Neuroimmune Crosstalk Between the Peripheral and the Central Immune System in Amyotrophic Lateral Sclerosis

Yu, Weiyi; He, Ji; Cai, Xiying; Yu, Zhou; Zou, Zhang‐Yu

doi:10.3389/fnagi.2022.890958

Cited by 15 publications

(14 citation statements)

References 126 publications

(132 reference statements)

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“…Interleukin-1 (IL1) that is secreted by activated microglia in context with PD pathogenesis [ 63 ] is a critical cytokine for Th17 cell differentiation [ 64 , 65 ]. As shown for other neurodegenerative diseases [ 66 ] a crosstalk between the brain and periphery may provide a potential explanation for our findings of increased TH17 counts in PD peripheral blood samples. In addition, we found an increased prevalence of a specific subtype of IL-17 producing gamma delta T cells in PD patients.…”

Section: Discussionsupporting

confidence: 72%

Time-resolved RNA signatures of CD4+ T cells in Parkinson’s disease

et al. 2023

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Parkinson’s disease (PD) emerges as a complex, multifactorial disease. While there is increasing evidence that dysregulated T cells play a central role in PD pathogenesis, elucidation of the pathomechanical changes in related signaling is still in its beginnings. We employed time-resolved RNA expression upon the activation of peripheral CD4+ T cells to track and functionally relate changes on cellular signaling in representative cases of patients at different stages of PD. While only few miRNAs showed time-course related expression changes in PD, we identified groups of genes with significantly altered expression for each different time window. Towards a further understanding of the functional consequences, we highlighted pathways with decreased or increased activity in PD, including the most prominent altered IL-17 pathway. Flow cytometric analyses showed not only an increased prevalence of Th17 cells but also a specific subtype of IL-17 producing γδ-T cells, indicating a previously unknown role in PD pathogenesis.

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Section: Discussionsupporting

confidence: 72%

Time-resolved RNA signatures of CD4+ T cells in Parkinson’s disease

et al. 2023

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“…Considerable evidence has revealed the presence of peripheral immunity abnormalities in the progress of ALS after diagnosis 2,35 . The peripheral immune system includes the innate immune system, with neutrophils at its core components, and the adaptive immune system, with lymphocytes at its core components.…”

Section: Discussionmentioning

confidence: 99%

“…However, the viewpoint was updated with the increasing number of studies, which revealed a functional crosstalk between peripheral immune cells and the CNS. 2 The peripheral immune system includes the innate immune system, with neutrophils as its core component, and the adaptive immune system, with lymphocytes as its core component. Different immune cell subpopulations display different functions in ALS disease progression; T regulatory cells (Tregs) appear to be protective, 3 whereas neutrophils, inflammatory monocytes, and CD8 + T cells may be destructive.…”

mentioning

confidence: 99%

“…The traditional view is that the blood–brain barrier (BBB) provides an immune‐privileged environment for the brain by preventing peripheral immune cells from invading the central nervous system (CNS). However, the viewpoint was updated with the increasing number of studies, which revealed a functional crosstalk between peripheral immune cells and the CNS 2 . The peripheral immune system includes the innate immune system, with neutrophils as its core component, and the adaptive immune system, with lymphocytes as its core component.…”

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confidence: 99%

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Neutrophils Are Associated with Higher Risk of Incident Amyotrophic Lateral Sclerosis in a BMI‐ and Age‐Dependent Manner

