Evidence for systemic immune system alterations in sporadic amyotrophic lateral sclerosis (sALS)

Zhang, Rongzhen; Gascon, Ron; Miller, Robert G.; Gelinas, Deborah; Mass, Jason; Hadlock, Ken; Jin, Xia; Reis, Jeremy; Narvaez, Amy; McGrath, Michael S.

doi:10.1016/j.jneuroim.2004.10.009

Cited by 136 publications

(156 citation statements)

References 55 publications

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“…Our investigations found perivascular and intraparenchymal CD4 + T lymphocytes in the proximity of degenerating corticospinal tracts and ventral horns in two-thirds of ALS patients (11). In the blood of patients with ALS, alterations in T lymphocyte populations have also been described as compared with controls (12)(13)(14)(15)(16); however, these studies do not address whether T lymphocytes directly or indirectly influence disease progression.…”

Section: Introductionmentioning

confidence: 62%

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

Beers¹,

Zhao²,

Wang³

et al. 2017

JCI Insight

153

138

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Section: Introductionmentioning

confidence: 62%

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

Beers¹,

Zhao²,

Wang³

et al. 2017

JCI Insight

153

138

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“…Interestingly, increased cell death and diminished T‐cell proliferation were also described 59. Moreover, increased activated circulating macrophages, abnormal numbers of CD4 T‐cells, antibodies and circulating immune complex have been described in blood of ALS patients, but the results have been inconsistent 70, 71. Interestingly, the development of C9orf72 null mouse models, after identification of a mutated version of this gene in a significant proportion of ALS patients, did not lead to overt motor impairment 72, 73.…”

Section: Status Of Neuroinflammation In Als and Smamentioning

confidence: 99%

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

Deguise

Kothary

2017

Ann Clin Transl Neurol

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Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by motor neuron degeneration, although defects in multiple cell types and tissues have also been implicated. Three independent laboratories recently identified immune organ defects in SMA. We therefore propose a novel pathogenic mechanism contributory to SMA, resulting in higher susceptibility to infection and exacerbated disease progression caused by neuroinflammation. Overall, compromised immune function could significantly affect survival and quality of life of SMA patients. We highlight the recent findings in immune organ defects, their potential consequences on patients, our understanding of neuroinflammation in SMA, and new research hypotheses in SMA pathogenesis.

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“…Malfunction of both innate and adaptive immune system can actively influence disease progression in animal models and in patients with familial and sporadic ALS [6,7]. Substantial numbers of infiltrating T cells and macrophages are found in the spinal cord of patients with ALS [8][9][10]; the majority of these migrating cells are described as T helper (Th) and T suppressor/cytotoxic cells [11], whereas a decreased number of regulatory T cells (Tregs) was observed in mice and patients with ALS during the rapidly progressing phase of the disease [12].…”

Section: Introductionmentioning

confidence: 99%

Fingolimod: A Disease-Modifier Drug in a Mouse Model of Amyotrophic Lateral Sclerosis

et al. 2016

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Fingolimod phosphate (FTY720), the first approved oral therapy for multiple sclerosis, primarily acts as an immunomodulator. Its concomitant effects in the central nervous system, however, indicate a potentially broader spectrum of activity in neurodegenerative diseases. In the present study, we investigated the possible effects of fingolimod in a mouse model of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by a strong neuroinflammatory component. Fingolimod (0.1 and 1 mg/kg i.p.) was administered to mSOD1 G93A mice, a well-characterized mouse model of ALS, starting from the onset of motor symptoms to the end stage of the disease. The drug was able to improve the neurological phenotype (p < 0.05) and to extend the survival (p < 0.01) of ALS mice. The beneficial effect of fingolimod administration was associated with a significant modulation of neuroinflammatory and protective genes (CD11b, Foxp3, iNOS, Il1β, Il10, Arg1, and Bdnf) in motor cortex and spinal cord of animals. Our data show, for the first time, that fingolimod is protective in ALS mice and that its beneficial effects are accompanied by a modulation of microglial activation and innate immunity. Considering that the treatment was started in already symptomatic mice, our data strongly support fingolimod as a potential new therapeutic approach to ALS.

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Evidence for systemic immune system alterations in sporadic amyotrophic lateral sclerosis (sALS)

Cited by 136 publications

References 55 publications

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

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

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

Fingolimod: A Disease-Modifier Drug in a Mouse Model of Amyotrophic Lateral Sclerosis

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