Experimental autoimmune myasthenia gravis: A sequential and quantitative study of the neuromuscular junction ultrastructure and electrophysiologic correlations

Andrew G. Engel, Mitsuhiro Tsujihata, Edward H. Lambert, Jon M. Lindstrom, Vanda A. Lennon

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

Neuromuscular junction ultrastructure in rat forelimb digit extensor muscle was sequentially and quantitatively investigated in experimental autoim-mune myasthenia gravis (EAMG). Experimental animals were immunized with highly purified eel electroplax acetylcholine receptor protein plus com-plete Freund’s adjuvant and B. pertussis vaccine; control animals received only adjuvant and vaccine.During the first 7 days (latent period) after immunization end-plate structure and neuromuscular transmission remained normal in the experimental group. Between day 7 and 11 (acute phase) mononuclear cells infiltrated those regions of muscle where the end-plates were located and there was intensedegeneration of the postsynaptic regions with splitting away of abnormal junctional folds from the underlying muscle fibers. Macrophages entered the gaps thus formed and removed the degenerating folds by phagocytosis. The nerve terminals were displaced from their usual location but maintained their structural integrity. Neuromuscular transmission was blocked in many muscle fibers. Miniature end-plate potentials (MEPPs), detectable in only a few fibers, were of abnormally low amplitude.After day 11 (chronic phase) the nerve terminals returned to the highly simplified postsynaptic regions and the inflammatory reaction subsided. Subsequently the postsynaptic folds became reconstituted and again degenerated. Immature junctions with poorly differentiated postsynaptic regions and nerve sprouts near end-plates were also observed. In two animals relapsing during the chronic phase degeneration of the postsynaptic folds was more intense than in the other chronic-phase animals. The postsynaptic membrane length and length per unit area and the MEPP amplitudes were significantly decreased in all chronic phase animals and the decreases were greater in the relapsing than in the non-relapsing animals. Minor morphometric alterations were also observed in the nerve terminals. These might have been secondary to the postsynaptic changes.The postsynaptic region is the primary target of the autoimmune reaction in EAMG. The ultra structural, morphometric and electrophysiological abnormalities of the end-plate in chronic EAMG resemble those which have been observed in human myasthenia gravis.

Original languageEnglish (US)
Pages (from-to)569-587
Number of pages19
JournalJournal of Neuropathology and Experimental Neurology
Volume35
Issue number5
DOIs
StatePublished - Jan 1 1976

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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