Although the etiology and pathogenesis of ALS is unknown, increasing evidence supports a role for autoimmune mechanisms in motoneuron degeneration and death. An animal model, experimental autoimmune gray matter disease, can be induced by the inoculation of spinal cord gray matter. The experimental disease is characterized by weakness secondary to the loss of upper and lower motoneurons, accompanied by inflammatory foci within the spinal cord, and IgG at the neuromuscular junction and within UMN and LMN. In human ALS, IgG is present within the UMN and LMN, and T-lymphocytes and activated microglia have been identified within spinal cord gray matter and motor cortex. ALS IgG can passively transfer physiological changes of the neuromuscular junction to mice resulting in enhanced release of acetylcholine. The ALS IgG selectively interact with calcium channels and alter channel function. These data suggest a potential role for autoimmune mechanisms in the destruction and loss of motoneurons in ALS.