia. When including both genders, the decline in the TH17 signature was only seen with mild dementia and not MCI (*P < 0.05, **P < 0.01, ***P < 0.001, Tukey test). (D) The neuropsychological consensus diagnosis for the visit when PBMCs were collected also showed a significant association of a lower TH17 signature with dementia (*P < 0.05, Tukey test). Markers are individual participants. Statistical tests used: (A) t-test, (B) linear regression, (C and D) one-way ANOVA with Tukey post hoc test.
Figure 4
Figure 4
The TH17 cytokine signature correlates with fluid biomarkers of neuronal injury and neuroinflammation. Plasma biomarkers, measured by Simoa assays, were correlated with the TH17 cytokine signature (mean z-score of IL-17A, IL-17F, IL-21, IL-22, CCL20) of the αCD3/αCD28 Dynabead-stimulated PBMCs. Aβ42/40 ratio (A) and p-tau181 (B) levels in plasma did not correlate with the TH17 cytokine signature. NF-L (C) and GFAP (D) were negatively correlated with the TH17 cytokine signature. Open circles are male participants. Closed diamonds are female participants. The dashed line shows 95% confidence interval for the linear regression. FDR values are for the unadjusted analysis. See also Supplemental Table 13.
Figure 5
Figure 5
Steady-state plasma cytokine levels fail to detect a dementia-associated immune signature. (A) Cytokine levels were measured in plasma. There was no effect of cognitive impairment status on TH1 (B) or TH17 (C) cytokine levels in the plasma. A mean z-score (D) of the four TH17 cytokines measured in the plasma (C) did not define a dementia-associated immune signature. See also Supplemental Table 14. The plasma cytokine levels did not correlate with cytokines produced by LPS (E) or αCD3/αCD28 Dynabead (F) stimulated PBMCs. The dashed line shows 95% confidence interval for the linear regression. P-values are uncorrected. Markers are individual participants. FDR values are for the unadjusted analysis. See also Supplemental Table 15. Statistical tests used: (AD) t-test, (E and F) linear regression. Multiple comparisons adjusted using the Benjamini–Hochberg FDR.
Figure 6
Figure 6
The frequency of CD4+ T cells correlates with TH17 cytokine signature. (A) Gating strategy and (B) representative example of CD4+ and CD8+ T-cell populations in the experimental groups. (C) A significant decrease in the percentage CD3+ CD4+ and CD4+/CD8+ ratio was found in women with cognitive decline compared with control women (FDR < 0.05, see also Supplemental Table 16). (D) The TH17 signature from stimulated PBMCs correlated with the percentage of T cells in the unstimulated PBMCs. Statistical tests used: (C) t-test and (D) linear regression.

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