Basic aspects of neuroimmunology as they relate to immunotherapeutic targets: present and future prospects.

The neurological diseases with definite or putative immune pathogenesis include myasthenia gravis; Lambert-Eaton myasthenic syndrome; IgM monoclonal anti-myelin-associated glycoprotein-associated demyelinating polyneuropathy; Guillain-Barré syndrome; chronic inflammatory demyelinating polyneuropathy; multifocal motor neuropathy with or without GM1 antibodies; multiple sclerosis; inflammatory myopathies; stiff-man syndrome; autoimmune neuromyotonia; paraneoplastic neuronopathies and cerebellar degeneration; and neurological diseases associated with systemic autoimmune conditions, vasculitis, or viral infections. The events that lead to these autoimmune diseases are not clear but the following sequential steps are critical: (a) the breaking of tolerance, a process in which cytokines, molecular mimicry, or superantigens may play a role in rendering previously anergic T cells to recognize neural autoantigens; (b) antigen recognition by the T-cell receptor complex and processing of the antigen via the major histocompatibility complex class I or II; (c) costimulatory factors especially B7 and B7-binding proteins (CD28, CTLA-4) and intercellular adhesion molecule (ICAM)-1 and its leukocyte function-associated (LFA)-1 ligand; (d) traffic of the activated T cells across the blood-brain or blood-nerve barrier via a series of adhesion molecules that include selectins, leukocyte integrins (LFA-1, Mac-1, very late activating antigen [VLA]-4) and their counterreceptors (ICAM-1, vascular cell adhesion molecule [VCAM]) on the endothelial cells; and (e) tissue injury when the activated T cells, macrophages, or specific autoantibodies find their antigenic targets on glial cells, myelin, axon, calcium channels, or muscle. In designing specific immunotherapy, the main players involved in every step of the immune response need to be considered. Targets for specific therapy in neurological diseases include agents that (a) interfere or compete with antigen recognition or stimulation, (b) inhibit costimulatory signals or cytokines, (c) inhibit the traffic of the activated cells to tissues, and (d) intervene at the antigen recognition sites in the targeted organ. The various immunomodulating procedures and immunosuppressive drugs currently used for nonselective neuroimmunotherapy are discussed in the context of their interference with the above-described immune mediators.