Inflammation in the nervous system. Basic mechanisms and immunological concepts.

The basic questions in the pathogenesis of inflammation in the nervous system are how inflammatory cells reach the brain, where they recognize their antigen, how the nervous system interacts with local immune regulation in the lesion, and how inflammatory cells induce irreversible tissue damage. These questions have been addressed by studying the pathogenesis of experimental models of encephalomyelitis. The minimal requirement to start brain inflammation is the presence of activated circulating T-cells directed against a brain antigen and of antigen presenting cells in meninges and perivascular spaces of the nervous system. Such a constellation, however, only results in the disease after hypersensitization, i.e. in the presence of very high numbers of circulating autoreactive T-cells. Other local and systemic immunological factors may profoundly lower the threshold for the induction of brain inflammation. They include antigen recognition on cells in the brain parenchyma (microglia, astroglia), local upregulation of MHC antigens and possibly adhesion molecules (by cytokines or as a consequence of brain injury) and the presence of additional humoral immune responses against brain antigens (autoantibodies). Focal production of cytokines by inflammatory cells as well as by resident cells of the brain plays an important role in determining the activity of the inflammatory process and in inducing effector cells and inflammatory mediators, responsible for tissue destruction. Whereas in pure T-cell mediated auto-immune encephalomyelitis these activated effector mechanisms have low selectivity and mainly induce a "bystander" damage of CNS tissue, additional presence of autoantibodies may focus the immune reaction to specific targets, thus inducing, in high sensitivity, very selective tissue destruction. The present experimental data suggest that different immunological pathways may finally lead to quite similar inflammatory demyelinating lesions. Thus, brain lesions in individual multiple sclerosis patients may develop on a quite diverse immunological background.