LYMPHOCYTE TARGETING OF THE CENTRAL-NERVOUS-SYSTEM - A REVIEW OF AFFERENT AND EFFERENT CNS-IMMUNE PATHWAYS

The central nervous system (CNS) is considered to be an immunological privileged site. However, inflammatory reactions in response to virus infections, in multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAE) suggest that there are definite connections be tween the CNS and the immune system. In this review, we examine eviden ce for afferent and efferent pathways of communication between the CNS and the immune system, the pivotal role of regional lymph nodes in T- cell mediated autoimmune disease of the CNS, and the factors involved in lymphocyte targeting of the CNS. Afferent pathways of lymphatic dra inage of the brain are well established in a variety of species, espec ially rodents. Fluid and antigens appear to drain along perivascular s paces populated by immunocompetent perivascular cells. Drainage pathwa ys connect directly via the cribriform plate to nasal lymphatics and c ervical lymph nodes. Soluble antigens draining from the brain induce a ntibody production in the cervical lymph nodes. Using a model of cryol esion-enhanced EAE, we review the role of lymphatic drainage and cervi cal lymph nodes in the enhancement of cerebral EAE. If a brain wound i n the form of a cryolesion is produced 8 days post inoculation (dpi) o f antigen in the induction of acute EAE, there is a 6-fold increase in severity of cerebral EAE by 15 dpi. Removal of the cervical lymph nod es significantly reduces such enhancement of EAE. These findings sugge st that drainage of antigens from the brain to the cervical lymph node s, in the presence of activated lymphocytes in the meninges or CNS, re sults in an enhanced second wave of lymphocytes targeting the brain. I n examining the efferent immune pathway by which lymphocytes home to t he CNS, several studies have characterized the phenotype of infiltrati ng T lymphocytes by the use of immunocytochemistry or FAGS analysis. T -cells infiltrating the CNS are recently activated/memory lymphocytes typified by their high expression of CD44, LFA-1 and ICAM-1 and low ex pression of CD45RB in the mouse. Following the induction of EAE in sus ceptible mice, ICAM-1 and VCAM-1 are dramatically upregulated on CNS v essels; lymphocytes bind to such vessels via the interaction of their known ligands, LFA-1/Mac-1 and alpha 4-integrins, at least in vitro. I t appears that alpha 4-integrin plays a key role in lymphocyte recruit ment across the blood-brain barrier and may be a major factor in lymph ocyte targeting of the CNS. Definition of factors involved in the affe rent and efferent connections between the CNS and the immune system ma y clarify mechanisms involved in immune privilege of the CNS and may o pen significant therapeutic opportunities for multiple sclerosis.