The immune system is inextricably linked with many neurodegenerative diseases 
including amyotrophic lateral sclerosis (ALS), a devastating neuromuscular 
disorder affecting motor cell function with an average survival of 3 years from 
symptoms onset. In ALS, there is a dynamic interplay between the resident innate 
immune cells, that is, microglia and astrocytes, which may become progressively 
harmful to motor neurons. Although innate and adaptive immune responses are 
associated with progressive neurodegeneration, in the early stages of ALS immune 
activation pathways are primarily considered to be beneficial promoting neuronal 
repair of the damaged tissues, though a harmful effect of T cells at this stage 
of disease has also been observed. In addition, although auto-antibodies against 
neuronal antigens are present in ALS, it is unclear whether these arise as a 
primary or secondary event to neuronal damage, and whether the auto-antibodies 
are indeed pathogenic. Understanding how the immune system contributes to the 
fate of motor cells in ALS may shed light on the triggers of disease as well as 
on the mechanisms contributing to the propagation of the pathology. Immune 
markers may also act as biomarkers while pathways involved in immune action may 
be targets of new therapeutic strategies. Here, we review the modalities by 
which the immune system senses the core pathological process in motor neuron 
disorders, focusing on tissue-specific immune responses in the neuromuscular 
junction and in the neuroaxis observed in affected individuals and in animal 
models of ALS. We elaborate on existing data on the immunological fingerprint of 
ALS that could be used to identify clues on the disease origin and patterns of 
progression.