Neuroimmunology of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that causes a selective, rapidly progressing and irreversible loss of motoneurons. ALS is a non-cell-autonomous disorder, in which neurons do not die alone, but numerous other cell types play critical roles in disease initiation and progression. The pathogenic processes underlying ALS are multifactorial, and different mechanisms of motoneuron injury and death have been proposed, including a dysregulated neuroinflammatory response. The emerging and generally accepted concept is that the immune system, both innate and adaptive, plays early and important neuroinflammatory roles in disease pathophysiology. In ALS, microglial activation, T cell infiltration and astrogliosis and their accompanying molecular signals are pathological hallmarks at sites of motoneuron injury. Such inflammation has been considered the consequence and not the cause of motoneuron injury, and it contributes to the pathology and tissue destruction. However, more recent evidence challenges this belief and suggests that at early phases of disease, the immune system may also contribute to neuroprotective functions. As disease progresses, there is an operational transformation from a supportive regulatory T cell (Treg)-M2 macrophage effect to an injurious Th1-M1 macrophage response, suggesting that at early stages of disease the immune system actively contributes to neuroprotection through its release of cytokines and neurotrophic factors, rendering resident microglia capable of motoneuron maintenance and repair. This chapter will review the proposed mechanisms of neuroinflammation in the context of motoneuron protection and injury based on what occurs in ALS patients and animal models of ALS. The cumulative evidence suggests that inflammation plays a central role in ALS pathology, and manipulating microglial and Treg functions may potentially modify the outcome of this devastating disease. This edition first published 2014