ABSTRACT
INTRODUCTION: Fast and minimally invasive approaches for early diagnosis of Alzheimer's disease (AD) are highly anticipated. Evidence of adaptive immune cells responding to cerebral ß-amyloidosis has raised the question of whether immune markers could be used as proxies for ß-amyloid accumulation in the brain. METHODS: Here, we apply multidimensional mass-cytometry combined with unbiased machine-learning techniques to immunophenotype peripheral blood mononuclear cells from a total of 251 participants in cross-sectional and longitudinal studies. RESULTS: We show that increases in antigen-experienced adaptive immune cells in the blood, particularly CD45RA-reactivated T effector memory (TEMRA) cells, are associated with early accumulation of brain ß-amyloid and with changes in plasma AD biomarkers in still cognitively healthy subjects. DISCUSSION: Our results suggest that preclinical AD pathology is linked to systemic alterations of the adaptive immune system. These immunophenotype changes may help identify and develop novel diagnostic tools for early AD assessment and better understand clinical outcomes.
Subject(s)
Alzheimer Disease , tau Proteins , Humans , Cross-Sectional Studies , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/pathology , T-Lymphocytes/metabolism , T-Lymphocytes/pathology , Amyloid beta-Peptides/metabolism , Alzheimer Disease/pathology , Brain/pathology , BiomarkersABSTRACT
The field of neuroimmunology endorses the involvement of the adaptive immune system in central nervous system (CNS) health, disease, and aging. While immune cell trafficking into the CNS is highly regulated, small numbers of antigen-experienced lymphocytes can still enter the cerebrospinal fluid (CSF)-filled compartments for regular immune surveillance under homeostatic conditions. Meningeal lymphatics facilitate drainage of brain-derived antigens from the CSF to deep cervical lymph nodes to prime potential adaptive immune responses. During aging and CNS disorders, brain barriers and meningeal lymphatic functions are impaired, and immune cell trafficking and antigen efflux are altered. In this context, alterations in the immune cell repertoire of blood and CSF and T and B cells primed against CNS-derived autoantigens have been observed in various CNS disorders. However, for many diseases, a causal relationship between observed immune responses and neuropathological findings is lacking. Here, we review recent discoveries about the association between the adaptive immune system and CNS disorders such as autoimmune neuroinflammatory and neurodegenerative diseases. We focus on the current challenges in identifying specific T cell epitopes in CNS diseases and discuss the potential implications for future diagnostic and treatment options.
ABSTRACT
Genetic, clinical, biochemical and histochemical data indicate a crucial involvement of inflammation in Alzheimer's disease (AD), but harnessing the immune system to cure or prevent AD has so far proven difficult. Clarifying the cellular heterogeneity and signaling pathways associated with the presence of the AD hallmarks beta-amyloid and tau in the brain, would help to identify potential targets for therapy. While much attention has been so far devoted to microglia and their homeostatic phagocytic activity, additional cell types and immune functions might be affected in AD. Beyond microglia localized in the brain parenchyma, additional antigen-presenting cell (APC) types might be affected by beta-amyloid toxicity. Here, we investigated potential immunomodulatory properties of oligomeric species of beta-amyloid-peptide (Aß) on microglia and putative APCs. We performed a comprehensive characterization of time- and pathology-dependent APC and T-cell alterations in a model of AD-like brain beta-amyloidosis, the APP-PS1-dE9 mouse model. We show that the deposition of first beta-amyloid plaques is accompanied by a significant reduction in MHC class II surface levels on brain APCs. Furthermore, taking advantage of customized in vitro systems and RNAseq, we demonstrate that a preparation containing various forms of oligomeric Aß1-42 inhibits antigen presentation by altering the transcription of key immune mediators in dendritic cells. These results suggest that, beyond their neurotoxic effects, certain oligomeric Aß forms can act as immunomodulatory agents on cerebral APCs and interfere with brain antigen presentation. Impaired brain immune surveillance might be one of the factors that facilitate Aß and tau spreading in AD.
Subject(s)
Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/immunology , Antigen Presentation , Peptide Fragments/chemistry , Peptide Fragments/immunology , Alzheimer Disease/immunology , Alzheimer Disease/pathology , Amyloid beta-Peptides/genetics , Amyloidosis/genetics , Amyloidosis/immunology , Amyloidosis/metabolism , Animals , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/pathology , Brain/immunology , Brain/pathology , Disease Models, Animal , Gene Expression , Histocompatibility Antigens Class II/metabolism , Humans , Immunomodulation , Mice , Mice, Inbred C57BL , Mice, Transgenic , Peptide Fragments/genetics , Plaque, Amyloid/immunology , Plaque, Amyloid/metabolism , Plaque, Amyloid/pathology , Protein Structure, Quaternary , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/immunology , T-Lymphocytes/immunology , T-Lymphocytes/pathologyABSTRACT
INTRODUCTION: In Alzheimer's disease, accumulation and pathological aggregation of amyloid ß-peptide is accompanied by the induction of complex immune responses, which have been attributed both beneficial and detrimental properties. Such responses implicate various cell types of the innate and adaptive arm of the immunesystem, both inside the central nervous system, and in the periphery. To investigate the role of the adaptive immune system in brain ß-amyloidosis, PSAPP transgenic mice, an established mouse model of Alzheimer's disease, were crossbred with the recombination activating gene-2 knockout (Rag2 ko) mice lacking functional B and T cells. In a second experimental paradigm, aged PSAPP mice were reconstituted with bone marrow cells from either Rag2 ko or wildtype control mice. RESULTS: Analyses from both experimental approaches revealed reduced ß-amyloid pathology and decreased brain amyloid ß-peptide levels in PSAPP mice lacking functional adaptive immune cells. The decrease in brain ß-amyloid pathology was associated with enhanced microgliosis and increased phagocytosis of amyloid ß-peptide aggregates. CONCLUSION: The results of this study demonstrate an impact of the adaptive immunity on cerebral ß-amyloid pathology in vivo and suggest an influence on microglia-mediated amyloid ß-peptide clearance as a possible underlying mechanism.
Subject(s)
Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , B-Lymphocytes/pathology , Peptide Fragments/metabolism , T-Lymphocytes/pathology , Adoptive Transfer , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/genetics , Animals , Cytokines/metabolism , DNA-Binding Proteins/deficiency , DNA-Binding Proteins/genetics , Disease Models, Animal , Exploratory Behavior/physiology , Female , Humans , Male , Maze Learning/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Peptide Fragments/genetics , Recognition, Psychology/physiologyABSTRACT
Recently, we have reported that, in addition to macrophages, also neutrophil granulocytes can phagocytose apoptotic neutrophils. Based on this finding, we hypothesized that "cannibalistic" neutrophils at sites of acute infection/inflammation play a major role in the clearance of apoptotic neutrophils. Since at sites of infection/inflammation neutrophils are exposed to microbial constituents and proinflammatory cytokines, in the present study we analyzed the effect of TLR-ligands and cytokines on the ability of neutrophils to phagocytose apoptotic cells in vitro. We observed that exposure to ligands of TLR2 (Malp2, Pam3CSK4), TLR4 (LPS), TLR7/TLR8 (R848), and TLR9 (ODN 2006) led to increased phagocytosis of apoptotic cells by neutrophils. In addition, proinflammatory cytokines such as TNF and GM-CSF strongly enhanced the uptake of apoptotic cells by neutrophils. These results support the hypothesis that neutrophils acquire the ability to phagocytose apoptotic cells at sites of acute infection/inflammation and thereby can contribute to the resolution of inflammation.
