The immune system and neurodegeneration. Death or damage of neurons can be mediated via several mechanisms in the CNS. Upon insult, healthy neurons become damaged, causing release of self-antigens or modified proteins. These antigens remain in the CNS to activate surrounding resting microglia to an activated phenotype. Reactive microglia produce proinflammatory mediators such as neurotoxic cytokines and reactive oxygen and nitrogen species (ROS/RNS), increase oxidative stress, and further contribute to neuronal damage. Modified and misfolded self-proteins that drain into secondary lymphoid tissues are phagocytized, processed, and presented on MHC by APCs to naïve T cells (N). Upon recognition of antigen, T cells differentiate into antigen-specific T effector (Teff) or T regulatory (Treg) phenotypes. Teff subsets include Th1 (1), Th2 (2), Th9 (9), Th17 (17), Th22 (22), and cytotoxic T lymphocytes (CTLs). Additionally, reactive microglia signal proximal endothelial cells by cytokine and chemokine gradients to upregulate CAMs. In turn, activated Teffs such as Th1 and Th17 with upregulated integrins and CAM ligands bind CAMs via CAM-ligand interactions and extravasate across the BBB. Upon recognition of modified self-antigen presented by MHC of microglia/macrophages, activated Teffs generate neurotoxic and proinflammatory factors that drive M1 microglia or resting microglia to a higher reactive state and support a neurotoxic cascade. CD4+ Th1 or Th17 Teffs induce FAS ligand or produce neurotoxic cytokines such as TNF-α, IL-17, and IFN-γ that may directly interact with cognate receptors expressed by neurons. CD8+ CTLs can recognize antigen/MHC I complexes on neurons to induce perforin- and/or granzyme-mediated cytolysis. In response to inflammatory events, Tregs (R) attempt to counteract the neurotoxic cascade through inhibition of antigen presentation, production of anti-inflammatory cytokines, metabolic disruption, cytolysis of Teffs or reactive microglia, and induction of neurotrophic factors by astrocytes; all mechanisms aim to interdict the neuroinflammatory-neurodegenerative cycle and ultimately support neuronal survival.