ALS patients’ regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity

Beers, David R.; Zhao, Weihua; Wang, Jinghong; Zhang, Xiujun; Wen, Shixiang; Neal, Dan; Thonhoff, Jason R.; Alsuliman, Abdullah; Shpall, Elizabeth J.; Rezvani, Katy; Appel, Stanley H.

doi:10.1172/jci.insight.89530

Cited by 168 publications

(182 citation statements)

References 52 publications

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“…In early disease, there is evidence of homeostatic microglia and Treg infiltration, while in later disease stages, M1 microglia and activated astrocytes predominate (157). Tregs themselves are defective in ALS (99,100). TLR4, which activates microglia, is upregulated in the spinal cord of ALS patients, and could thereby mediate neurodegeneration (158).…”

Section: Immune-directed Therapies For Neurodegenerative Diseasesmentioning

confidence: 99%

CNS inflammation and neurodegeneration

Chitnis¹,

Weiner²

2017

Journal of Clinical Investigation

398

240

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Section: Immune-directed Therapies For Neurodegenerative Diseasesmentioning

confidence: 99%

CNS inflammation and neurodegeneration

Chitnis¹,

Weiner²

2017

Journal of Clinical Investigation

398

240

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“…This shows unequivocally that Nf-L and Nf-H proteins, to a different degree, outperform their Abs/ICs in the separation of ALS sub-groups from HC based on rate of disease progression in line with previously reported data 8,20,29 Mutations that diminish or eliminate C9orf72 function in mice cause a severe state of autoimmunity with loss of tolerance for many nervous system autoantigens 30 . The significant down-regulation of T-regulatory cells, a prominent feature in ALS individuals with fast disease progression, is also likely to contribute to a reduced immunotolerance 4,31 . It is tempting to speculate that the increased levels of Nf Abs and of NfL ICs in ALS-F and in C9+ve cases may be the result of altered immunotolerance and enhanced autoimmunity to brain antigens which become established throughout disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…The genetic mutations causing ALS may partially explain this conditions' clinical heterogeneity, where survival from disease onset varies from less than a year to more than a decade [1][2][3] . The pathology underpinning the clinical heterogeneity of ALS is centred around the role of disordered proteins and on the modifying effect on progressive neuronal loss of disease-specific immune responses, such as the reduction of T-regulatory cells predominantly in fast progressing ALS, which is likely to induce a state of diminished self-immune tolerance and the formation of antibodies (Abs) and immuno-complexes (ICs) to brain proteins 4,5 . Intronic expansions of the C9orf72 gene, the most common genetic mutation in ALS, are also thought to enhance a state of autoimmunity possibly induced by loss of function of translation products like dipeptide repeats (DPR) 6 .…”

Section: Introductionmentioning

confidence: 99%

Immune reactivity to neurofilaments and dipeptide repeats in ALS progression

Puentes

Lombardi

et al. 2020

Preprint

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Objective: To test antibody response and formation of immune-complexes to neurofilaments and dipeptide-repeats, the translational products of the mutated C9orf72 gene, as potential biomarkers for clinical stratification of amyotrophic lateral sclerosis (ALS). Methods:Using neurofilament protein isoforms plasma expression as reference, antibodies and immune-complexes against neurofilament-light, medium and heavy chain and poly-(GP)-GR dipeptide-repeats were tested in blood from 105 fast and slow progressing ALS patients, 26 C9orf72 mutation carriers (C9+ve) ALS patients and 77 healthy controls (HC) using single-molecule and immune-capture assays.Longitudinal antibody/immune-complex responses were measured in serial blood samples from 37 (including 11 C9+ve) patients.Results: Antibodies and immune-complex reactivity was higher in ALS patients than HC, particularly in C9+ve ALS patients, and modestly correlated with total neurofilament protein isoforms (r:0.24 p=0.002; r:0.18 p=0.02 respectively). Neurofilament-light immune-complexes and neurofilament-heavy antibodies had the best diagnostic performances distinguishing ALS subtypes from HC (AUC=0.68 p<0.01; AUC=0.68 p<0.001 respectively). Neurofilament-light immune-complexes (AUC=0.69 p<0.01) and poly-(GP) dipeptide-repeats antibodies (AUC=0.71 p<0.001) separated C9+ve from C9-ve patients. Multivariate mortality hazard ratio and Kaplan-Meier analyses showed low neurofilament-heavy antibody levels associated with increased survival. Longitudinal analysis identified raising levels of antibodies against neurofilaments in fast progressing ALS and of neurofilament-light immunecomplexes in C9+ve patients. Interpretation: C9+ve and fast progressing ALS patients have a distinct neurofilament and dipeptide-repeat immuno-phenotype, with increasing levels of blood neurofilament-light immune-complexes and neurofilament antibodies with disease progression. The study of the expression of these biomarkers in the natural history of ALS may shed light on disease initiation and progression and provide novel pharmacodynamic biomarkers in emerging C9orf72 gene silencing therapies.

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“…Mouse models as well as ALS patients also have high levels of cytotoxic CD8 lymphocytes and circulating natural killer cells [133, 139, 140]. Patients also show dysfunctional regulatory T cells (Treg), which correlate with the progression and severity of symptoms [135, 141, 142]. This finding is currently under evaluation as a potential therapeutic strategy in ALS [135].…”

Section: Neuroinflammation In Neurodegenerative Diseasesmentioning

confidence: 99%

Neuroimmune and Inflammatory Signals in Complex Disorders of the Central Nervous System

Liberman

Trías

Chagas

et al. 2018

Neuroimmunomodulation

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An extensive microglial-astrocyte-monocyte-neuronal cross talk seems to be crucial for normal brain function, development, and recovery. However, under certain conditions neuroinflammatory interactions between brain cells and neuroimmune cells influence disease outcome and brain pathology. Microglial cells express a range of functional states with dynamically pleomorphic profiles from a surveilling status of synaptic transmission to an active player in major events of development such as synaptic elimination, regeneration, and repair. Also, inflammation mediates a series of neurotoxic roles in neuropsychiatric conditions and neurodegenerative diseases. The present review discusses data on the involvement of neuroinflammatory conditions that alter neuroimmune interactions in four different pathologies. In the first section of this review, we discuss the ability of the early developing brain to respond to a focal lesion with a rapid compensatory plasticity of intact axons and the role of microglial activation and proinflammatory cytokines in brain repair. In the second section, we present data of neuroinflammation and neurodegenerative disorders and discuss the role of reactive astrocytes in motor neuron toxicity and the progression of amyotrophic lateral sclerosis. In the third section, we discuss major depressive disorders as the consequence of dysfunctional interactions between neural and immune signals that result in increased peripheral immune responses and increase proinflammatory cytokines. In the last section, we discuss autism spectrum disorders and altered brain circuitries that emerge from abnormal long-term responses of innate inflammatory cytokines and microglial phenotypic dysfunctions.

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ALS patients’ regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity

Cited by 168 publications

References 52 publications

CNS inflammation and neurodegeneration

CNS inflammation and neurodegeneration

Immune reactivity to neurofilaments and dipeptide repeats in ALS progression

Neuroimmune and Inflammatory Signals in Complex Disorders of the Central Nervous System

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