With the aid of monoclonal antibodies to brain acetylcholinesterase (AChE), a new autoimmune model of cholinergic dysfunction has been created in rats. One antibody with a surprising tendency to accumulate in the central nervous system (CNS) has the potential to cause widespread abnormalities. It is proposed to study the factors that facilitate the access of this antibody to targets in the brain and to characterize the structural and chemical abnormalities that it mediates there. This work may refine our concepts of the blood brain barrier in relation to immunoglobulins. The experimental system also has the potential to provide data relevant to neurodegenerative diseases of central cholinergic systems, including Alzheimer's disease. Another set of experiments will utilize antibodies that do not have access to ACHE epitopes in the CNS. When injected systemically, these antibodies induce a novel disorder of preganglionic sympathetic nerves but have minimal apparent effects on other cholinergic systems. It is planned to investigate the mechanisms of destruction of the preganglionic sympathetic terminals and to map out the cellular distribution of the immunologic damage. The more modest effects of AChE-antibodies on the motor and parasympathetic nervous systems will also be examined in detail. Special attention will be focused on the factors that prevent a normal regenerative response of sympathetic terminals in antibody treated rats and result in permanent dysautonomia. Finally, attempts will be made to determine which of the several types of human dysautonomias might have a similar autoimmune mechanism.
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