The role of innate and adaptive immunity in Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is an adult-onset, neurodegenerative disorder characterized by loss of upper and lower motor neurons, leading to paralysis and death usually within 2-5 years. ALS is the most common motor neuron disease, with a prevalence of 5 in 100,000 individuals. At present, the etiology of disease remains unelucidated and there are no effective treatments for ALS. The most common form of familial ALS is linked to mutations in the antioxidant enzyme Cu/Zn superoxide dismutase-1 (SOD1). Transgenic mice expressing mutant SOD1 alleles develop late-onset motor neuron degeneration resembling ALS. Activated cellular and molecular components of the immune system are present in the central nervous system (CNS) of patients and mutant SOD 1 transgenic mice, but the role of neuro-inflammation in pathogenesis is not well characterized.;This dissertation focuses on defining the activation and function of the immune system in the mutant SOD1G93A transgenic mouse model of ALS. Investigating the neuro-inflammatory response in the CNS, we found significant infiltration of adaptive immune CD4+ and CD8+ T cells during disease progression. Expression profiling of microglia revealed concurrent upregulation of dendritic cell receptors and neurotrophic factors. Spinal cord leukocytes secreted the Th2 cytokine, IL-4, which polarized microglia to a neuroprotective phenotype. On a T cell deficient background, mutant SOD1 disease phenotype was significantly accelerated. These data demonstrate a surprising, neuroprotective role for adaptive immunity in ALS.;In mutant SOD1 spinal cord, we found upregulation of several components of the humoral complement system. To investigate the classical and lectin complement pathways, the mutant SOD 1 transgene was bred onto a C4 deficient background. Absence of C4 led to a specific decrease in microglia activation, but did not lead to a change in motor phenotype.;Finally, we investigated the role of neuro-inflammation in the peripheral nervous system of mutant SOD1 mice. We found progressive infiltration and activation of macrophages, which is partially mediated by deposition of antibodies and complement. Therefore, inflammatory activation occurs throughout the nervous system of ALS transgenic mice and immunity modulates the response to motor neuron injury, leading to functional consequences for disease progression.