Interleukin‐12 and interferon‐γ are not detectable in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis

Ford, Lara S.; Rowe, Dominic B.

doi:10.1080/14660820410019125

Cited by 12 publications

(8 citation statements)

References 6 publications

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“…Thus, thymic defects, resulting in reduced T‐cell availability, might be a factor in the limited ability to recruit the peripheral blood‐borne monocytes required for regulating the local microglial response and for restoration of homeostasis. This distinctive contribution to the ALS pathology of the peripheral immune deficit and the local cytotoxic immune activation in the spinal cord, is in line with previous studies demonstrating increased levels of pro‐inflammatory cytokines in the CSF of ALS patients [69], whereas the T‐cell associated cytokine IFN‐γ could not be detected [70]. The necessity for T‐cell support for controlling the local inflammation in the diseased spinal cord is also consistent with the detrimental effect of treating ALS patients with the immunosuppressive drug, minocycline [71], or of frequent treatment of mSOD1 mice with adjuvant‐free glatiramer acetate (Copaxone) [72], a regimen that suppresses peripheral immunity in multiple sclerosis [73].…”

Section: Discussionsupporting

confidence: 90%

Thymic involution, a co‐morbidity factor in amyotrophic lateral sclerosis

Seksenyan

Ron-Harel

Azoulay

et al. 2009

J Cellular Molecular Medi

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Amyotrophic lateral sclerosis (ALS) is a devastating disease, characterized by extremely rapid loss of motor neurons. Our studies over the last decade have established CD4+ T cells as important players in central nervous system maintenance and repair. Those results, together with recent findings that CD4+ T cells play a protective role in mouse models of ALS, led us to the current hypothesis that in ALS, a rapid T-cell malfunction may develop in parallel to the motor neuron dysfunction. Here, we tested this hypothesis by assessing thymic function, which serves as a measure of peripheral T-cell availability, in an animal model of ALS (mSOD1 [superoxide dismutase] mice; G93A) and in human patients. We found a significant reduction in thymic progenitor-cell content, and abnormal thymic histology in 3–4-month-old mSOD1 mice. In ALS patients, we found a decline in thymic output, manifested in the reduction in blood levels of T-cell receptor rearrangement excision circles, a non-invasive measure of thymic function, and demonstrated a restricted T-cell repertoire. The morbidity of the peripheral immune cells was also manifested in the increase of pro-apoptotic BAX/BCXL2 expression ratio in peripheral blood mononuclear cells (PBMCs) of these patients. In addition, gene expression screening in the same PBMCs, revealed in the ALS patients a reduction in key genes known to be associated with T-cell activity, including: CD80, CD86, IFNG and IL18. In light of the reported beneficial role of T cells in animal models of ALS, the present observation of thymic dysfunction, both in human patients and in an animal model, might be a co-pathological factor in ALS, regardless of the disease aetiology. These findings may lead to the development of novel therapeutic approaches directed at overcoming the thymic defect and T-cell deficiency.

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Section: Discussionsupporting

confidence: 90%

Thymic involution, a co‐morbidity factor in amyotrophic lateral sclerosis

Seksenyan

Ron-Harel

Azoulay

et al. 2009

J Cellular Molecular Medi

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“…For example, increased TNF␣ in the serum and CSF of ALS patients and mouse models has been correlated with the severity of disease (41)(42)(43). Similarly, enhanced IL-6 production in the serum and CSF has also been noted in ALS patients (44 -46), but others have also noted no differences (47,48). We hypothesized that enhanced production of these proinflammatory cytokines by SOD1 G93A -expressing glial cells might be linked to ROS production and the mechanism of neuronal cell death in co-culture.…”

Section: Enhanced Production Of Tnf␣ But Not Il-6 By Sod1mentioning

confidence: 99%

Alsin and SOD1G93A Proteins Regulate Endosomal Reactive Oxygen Species Production by Glial Cells and Proinflammatory Pathways Responsible for Neurotoxicity

