Death of intermediolateral spinal cord neurons follows selective, complement-mediated destruction of peripheral preganglionic sympathetic terminals by acetylcholinesterase antibodies.
Systemically injected anti-acetylcholinesterase antibodies in rats cause selective lesions of preganglionic sympathetic neurons. Adult rats were examined up to four months after a single i.v. injection of murine monoclonal acetylcholinesterase antibodies or normal immunoglobulin G (1.5 mg). Within 4 h, antibody-treated rats developed ptosis, a sign of sympathetic dysfunction that was never reversed. Persistent pupillary constriction reflected preserved and unopposed parasympathetic function. Weight gain was depressed, but locomotor activity, excitability, and sensorimotor responses were normal, and gross neuromuscular performance was near normal. These findings were supported by biochemical evidence for selective sympathetic damage. Acetylcholinesterase activity was reduced for the whole period of observation in sympathetic ganglia and adrenal glands but fell only transiently in muscle and serum. At all times, choline acetyltransferase activity (a marker of presynaptic terminals) was unaffected in muscle but grossly depleted in ganglia. Light and electron microscopy showed that preganglionic sympathetic terminals of superior cervical ganglia were severely damaged while parasympathetic ganglia were less affected and motor endplates of skeletal muscle were apparently spared. Immunocytochemistry revealed punctate deposits of murine immunoglobulin G and complement component C3 in ganglionic neuropil 12 h after antibody injection. This finding was consistent with complement-mediated lysis of preganglionic terminals. Morphometric analysis of preganglionic neurons in the intermediolateral nucleus of the spinal cord showed progressive loss of cholinergic perikarya over several months. We conclude that antibody-induced destruction of ganglionic terminals leads to death of preganglionic sympathetic neurons and, hence, permanent dysautonomia.
Department of Pharmacology, Mayo Clinic, Rochester, MN 55905.
S
S
Brimijoin
V
V
Moser
P
P
Hammond
N
N
Oka
V A
VA
Lennon
D000110:Acetylcholinesterase / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000276:immunology; D001522:Behavior, Animal / Q000187:drug effects; D015415:Biomarkers; D016923:Cell Death; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003165:Complement System Proteins / Q000502:physiology*; D005728:Ganglia, Sympathetic / Q000473:pathology*; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D009409:Nerve Crush; D009411:Nerve Endings / Q000473:pathology; D009474:Neurons / Q000502:physiology*; D010525:Peripheral Nerves / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000473:pathology*
D000906:Antibodies; D015415:Biomarkers; D007074:Immunoglobulin G; D003165:Complement System Proteins; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase