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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by a progressive death of motor neurons for which there is no cure or effective treatment. The cause of ALS and the specific mechanisms of neuronal death remain unknown. However, considerable evidence supports the existence of autoimmune mechanisms contributing to pathogenesis in ALS, including biochemical, morphological, pharmacological, and physiological studies performed in animal models, cell culture, or with ex vivo preparations (1–6). Typical hallmarks of autoimmunity, such as circulating immune complexes, higher frequency of a particular histocompatibility type, or association with other autoimmune diseases, have also been reported (7, 8). An important marker of autoimmunity is the degree of T-lymphocytic infiltration in the anterior horn of the spinal cord from ALS patients (9, 10). Using monoclonal antibodies against T-cells, B-cells, and macrophages, almost 80% of the specimens show a cellular mononuclear infiltration. The cellular composition of the spinal cord inflammation consists of subsets of suppressor or cytotoxic T-cells and macrophages in the anterior and lateral corticospinal tracts and anterior horns (10). T-helper cells are also observed in proximity to corticospinal tract degeneration (11). Hence, inflammation in ALS spinal cord and brain appears to be primarily due to T-cells and macrophages (12), and aberrant macrophage activity is believed by many investigators to contribute to the pathology underlying ALS. This may explain the recent promising results of an ALS phase 2 clinical trial of NP001, a regulator of inflammatory macrophage activity (13). Although the predefined endpoints in this study did not reach statistical significance, administration of NP001 was associated with cessation in disease progression in 27% of patients, approximately 2.5 times greater than the percentage in patients on placebo. Two major plasma markers of inflammation, interleukin-18 (IL-18) and lipopolysaccharide (LPS), differentiated NP001 responders from non-responders, suggesting that the subgroup of patients with greater baseline biomarkers of neuroinflammation experienced the most benefit (13). Additional evidence pointing toward pathologic involvement of autoimmune processes has been the finding that immunoglobulins from ALS patients have been shown to cause apoptosis of motor neurons in primary spinal cord cultures (14) and that passive transfer of immunoglobulins to mice caused abnormalities at motor end-plates and degeneration of motor neurons (4, 15). These findings suggest that antibodies can contribute to disease pathogenesis. Increased levels of interleukins IL-17 and IL-23 have also been found in serum and cerebrospinal fluid of ALS patients (16). This increment is thought to be a sign of T-helper 17 (Th17) activation, a subset of T-cells suggested to be crucial in destructive autoimmunity. Astrocytes have also been shown to participate in the pathogenesis of ALS by producing a microenvironment toxic to motor neurons through increased neuroinflammation, oxidative damage, and glutamate excitotoxicity (17, 18). Overactivated astroglia produce high levels of protein S100B and other proinflammatory factors, which exacerbate neuroinflammation. The extracellular effects of S100B vary, depending on the concentration attained; at nanomolar concentrations, S100B is trophic to neurons, but at micromolar concentrations, S100B causes neuronal apoptosis (19, 20). Many of the effects of S100B on neurons are transduced by the receptor for advanced glycation end-products (RAGE), which participates in the pathophysiology of brain inflammatory disorders by regulating several inflammation-related events, including activation and migration of microglia and neutrophils to inflammatory sites (19–21). Extravasation of S100B into the systemic circulation can also trigger a pathologic autoimmune reaction with circulating antibodies that may re-enter the CNS to initiate an autoimmune response (22). Hence, S100B can be viewed as an astrocytic endokine that can act as an immunoregulator to participate in inflammation and autoimmunity. Additional support for the autoimmune pathogenesis hypothesis is the finding that ALS has recently been included in the spectrum of neurologic manifestations associated with voltage-gated potassium channel (VGKC) autoimmunity (23–25).

Immunoablation and Stem Cell Transplantation in Amyotrophic Lateral Sclerosis: The Ultimate Test for the Autoimmune Pathogenesis Hypothesis