Meningeal inflammation in MS may include B-cell-rich collections of immune cells [97], and secretory products of MS B cells have been shown to be cytotoxic to oligodendrocytes [98]

Meningeal inflammation in MS may include B-cell-rich collections of immune cells [97], and secretory products of MS B cells have been shown to be cytotoxic to oligodendrocytes [98]. relationship to antibody-mediated CNS disorders, paraneoplastic neurological diseases, and multiple sclerosis. New insights into neuroinflammation offer exciting opportunities to investigate potential therapeutic targets for debilitating CNS diseases. == Electronic supplementary material == The online version of this article (doi:10.1007/s13311-015-0385-3) contains supplementary material, which is available to authorized users. Keywords:Central nervous system, immunology, inflammation, microglial cells, B cells, paraneoplastic syndromes, multiple sclerosis. == Introduction == The concept of neuroinflammation has widened over the last few decades to include the response of brain Mmp27 cells toward infections and other causes of cell death, as well as infiltration of the brain and spinal cord by cells of the innate and adaptive immune systems. Thus, neuroinflammation is defined as the response of the reactive central nervous system (CNS) elements to altered homeostasis, whether imposed from inside or outside the CNS, and characterizes all neurological diseases, including developmental, traumatic, ischemic, inflammatory, metabolic, infectious, toxic, neoplastic, and neurodegenerative diseases. Mechanisms reminiscent of neuroinflammation, such as the involvement of complement components and microglia in synapse pruning, also occur in healthy brain development. The CNS inflammatory response is also driven by processes as varied as aging, systemic infection, metabolic syndrome, and intrinsic CNS disease. Microglial cells and infiltrating myeloid cells, astrocytes, oligodendrocytes, and NG2+glia (also termed polydendrocytes or oligodendrocyte progenitor cells), along with the bloodbrain barrier (BBB), cytokines, and cytokine signaling, form the main reactive components of the CNS. Notably, all cells of the CNS appear to have the capacity to contribute to the inflammatory process. Microglial cells enter very early in embryonic development and play crucial roles in normal brain development, brain maintenance over the lifespan of the animal, and disease [13]. The adaptive immune system also affects neuroinflammation. T cells act Pelitinib (EKB-569) in the periphery to initiate immune responses through interactions with antigen-presenting cells (such as dendritic cells). However, no cell exists in the normal brain parenchyma capable of taking up antigen for presentation, exiting the CNS, entering a local lymphatic en route to a lymph node, and initiating an immune response, as is seen in adaptive immune responses elsewhere in the body [46]. This fundamental difference represents the cellular basis of immune privilege of the CNS. Thus, T cells respond in the periphery and traffic to the CNS to respond to disease, as shown in Fig.1[6]. This efferent system by which immune cells respond to an antigen depot in the brain is efficient and implies Pelitinib (EKB-569) immunosurveillance. == Fig. 1. == Central memory T cells of cerebral spinal fluid (CSF) are mediators of central nervous system immune surveillance. FromThe New England Journal of Medicine, Israel F. Charo and Richard M. Ransohoff, The many roles of chemokines and chemokine receptors in inflammation, 354, pages 610621. Copyright 2006. Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society [6]. Central memory CD4+T cells in the cerebral spinal fluid (CSF) carry out immunosurveillance. These cells enter the CSF across the choroid plexus and meningeal veins, and exit in large part via the cribriform plate to the deep cervical lymph nodes, which are accessed via lymphatics in the nasal mucosa [79], or as previously shown by Andres et al. [10] and recently revisited [7]. Immune cells cross the parenchymal BBB only under conditions of pathology and indicate the presence of an immune effector response [9]. Leukocyte migration is also an integral component of many neuroinflammatory reactions but has been only partially characterized. Leukocyteendothelial cell interactions occur in an enormous number of different contexts (physiological, pathological) involving varied cells types and a diversity of vascular beds. This panoply of processes is mediated by molecular combinatorial diversity that includes selectins/carbohydrate ligands; chemokines or other G protein-coupled receptor ligands and their receptors; and integrins/cellular adhesion molecules, with some overlap in trafficking between physiological and pathological processes [11,12]. B cells produce antibodies after injection of antigen into the CNS Pelitinib (EKB-569) [13], indicating that humoral (unlike cellular) adaptive immune reactions can be initiated within the CNS. B cells can differentiate to plasmablasts or plasma cells that produce antibodies with varying functionalities. B cells.