Cao

Tian

et al. 2023

Annals of Neurology

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ObjectivePeripheral immune markers have been associated with the progression and prognosis of amyotrophic lateral sclerosis (ALS). However, whether dysregulation of peripheral immunity is a risk factor for ALS or a consequence of motor neuron degeneration has not yet been clarified. We aimed to identify longitudinal associations between prediagnostic peripheral immunity and the risk of incident ALS.MethodsA total of 345,000 individuals from the UK Biobank between 2006 and 2010 were included at the baseline. The counts of peripheral immune markers (neutrophils, lymphocytes, monocytes, platelets and CRP) and its derived metrics (NLR、PLR、SII、LMR) were analyzed in relation to the following incident ALS by Cox‐proportional hazard models. Subgroup and interaction analyses were performed to explore the covariates of these relationships further.ResultsAfter adjusting for all covariates, the multivariate analysis showed that high neutrophil counts and their derived metrics (NLR, SII) were associated with an increased risk of ALS incidence (per SD increment HR, 95% CI: 1.15, 1.02‐1.29 for neutrophils; 1.15, 1.03‐1.28 for NLR; and 1.17, 1.05‐1.30 for SII). Subgroup and interaction analyses revealed that BMI and age had specific effects on this association. In participants with BMI≥25 or age<65, higher neutrophil counts and their metrics increased the risk of incident ALS; however, in participants with BMI<25 or age≥65, neutrophils had no effect on incident ALS.InterpretationOur study provides evidence that increased neutrophil levels and neutrophil‐derived metrics (NLR and SII) are associated with an increased risk of developing ALS.This article is protected by copyright. All rights reserved.

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“…Accumulating evidence implicates neuroimmune crosstalk between the peripheral immune system (PIS) and central immune system (CIS) in ALS, cooperatively contributing to the death of motor neurons (Yu et al, 2022). An increased infiltration of peripheral immune cells into the spinal cord and motor cortex of patients with ALS has been observed, which, together with activated microglia and astrocytes, constitute a pro-inflammatory immune microenvironment (Beers and Appel, 2019).…”

Section: Introductionmentioning

confidence: 99%

Natural killer cells-related immune traits and amyotrophic lateral sclerosis: A Mendelian randomization study

Gong

Liu²,

Ding³

et al. 2022

Front. Neurosci.

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BackgroundObservational studies have suggested that peripheral immune disorders are associated with amyotrophic lateral sclerosis (ALS). Previous studies predominantly focused on changes in adaptive immunity. However, emerging evidence showed natural killer (NK) cells, an essential component of innate immunity, were involved in the degeneration of motor neurons. However, the causal relationship between dysregulated NK cells-related immune traits and ALS remains unclear.ObjectiveThis study aimed to explore the causal relationship between NK cells-related immune traits and the risk of ALS.Materials and methodsSingle nucleotide polymorphisms (SNPs) significantly associated with NK cells-related immune traits were selected as instrumental variables to estimate their causal effects on ALS. SNPs from a genome-wide association study (GWAS) on NK cells-related immune traits were used as exposure instruments, including an absolute NK-cells count, absolute HLA-DR+ NK-cells count, NK cells/lymphocytes, NK cells/CD3– lymphocytes, HLA DR+ NK cells/NK cells, HLA DR+ NK cells/CD3– lymphocytes, and the median fluorescence intensities of CD16–CD56+ on NK cells and HLA-DR+ NK cells. Summary-level GWAS statistics of ALS were used as the outcome data. Exposure and outcome data were analyzed using the two-sample Mendelian randomization (MR) method.ResultsEach one standard deviation increase in the expression levels of CD16–CD56+ on NK cells and HLA-DR+ NK cells were associated with a lower risk of ALS in both the MR-Egger and inverse variance weighted methods (P < 0.05). The results proved robust under all sensitivity analyses. Neither instrumental outliers nor heterogeneity were detected.ConclusionOur results suggest that higher expression levels of CD16–CD56+ on NK cells and HLA-DR+ NK cells are associated with a lower risk of ALS.

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Neuroimmune Crosstalk Between the Peripheral and the Central Immune System in Amyotrophic Lateral Sclerosis

Cited by 15 publications

References 126 publications

Time-resolved RNA signatures of CD4+ T cells in Parkinson’s disease

Time-resolved RNA signatures of CD4+ T cells in Parkinson’s disease

Neutrophils Are Associated with Higher Risk of Incident Amyotrophic Lateral Sclerosis in a BMI‐ and Age‐Dependent Manner

Natural killer cells-related immune traits and amyotrophic lateral sclerosis: A Mendelian randomization study

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