Inflammation, Immunity, and amyotrophic lateral sclerosis: I. Etiology and pathology

Lyon, Miles S.; Wosiski‐Kuhn, Marlena; Gillespie, Rachel; Caress, James B.; Milligan, Carol

doi:10.1002/mus.26289

Cited by 85 publications

(65 citation statements)

References 148 publications

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“…Emerging evidence suggests that neuroinflammation is involved in the degenerative process of MNs in ALS, indicating a vital role of the systemic immune system in the pathophysiology of ALS [31][32][33] . However, the impact of the immune system in ALS is not clear and contradictory results for the immune and cytokine profile in blood and CSF of ALS patients were recently published 16,18,19,[21][22][23] .…”

Section: Discussionmentioning

confidence: 99%

Peripheral proinflammatory Th1/Th17 immune cell shift is linked to disease severity in amyotrophic lateral sclerosis

Jin

Günther

Akgün

et al. 2020

Sci Rep

110

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Neuroinflammation is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS), but only limited data are available on systematic peripheral and central immune cell profiles in ALS. We studied detailed immune profiles of 73 ALS patients and 48 healthy controls (controls) in peripheral blood by fluorescence-activated cell sorting as well as cytokine expression profiles in serum. In a subgroup of 16 ALS patients and 10 controls we additionally studied cerebrospinal fluid (CSF) samples. In peripheral blood, T cell subtypes presented a shift towards pro-inflammatory Th 1 and Th 17 cells whereas anti-inflammatory Th2 and T regulatory cells were decreased. Important players in innate immunity including distinct monocyte (Mo) and natural killer (NK) cell subtypes were changed in ALS patients compared to controls. Pro-inflammatory serum cytokines such as interleukin (IL)-1 beta, IL-6 and interferon-gamma (IFN-gamma) were increased and the anti-inflammatory cytokine IL-10 was decreased. Correlation analysis revealed moderate negative correlations between Th1 and Th17 to the ALS functional rating scale revised (ALSFRS-R) and to forced vital capacity. In CSF samples, no relevant alteration of the immune profile was found. In conclusion, the immune profile in ALS was shifted towards a Th1/Th17 cell-mediated pro-inflammatory immune response and correlated to disease severity and progression. Large prospective studies are needed to confirm these findings. Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, which affects the upper and lower motoneurons (MN) leading to progressive muscle weakness, paralysis and ultimately death due to respiratory failure. The pathophysiological mechanisms are still unresolved, although increasing knowledge gained in the last two decades. Multiple studies corroborated that numerous pathological processes are involved in MN degeneration and neuroinflammation gained increasing attention and had deemed as a pathological hallmark of ALS 1-3. It is commonly accepted that the non-neuronal neighbors play a significant role in the degenerative process of this vulnerable cell type 4. One of the most impressive pathohistological characteristics during disease progression is activation and increase abundance of microglial cells in the central nervous system (CNS) shown in animal models of ALS 5 as well as in human studies 6-8. Microglial cells are considered to be the resident mononuclear phagocytes in the CNS and can be renewed by bone marrow cells under special circumstances 9,10. It is supposable that specialized peripheral immune cell subsets are attracted to the central compartment to contribute and perpetuate the pathological processes in ALS disease by local inflammation or activation of resident cells. Therefore, neuroinflammation is not limited to the CNS, it needs a systemic inflammatory response to enable the local inflammation. In general, a systemic inflammatory response is very complex, a plethora of different immune cells are involved, diverse cytokines a...

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Section: Discussionmentioning

confidence: 99%

Peripheral proinflammatory Th1/Th17 immune cell shift is linked to disease severity in amyotrophic lateral sclerosis

Jin

Günther

Akgün

et al. 2020

Sci Rep

110

View full text Add to dashboard Cite

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“…perivascular) but entered the brain parenchyma. Since the involvement of adaptive immune response in ALS is debated 20 , we also investigated the infiltrating lymphocyte populations. Spinal cord and motor cortex of hSOD1 G93A mice showed increased accumulation of CD19 + B cells, CD8 + and CD4 + T cells, with a time dependent reduction of CD8 + T cells at later stages ( Supplementary Fig.…”

Section: Nk Cell Analyses In Als Patientsmentioning

confidence: 99%

Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis

et al. 2020

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In amyotrophic lateral sclerosis (ALS), immune cells and glia contribute to motor neuron (MN) degeneration. We report the presence of NK cells in post-mortem ALS motor cortex and spinal cord tissues, and the expression of NKG2D ligands on MNs. Using a mouse model of familial-ALS, hSOD1 G93A , we demonstrate NK cell accumulation in the motor cortex and spinal cord, with an early CCL2-dependent peak. NK cell depletion reduces the pace of MN degeneration, delays motor impairment and increases survival. This is confirmed in another ALS mouse model, TDP43 A315T . NK cells are neurotoxic to hSOD1 G93A MNs which express NKG2D ligands, while IFNγ produced by NK cells instructs microglia toward an inflammatory phenotype, and impairs FOXP3 + /Treg cell infiltration in the spinal cord of hSOD1 G93A mice. Together, these data suggest a role of NK cells in determining the onset and progression of MN degeneration in ALS, and in modulating Treg recruitment and microglia phenotype.

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“…According Lyon M et al, "Amyotrophic lateral sclerosis is a severe debilitating pathology characterized by progressive degeneration of motor neurons. Charcot irst described ALS in 1869 1 ; its pathogenesis remains unknown, and the effective treatments remain elusive. New paradigms must be investigated to understand the effectors of ALS, including in lammation, immune responses, and the body's response to stress and to the injury.…”

Section: From Literaturementioning

confidence: 99%

“…While immune system components may indeed play a role in ALS pathogenesis, results to indicate these cell, antibodies, and cytokines are localized to areas of early pathology are limited. We propose more focused studies that examine the role of the immune system with characterized pathogenesis to determine when, where and if immune and in lammatory processes are critical to disease progression, and thus worthy targets of intervention" [1].…”

Section: From Literaturementioning

confidence: 99%

Amyotropyc Lateral Sclerosis and Endogenous -Esogenous Toxicological Movens: New model to verify other Pharmacological Strategies

Luisetto¹

2018

Arch Pathol Clin Res

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In 1874 J.M. Charcot was the fi rst to describe ALS amyotrophic lateral sclerosis, a disease with an high non response therapy rate also to the actual therapy. ALS is not clearly associate to only single etio-patogenetic movens but many process seem involved. Also the strange geographic diffusion of different forms contribute to a complex syndromic pathology. The introducing of new theories and approach can help to fi nd more effi cacy therapeutic strategies. In this work the different neuronal damage movens and new therapeutic strategies are analyzed to produce a Unic global response to the pathologic process useful in next clinical application. Genetic factors must be considered also added to environmental movens but also to the endogenous microenvironment of motoneuron involved. A toxicological-biochemical-imunological approach can be useful tool to fi nd new therapeutic strategies. Or to improve local availability of pharmacological molecules.

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Inflammation, Immunity, and amyotrophic lateral sclerosis: I. Etiology and pathology

Cited by 85 publications

References 148 publications

Peripheral proinflammatory Th1/Th17 immune cell shift is linked to disease severity in amyotrophic lateral sclerosis

Peripheral proinflammatory Th1/Th17 immune cell shift is linked to disease severity in amyotrophic lateral sclerosis

Natural killer cells modulate motor neuron-immune cell cross talk in models of Amyotrophic Lateral Sclerosis

Amyotropyc Lateral Sclerosis and Endogenous -Esogenous Toxicological Movens: New model to verify other Pharmacological Strategies

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