Autoimmunity in Amyotrophic Lateral Sclerosis: Past and Present

Pagani, Mario Rafael; González, Laura; Uchitel, Osvaldo D.

doi:10.1155/2011/497080

Cited by 56 publications

(55 citation statements)

References 143 publications

(198 reference statements)

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“…Likewise, the recent identification of loss-of-function mutations in TBK1, a well-characterized regulator of innate immunity, as a cause of ALS/FTD (18,129,130) further reinforces the concept that immune dysregulation might be a characteristic feature of the disease. Despite the strong case for a connection between ALS/FTD and autoimmunity, there is also convincing evidence against the idea that ALS is itself a classical autoimmune condition, given that administration of immunosuppressive drugs including corticosteroids, azathioprine, and cyclophosphamide (alone or in combination), as well as plasmapheresis or intravenous Igs (IVIGs), has failed to alter the progression of the disease (131)(132)(133)(134)(135)(136)(137). Several reasons have been posited to explain the failure of these drugs to slow disease progression in ALS patients.…”

Section: R E V I E W S E R I E S : G L I a A N D N E U R O D E G E N mentioning

confidence: 99%

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

Lall¹,

Baloh²

2017

Journal of Clinical Investigation

145

102

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Genetic connections between microglia and neurodegenerationMicroglia are the main cells in the CNS responsible for immune surveillance and are critical for normal development and homeostasis (34)(35)(36). Under steady-state conditions, "ramified" microglia continuously survey the local microenvironment for any foreign antigens and insults. The resident microglia are Amyotrophic lateral sclerosis (ALS) is a degenerative disorder that is characterized by loss of motor neurons and shows clinical, pathological, and genetic overlap with frontotemporal dementia (FTD). Activated microglia are a universal feature of ALS/FTD pathology; however, their role in disease pathogenesis remains incompletely understood. The recent discovery that ORF 72 on chromosome 9 (C9orf72), the gene most commonly mutated in ALS/FTD, has an important role in myeloid cells opened the possibility that altered microglial function plays an active role in disease. This Review highlights the contribution of microglia to ALS/FTD pathogenesis, discusses the connection between autoimmunity and ALS/FTD, and explores the possibility that C9orf72 and other ALS/FTD genes may have a "dual effect" on both neuronal and myeloid cell function that could explain a shared propensity for altered systemic immunity and neurodegeneration.

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Section: R E V I E W S E R I E S : G L I a A N D N E U R O D E G E N mentioning

confidence: 99%

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

Lall¹,

Baloh²

2017

Journal of Clinical Investigation

145

102

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“…The pathogenesis of sporadic ALS (˜90% of all ALS cases) remains largely obscure, explaining the absence of effective treatments. ALS can be viewed as a “phenotypic tank” in which groups of pathogenically heterogeneous patients coexist while activation of the immune system during the neurodegeneration process has been observed 2–5. Identifying specific biomarkers might allow subgrouping of ALS patients, early diagnosis, and effective intervention 6…”

Section: Introductionmentioning

confidence: 99%

LRP 4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients

Tzartos

Zisimopoulou

Rentzos

et al. 2013

Ann Clin Transl Neurol

101

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ObjectiveAmyotrophic lateral sclerosis (ALS) and myasthenia gravis (MG) are caused, respectively, by motor neuron degeneration and neuromuscular junction (NMJ) dysfunction. The membrane protein LRP4 is crucial in the development and function of motor neurons and NMJs and LRP4 autoantibodies have been recently detected in some MG patients. Because of the critical role in motor neuron function we searched for LRP4 antibodies in ALS patients.MethodsWe developed a cell-based assay and a radioimmunoassay and with these we studied the sera from 104 ALS patients.ResultsLRP4 autoantibodies were detected in sera from 24/104 (23.4%) ALS patients from Greece (12/51) and Italy (12/53), but only in 5/138 (3.6%) sera from patients with other neurological diseases and 0/40 sera from healthy controls. The presence of LRP4 autoantibodies in five of six tested patients was persistent for at least 10 months. Cerebrospinal fluid samples from six of seven tested LRP4 antibody-seropositive ALS patients were also positive. No autoantibodies to other MG autoantigens (AChR and MuSK) were detected in ALS patients. No differences in clinical pattern were seen between ALS patients with or without LRP4 antibodies.ConclusionsWe infer that LRP4 autoantibodies are involved in patients with neurological manifestations affecting LRP4-containing tissues and are found more frequently in ALS patients than MG patients. LRP4 antibodies may have a direct pathogenic activity in ALS by participating in the denervation process.

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“…[37] Because of the large amount of inflammatory cells infiltrating the CNS during disease progression, it was postulated that, similar to MS, ALS may also be in part an autoimmune disease. [38,39] Several anti-inflammatory and/or immuno-compromising drugs also support the contribution of inflammatory components in the pathogenesis of ALS. While the gene mutation and the resultant protein in MN may mediate a direct toxic effect for neuron, dysfunctional microglial cells and astrocytes with gene mutations may also contribute to neuronal death.…”

Section: Immune Dysfunction In Alsmentioning

confidence: 99%

How are necroptosis, immune dysfunction, and motoneuron death connected in amyotrophic lateral sclerosis?

Liu¹,

Zheng²,

Xin³

et al. 2017

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How to cite this article: Liu JF, Zheng OX, Xin JG, Chen HH, Xin JJ. How are necroptosis, immune dysfunction, and motoneuron death connected in amyotrophic lateral sclerosis ? Neuroimmunol Neuroinflammation 2017;4:109-16. Abnormal immune response/inflammation is present in patients of amyotrophic lateral sclerosis (ALS). Autoimmune-related inflammation has been thought to be involved in the pathogenesis of ALS. However, how the abnormal immune responses are initiated, what specific immune cells and how these immune cells are involved in this disease have not been well understood. This is partly owing to two facts of ALS: late diagnosis and chronic nature. The late diagnosis makes it difficult to conclude whether the abnormal immune responses/inflammation is the cause or result of the disease. The chronic nature makes it difficult to determine the best timing for the detection of such autoimmune responses. To resolve these two challenges for research, the authors introduced motor nerve injury (facial nerve axotomy, FNA) into a pre-symptomatic mouse ALS model (8-week-old SOD1 G93A mice), which induces a readily detectable immune response in a predictable time period (3-14 days). The authors found that pre-symptomatic SOD1 G93A mice showed a higher basal level of T cell activation and Th17 cells than WT mice, which can be further increased by FNA. However, why these pro-inflammatory Th lymphocyte MinireviewThis is an open access article distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

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Autoimmunity in Amyotrophic Lateral Sclerosis: Past and Present

Cited by 56 publications

References 143 publications

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

LRP 4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients

How are necroptosis, immune dysfunction, and motoneuron death connected in amyotrophic lateral sclerosis?

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