Letter to the editor: autoimmune pathogenic mechanisms in amyotrophic lateral sclerosis

The innate immune system may affect the function and survival of motor neurons in ALS by at least three mechanisms. First, there is evidence to suggest that aggregates of mutant SOD1—which is derived from microglial and astroglial cells—activate neighbouring microglia by binding to TLR2, TLR4, and CD14, and subsequently promote neuronal cell death [9]. Second, the release of pro- inflammatory cytokines may drive motor neuron damage. Third, although poorly understood, a mechanism has been suggested on the basis of the functional analysis of microglial cells that express mutant SOD1 [10]. These cells showed impaired overall motility and a reduced capacity to clear neuronal cell debris. Impairment of microglial cell phagocytosis may therefore contribute to the accumulation of further immunostimulatory proteins, including mutant SOD1, chromogranin A, and dsRNA, thereby resulting in disease progression.