Dysregulation of Systemic Immunity in Aging and Dementia

Jenny Lutshumba, Barbara S Nikolajczyk, Adam D Bachstetter, Jenny Lutshumba, Barbara S Nikolajczyk, Adam D Bachstetter

Abstract

Neuroinflammation and the tissue-resident innate immune cells, the microglia, respond and contribute to neurodegenerative pathology. Although microglia have been the focus of work linking neuroinflammation and associated dementias like Alzheimer's Disease, the inflammatory milieu of brain is a conglomerate of cross-talk amongst microglia, systemic immune cells and soluble mediators like cytokines. Age-related changes in the inflammatory profile at the levels of both the brain and periphery are largely orchestrated by immune system cells. Strong evidence indicates that both innate and adaptive immune cells, the latter including T cells and B cells, contribute to chronic neuroinflammation and thus dementia. Neurodegenerative hallmarks coupled with more traditional immune system stimuli like infection or injury likely combine to trigger and maintain persistent microglial and thus brain inflammation. This review summarizes age-related changes in immune cell function, with special emphasis on lymphocytes as a source of inflammation, and discusses how such changes may potentiate both systemic and central nervous system inflammation to culminate in dementia. We recap the understudied area of AD-associated changes in systemic lymphocytes in greater detail to provide a unifying perspective of inflammation-fueled dementia, with an eye toward evidence of two-way communication between the brain parenchyma and blood immune cells. We focused our review on human subjects studies, adding key data from animal models as relevant.

Keywords: CD4; CD8; T cells; Th17; Treg; monocytes; neuroimmunology; neuroinflammation.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Lutshumba, Nikolajczyk and Bachstetter.

Figures

FIGURE 1
FIGURE 1
Summary of age-related changes in monocyte and dendritic cells. (A) In the blood of older aged people, there is a decrease in the proportion of classical monocytes, while the intermediate and non-classical monocyte populations are increasing compared to younger adults. (B) Monocytes also have an age-dependent decrease in proinflammatory cytokines at baseline, but with TLR4 stimulation (LPS) the aged monocytes produce more proinflammatory cytokines than monocytes from younger individuals. (C) There are age-related changes in subpopulations for dendritic cells (DC), and (D) the aged DCs produced more proinflammatory and less anti-inflammatory cytokines.
FIGURE 2
FIGURE 2
Summary of age-related changes in systemic immune function. (1) As we age, there is an imbalance in the production of innate immune cells and adaptive immune cells that favor cells of the myeloid lineage. (2) The microenvironment decreases with age, and there is a reduction in recent thymic emigrants (RTEs), reducing the naïve T cell poll in the circulation. (3) Antigen presentation by dendritic cells declines with age. (4) In the blood, the immunosenescence leads to a state of chronic inflammation, associated with elevated circulating cytokines, a decrease in naïve T cells able to respond to new pathogens, and monocytes over-produce inflammatory mediators and fail to resolve the inflammatory response.
FIGURE 3
FIGURE 3
Age-related TH17 changes. Bharath et al. (2020) demonstrated that peripheral blood CD4+ cells from healthy older adults (∼60 years old) had an exaggerated TH17 profile. The TH17 signature was driven by impaired non-mitochondrial autophagy and dysfunctional mitochondria, at least in part via a STAT3 dependent mechanism.
FIGURE 4
FIGURE 4
Blood cell counts and risk for all cause dementia. van der Willik et al. (2019) evaluated blood cell counts on 8313 participants who were dementia-free at the start of the study (mean age: 61 years old at the start). During a median follow-up of 8.6 years, 664 developed dementia. For those who did not have a stroke during the study (N = 8008), changes in blood cell counts, and the ratio of blood cell populations were statistically associated with dementia risk. Plotted results are from Table 3 of van der Willik et al. (2019). *p < 0.05.
FIGURE 5
FIGURE 5
Changes in T cell subsets in AD. Recent studies have identified changes in effector memory and terminally differentiated T cells in AD patients’ peripheral blood compared to aged-matched controls. The changes in the T cells subsets were found to significantly correlate with cognitive scores. References for changes correspond to the following: [1] (Busse et al., 2017) and [2] (Gate et al., 2020). The symbols indicate the following: ⟷ no change, ↑ increase in the cell population, ↓ decrease in the cell population in AD cases compared to aged-matched controls. *p < 0.05.
FIGURE 6
FIGURE 6
Whole blood cultures show an exaggerated response to LPS. (A)Lombardi et al. (1999) stimulated whole blood cultures from individuals with Alzheimer’s disease (AD), vascular dementia (VaD), and compared these to aged-matched controls. Cell culture supernatant was collected at 24-h intervals for 72 h for ELISA cytokine assays. (B) All cytokines measured showed higher cytokine production in the AD group, compared to the control or VaD groups. The plotted data is from the 24 h post-stimulation time point, from Table 3 of Lombardi et al. (1999). A similar trend was seen for the 48 and 72 h post-stimulation timepoint. *p < 0.05 compared to control.
FIGURE 7
FIGURE 7
Systems approach to evaluate systemic immune changes in dementia. In a community-based cohort of individuals who are followed longitudinally and have agreed to brain autopsy and donation, the study can begin with a cross-sectional design of participants without cognitive impairment and comparing those with mild cognitive impairment to profound dementia, and incorporating clinical evaluations as part of the study (1). By piggybacking on a larger study that incorporates genomic (2), blood collection (3), and fluid biomarker assessment (including assays for systemic inflammation), (4) it is possible to leverage ongoing cohort studies to better define the role of immune dysfunction in AD. Peripheral blood mononuclear cells (PBMC) are isolated from the fresh whole blood and are archived for future studies (3). The isolated PMBCs can be used for gene expression and gene sequencing to identify changes in immune cell populations and clonal expansion of T cells (5). Immunophenotyping of immune cell subsets can be done to evaluate changes in a population of immune cells (6). Select populations of immune cells can be enriched (7). The PBMC or select cells can be directly stimulated with activators such as LPS or CD3/CD28 (8), to evaluate cellular mechanisms and therapeutic targets, inhibitors can be added along with the mitogens (9). The cell culture supernatant can then be used for cytokines multiplex immune profiling assays (10). By enriching the cross-sectional design for healthy controls, it is possible to evaluate people’s possible conversion into varying neurodegenerative diseases (11), which are ultimately pathologically confirmed at autopsy (12). The wealth of data that is captured will require a very robust statistical and bioinformatical infrastructure to integrate all the data (13). Finally, “hits” will require validation in a subsequent set of study participants, and clinical experimentation can test positive intervention strategies targeted at restoring the immune balance (14).

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