Abstract
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that is defined by loss of upper and lower motor neurons, associated with accumulation of protein aggregates in cells. There is also pathology in extra-motor areas of the brain, Possible causes of cell death include failure to deal with the aggregated proteins, glutamate toxicity and mitochondrial failure. ALS also involves abnormalities of metabolism and the immune system, including neuroinflammation in the brain and spinal cord. Strikingly, there are also abnormalities of the peripheral immune system, with alterations of T lymphocytes, monocytes, complement and cytokines in the peripheral blood of patients with ALS. The precise contribution of the peripheral immune system in ALS pathogenesis is an active area of research. Although some trials of immunomodulatory agents have been negative, there is strong preclinical evidence of benefit from immune modulation and further trials are currently underway. Here, we review the emerging evidence implicating peripheral immune alterations contributing to ALS, and their potential as future therapeutic targets for clinical intervention.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, defined by the presence of muscle weakness and the progressive death of upper and lower motor neurons [1]
Calculations suggest that 61% of the variance in risk of developing ALS is due to genetic factors [16], which means that ∼40% of the variance in risk is due to non-genetic factors, which could include environmental exposures
Passive transfer leads to motor neurone degeneration Lack of C5a is protective in animal model Mixed effects on motor neuron survival, depending on receptor Blocking Interleukin 1 (IL-1) led to prolonged survival in animal model of ALS Treatment with IL33 reduced disease in animal model of ALS Genetic variation of Interleukin 6 (IL-6) receptor influences the severity of ALS
Summary
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that is defined by loss of upper and lower motor neurons, associated with accumulation of protein aggregates in cells. There is pathology in extra-motor areas of the brain, Possible causes of cell death include failure to deal with the aggregated proteins, glutamate toxicity and mitochondrial failure. ALS involves abnormalities of metabolism and the immune system, including neuroinflammation in the brain and spinal cord. There are abnormalities of the peripheral immune system, with alterations of T lymphocytes, monocytes, complement and cytokines in the peripheral blood of patients with ALS. The precise contribution of the peripheral immune system in ALS pathogenesis is an active area of research. We review the emerging evidence implicating peripheral immune alterations contributing to ALS, and their potential as future therapeutic targets for clinical intervention
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