Spencer

Pantazis

et al. 2011

Journal of Biological Chemistry

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Recent studies have implicated enhanced Nox2-mediated reactive oxygen species (ROS) by microglia in the pathogenesis of motor neuron death observed in familial amyotrophic lateral sclerosis (ALS). In this context, ALS mutant forms of SOD1 enhance Rac1 activation, leading to increased Nox2-dependent microglial ROS production and neuron cell death in mice. It remains unclear if other genetic mutations that cause ALS also function through similar Nox-dependent pathways to enhance ROS-mediate motor neuron death. In the present study, we sought to understand whether alsin, which is mutated in an inherited juvenile form of ALS, functionally converges on Rac1-dependent pathways acted upon by SOD1G93A to regulate Noxdependent ROS production. Our studies demonstrate that glial cell expression of SOD1 G93A or wild type alsin induces ROS production, Rac1 activation, secretion of TNF␣, and activation of NFB, leading to decreased motor neuron survival in co-culture. Interestingly, coexpression of alsin, or shRNA against Nox2, with SOD1 G93A in glial cells attenuated these proinflammatory indicators and protected motor neurons in co-culture, although shRNAs against Nox1 and Nox4 had little effect. SOD1G93A expression dramatically enhanced TNF␣-mediated endosomal ROS in glial cells in a Rac1-dependent manner and alsin overexpression inhibited SOD1 G93A -induced endosomal ROS and Rac1 activation. SOD1 G93A expression enhanced recruitment of alsin to the endomembrane compartment in glial cells, suggesting that these two proteins act to modulate Nox2-dependent endosomal ROS and proinflammatory signals that modulate NFB. These studies suggest that glial proinflammatory signals regulated by endosomal ROS are influenced by two gene products known to cause ALS.Amyotrophic lateral sclerosis (ALS) is a lethal degenerative neurological disorder characterized by progressive degeneration of motor neurons in the brain and spinal cord (1, 2). The majority of ALS patients have onset of disease between 40 and 50 years of age and about 50% of patients die within 3 years. The majority of ALS cases are categorized as sporadic with no family history of disease. In this context, the causative genes and environmental factors that initiate the disease process remain poorly defined. Only ϳ10% of ALS cases have a clearly inherited genetic component and hence are classified as familial ALS (1, 2).The best-characterized forms of familial ALS include those caused by mutations in the gene encoding Cu/Zn-superoxide dismutase (SOD1) 2 (3). Approximately 20% of familial ALS cases are caused by a variety of dominant SOD1 mutations (1, 3). There remains great uncertainty as to the primary mechanism(s) by which mutant SOD1 leads to pathology observed in ALS (1, 4). Proposed mechanisms include toxicity associated with misfolding of mutant SOD1, such as ER stress and inhibition of the proteasome, enhanced proinflammatory ROS production, altered axonal transport, excitotoxicity caused by glutamate mishandling, and mitochondrial damage (1, 4). Relevant to the studi...

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“…Recent findings suggest that glial cells (astrocytes and microglia) play a role in motor neuron degeneration [5][6][7] . Although contrasting results have been reported as to cytokine levels in the cerebrospinal fluid or plasma of ALS patients, high concentrations of IL-6, TNF and MCP-1 suggest a neuroinflammatory component [8][9][10][11][12][13][14][15][16] . Inflammation has been implicated in the pathogenesis of many neurodegenerative diseases, and the presence of chemokine receptors has been described in the central nervous system (CNS) [for review see, 17] .…”

Section: Introductionmentioning

confidence: 99%

Chemokine MIP-2/CXCL2, Acting on CXCR2, Induces Motor Neuron Death in Primary Cultures

Paola

Buanne

Biordi

et al. 2007

Neuroimmunomodulation

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Objectives: Chemokines are implicated in many diseases of the central nervous system (CNS). Although their primary role is to induce inflammation through the recruitment of leukocytes by their chemotactic activity, they may also have direct effects on neuronal cells. We evaluated the expression of CXCR1 and CXCR2 and investigated the effect of CXCR2 activation by the agonist MIP-2 (CXCL2) on primary cultured motor neurons. To specifically assess the role of CXCR2 in the neurotoxicity induced by MIP-2, we used the CXCR1/2 inhibitor reparixin and studied the effect of the chemokine on motor neuron cultures from CXCR2-deficient mice. Methods: Primary motor neurons prepared from rat or mouse embryos were treated with MIP-2 and reparixin. Motor neuron viability and receptor expression were assessed by immunocytochemical techniques. Results: Rat primary motor neurons expressed CXCR2 receptors and recombinant rat MIP-2 induced dose-dependent neurotoxicity. This neurotoxicity was counteracted by reparixin, a specific CXCR1/2 inhibitor, and was not observed in motor neurons from CXCR2-deficient mice. Conclusions: CXCR2 activation might directly contribute to motor neuron degeneration. Thus, chemokines acting on CXCR2, including IL-8, may have direct pathogenic effects in CNS diseases, independent of the induction of leukocyte migration.

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Interleukin‐12 and interferon‐γ are not detectable in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis

Cited by 12 publications

References 6 publications

Thymic involution, a co‐morbidity factor in amyotrophic lateral sclerosis

Thymic involution, a co‐morbidity factor in amyotrophic lateral sclerosis

Alsin and SOD1G93A Proteins Regulate Endosomal Reactive Oxygen Species Production by Glial Cells and Proinflammatory Pathways Responsible for Neurotoxicity

Chemokine MIP-2/CXCL2, Acting on CXCR2, Induces Motor Neuron Death in Primary Cultures

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