12 Chapter 1 Table 1. Current and predicted incidence of neuroinflammatory diseases (continued) Disease (Proposed) Aetiology Innate immune response involvement Adaptive immune response involvement Incidence % or number/ 100000 Predicted change in prevalence Ref Autism Genetic / Environmental ↑proinflammatory cytokines ↓T-cells 425-760 variable 23-25 Depression Multifactorial e.g. genetics, hormonal Microglial activation, ↑ cytokines, ↑chemokines ↑ T-reg cells 3% ↑ 26-28 Schizophrenia Multifactorial Microglial activation, ↑ROS, ↑proinflammatory cytokines, ↑chemokines, ↑TLRs, ↓NK cells not reported 18.5 not reported 29-31 Bipolar disorder Genetic / Environmental Microglial activation, ↑proinflammatory cytokines, ↑complement, ↑TNF-α ↑T-cell activation 2.4% debated 32-34 Abbreviations: AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; APP, amyloid-β precursor protein; CD, cluster of differentiation; CNS, central nervous system; FUS, Fused in Sarcoma; HD, Huntington’s disease; HIV/AIDS, human immunodeficiency virus/acquired immunodeficiency syndrome; HSP, heat shock protein; IFN, interferon, IL, interleukin; MS, multiple sclerosis; NK, natural killer; PD, Parkinson’s disease; PML, progressive multifocal leukoencephalopathy; ROS, reactive oxygen species; SMA, spinal muscular atrophy; SOD1, superoxide dismutase 1; SMN, Survival of Motor Neuron protein; SN, substantia nigra; TBI, traumatic brain injury; TDP, TAR DNA-binding protein 43 kDa; TLR, toll-like receptor; TNF, tumor necrosis factor. Neuroimmune privilege and CNS barriers The concept of immune privilege originated from Sir Peter Medawar’s studies in the mid20th century showing that tissue grafts in the CNS were not rejected. It also takes into account the presence of the BBB which was revealed by Paul Ehrlich’s studies in the late 1800s showing that solutes and molecules were excluded from the brain. However, it is now clear that entry of compounds into the CNS occurs via capillary venules, while cell migration occurs at the post-capillary venules and is controlled by adhesion molecules, cytokines, and chemokines35. Anatomically, the CNS is separated by three barriers: the BBB/blood spinal cord barrier (BSCB), the blood-cerebrospinal fluid barrier (BCSFB) at the choroid plexus (CP), and the arachnoid barrier. Differences in the structure of the BBB and BSCB, as well as differences in the cranial and spinal meninges, in white and grey matter, and other regional differences may explain the differential susceptibility of anatomical regions to neuroinflammatory events. For example, the BSCB has reduced levels of ZO-1, occludin, VE cadherin and P-gp (p-glycoprotein), and fewer pericytes than the BBB36, indicating that the spinal cord may well be more susceptible to inflammatory insults than the brain. The presence of barriers originally explained why CNS antigens in the brain were ignored by the peripheral immune response. However, this dogma has been challenged recently by the identification of the glymphatic system37 and rediscovery of lymphatic vessels in the dura mater38,39 that are crucial to clear waste products such as Aβ peptides and tissue debris that accumulate during disease. Dysfunction of these barriers is well known to occur in neuroinflammatory disorders including MS, Parkinson’s disease (PD), Alzheimer’s disease (AD), stroke, epilepsy and traumatic brain injury (TBI)40 and is associated with activated endothelial cells that display an altered pheno-
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