Involvement of Immune Response in the Pathogenesis of Amyotrophic Lateral Sclerosis: A Therapeutic Opportunity?

Abstract

The immune system has been found to be involved with positive and negative effects in the nervous system of amyotrophic lateral sclerosis (ALS) patients. In general, T cells, B cells, NK cells, mast cells, macrophages, dendritic cells, microglia, antibodies, complement and cytokines participate in limiting damage. Several mechanisms of action, such as production of neurotrophic growth factors and interaction with neurons and glial cells, have been shown to preserve these latter from injury and stimulate growth and repair. The immune system also participates in proliferation of neural progenitor stem cells and their migration to sites of injury and this activity has been documented in various neurologic disorders including traumatic injury, ischemic and hemorrhagic stroke, multiple sclerosis, infection, and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease and ALS). Many therapies have been shown to stimulate the protective and regenerative aspects of the immune system in humans, such as intravenous immunoglobulins, and other experimental interventions such as vaccination, minocycline, antibodies and neural stem cells, have shown promise in animal models of ALS. Consequently, several immunosuppressive and immunomodulatory therapies have been tried in ALS, generally with no success, in particular intravenous immunoglobulins. The multiple aspects of the immune response in ALS are beginning to be appreciated, and their potential as pharmacologic targets in neurologic disease is being explored.

Identification of Epigenetically Altered Genes in Sporadic Amyotrophic Lateral Sclerosis

“…3). This suggests a role for epigenetic regulation in molecular mechanisms known to drive sALS pathogenesis [16]–[18]. Furthermore, the identified DMGs included previously reported epigenetically regulated genes such as runt-related transcription factor 3 ( RUNX3 ), TNF-related apoptosis-inducing ligand ( TRAIL/TNFSF10 ), H19, neuritin 1 ( NRN1) and signal transducer and activator of transcription 5A ( STAT5A) [19]–[23], validating our approach.…”

Amyotrophic Lateral Sclerosis, 2016: existing therapies and the ongoing search for neuroprotection

“…Other immunomodulatory drugs have been tested in ALS 160,161 . A multicenter phase II/III RCT of masitinib (4.5 or 3 mg/kg/day) with concomitant riuzole given over 48 weeks has started.…”

The Role of TNF-Alpha in ALS: New Hypotheses for Future Therapeutic Approaches

“…Inflammation is one of the aspects of the innate immune response. Interactions between innate immune system, brain and neurodegenerative diseases are known (Ghezzi et al, 1998;Gowing et al, 2006) and it has been reported that mast cells, macrophages, dendritic cells, microglia, complement and cytokines participate in limiting the damage (Calvo et al, 2010). Innate system was found activated in central and in peripheral system of ALS patients (Chandels et al, 2001;Elliott et al, 2001;Sta et al, 2011).…”

“…Through such processes, microglia releases reactive oxygen species, proinflammatory cytokines, complement factors, and neurotoxic molecules, leading to further neuronal dysfunction and death (Heneka et al, 2011;Lasiene et al, 2011). In addition, the implication of the peripheral system and its participation in the cellular mechanisms that direct to neurodegeneration, as white blood cells, is well documented (Calvo et al, 2010;Ghezzi et al, 1998;Gowing et al, 2006). Many data from autoptic spinal cord and blood examinations of the ALS patients, animal and cellular models support an immune system involvement in ALS pathogenesis.…”