The immunological microenvironment in the CNS: implications on neuronal cell death and survival

Microenvironmental factors have a profound influence on resident cell populations and their ability to modulate an immune response. The unique central nervous system (CNS) microenvironment has important effects in this regard, resulting in the establishment of immune privilege. The immune response in the CNS is under tight control of bipolar regulatory mechanisms. Neurons have a suppressive potential, which prevents and limits the formation of inflammatory responses. In contrast, activated lymphocytes, which can invade the CNS, deposit potentially pro-inflammatory mediators. The balance between pro- and anti-inflammatory factors determines localization, intensity and course of immune responses in the brain. Thus, an overwhelming invasion of activated lymphocytes, which may have emerged from a recent anti-microbial immune response, may create inflammation in intact parts of the CNS. In contrast, in compromised brain areas, much weaker proinflammatory forces are required to create the same effect. Thus, in degenerative brain lesions, inflammatory infiltrates may be formed easily. Immune cell invasion and expression of immune effector molecules in degenerative CNS disease could exert a variety of actions on the neurons. In the first instance, activation of the local immune response could be harmful to resident brain cells, possibly resulting in neuronal cell death. Alternatively, immune cell-derived mediators could protect and support the regeneration of damaged neurons. Recently, it has been realized that normal inflammatory cells (lymphocytes and macrophages) produce neurotrophic factors. In addition, pro-inflammatory cytokines released by invading immune cells may have a role in neuroprotection. Infiltration of degenerative brain areas by inflammatory cells could thus reflect a beneficial process encouraging neuronal survival and local cell regeneration.