Something in the Blood? A history of the autoimmune hypothesis regarding myasthenia gravis.

From the first descriptions of myasthenia gravis (MG) in the late nineteenth century, speculation about the cause of MG has centered on the possibility of some curare-like factor circulating in the blood. The transfer of transient myasthenic symptoms from a myasthenic mother to her newborn reinforced this speculation. However, it was not until 1960, when William Nastuk and coworkers noted that serum complement correlated with the clinical course in MG, and Arthur Strauss and colleagues described antiskeletal muscle antibodies in the sera of some MG patients, that a paradigm shift occurred from prior exclusive focus on the neuromuscular junction to a broader consideration of the relevance of immunological mechanisms in myasthenia. These findings coincided with an even greater scientific revolution pioneered by Macfarlane Burnet towards cell-mediated and away from chemical immunology. The dominant immunological question of the decade 1955-1965, however, was whether human autoimmune diseases actually existed. During the next decade, 1965-1975, various diseases were accepted as being autoimmune in character, and although comparatively rare, MG became prominent among them because of a known antigen, the acetylcholine receptor, and an excellent experimental model.

How electric fish became sources of acetylcholine receptor.

The purpose of this communication is to describe the historical steps by which fish electric organs were eventually determined to be modified motor endplates and therefore a plentiful source of acetylcholine receptor. A brief description of the early history of electric fish concerned with the nature of the discharge will provide the background for studies of the anatomy, embryology, and physiology of electric organs in the nineteenth century that suggested that electric organs were derived from modified muscles. In the twentieth century, transmission between nerve and electric organ was shown to be cholinergic, and because of their size and abundant cholinergic nerve supply, the electric organs of Torpedo and Electrophorus were chosen by biochemists and molecular biologists as possible rich sources of acetylcholine receptor.

A history of treatments for myasthenia gravis.

Much of the improvement in the treatment of myasthenia gravis (MG) over the past 125 years can be attributed to the effectiveness of general medical measures such as advances in respiratory care and the discovery of antibiotics. Although MG became the model of an antibody-mediated autoimmune disease in the 1970s (the most documented antigen being the muscle acetylcholine receptor at the neuromuscular junction), the pathogenesis of MG has not been the rationale for most treatments found to be useful for this disease. The serendipitous benefit of anticholinesterases for MG in the 1930s subsequently focused attention on the neuromuscular junction. The beginnings of the controversy over thymectomy for MG in the 1940s and 1950s preceded the discovery in 1960 of the function of the thymus. Before the autoimmune pathogenesis of MG was known, adrenocorticotropic hormone (ACTH) and steroids for MG were tried for reasons that turned out to be incorrect. Further immunosuppressive treatments for MG were largely empirical, following their use in organ transplantation and other autoimmune diseases. More specific treatments, based on our knowledge of pathogenesis, are still experimental but hopefully will be the history of the future.

Clinical evaluation and management of myasthenia gravis.

Myasthenia gravis (MG) is a syndrome of fluctuating skeletal muscle weakness that worsens with use and improves with rest. Eye, facial, oropharyngeal, axial, and limb muscles may be involved in varying combinations and degrees of severity. Its etiology is heterogeneous, divided initially between those rare congenital myasthenic syndromes, which are genetic, and the bulk of MG, which is acquired and autoimmune. The autoimmune conditions are divided in turn between those that possess measurable serum acetylcholine receptor (AChR) antibodies and a smaller group that does not. The latter group includes those MG patients who have serum antibodies to muscle-specific tyrosine kinase (MuSK). Therapeutic considerations differ for early-onset MG, late-onset MG, and MG associated with the presence of a thymoma. Most MG patients can be treated effectively, but there is still a need for more specific immunological approaches.

The role of Herman Hoppe of Cincinnati in the initial clinical recognition of myasthenia gravis.

One of the earliest papers describing a case of what came to be known as myasthenia gravis was written in 1892 in the German language by an American, Herman Hoppe, who at the time was an assistant in the Berlin polyclinic of the prominent German neurologist. Hermann Oppenheim. At Oppenheim's instigation, Hoppe published the pathology of a case that Oppenheim had diagnosed during life; he collected all the reported similar cases and tried to establish a symptom-complex, for which he was given credit in Oppenheim's great neurology textbook of 1894. Upon his return to Cincinnati, Ohio, Hoppe's European experience qualified him as a specialist in nervous and mental diseases. His private practice of "neuropsychiatry" was his main occupation, but he also volunteered to teach as Professor of Nervous and Mental Diseases at the University of Cincinnati. In 1901 Oppenheim published the first monograph about what he called "Die Myasthenische Paralyse (Bulbarparalyse ohne anatomischen Befund)", summarizing 60 cases described in the medical literature up to that time. Hoppe, on the other hand, wrote on myasthenia gravis only once again, a review article in 1914 in a Cincinnati weekly, giving Oppenheim credit for the establishment of the disease as a clinical entity.

Novel delta subunit mutation in slow-channel syndrome causes severe weakness by novel mechanisms.

We investigated the basis for a novel form of the slow-channel congenital myasthenic syndrome presenting in infancy in a single individual as progressive weakness and impaired neuromuscular transmission without overt degeneration of the motor endplate. Prolonged low-amplitude synaptic currents in biopsied anconeus muscle at 9 years of age suggested a kinetic disorder of the muscle acetylcholine receptor. Ultrastructural studies at 16 months, at 9 years, and at 15 years of age showed none of the typical degenerative changes of the endplate associated with the slow-channel congenital myasthenic syndrome, and acetylcholine receptor numbers were not significantly reduced. We identified a novel C-to-T substitution in exon 8 of the delta-subunit that results in a serine to phenylalanine mutation in the region encoding the second transmembrane domain that lines the ion channel. Using Xenopus oocyte in vitro expression studies we confirmed that the deltaS268F mutation, as with other slow-channel congenital myasthenic syndrome mutations, causes delayed closure of acetylcholine receptor ion channels. In addition, unlike other mutations in slow-channel congenital myasthenic syndrome, this mutation also causes delayed opening of the channel, a finding that readily explains the marked congenital weakness in the absence of endplate degeneration. Finally, we used serial morphometric analysis of electron micrographs to explore the basis for the progressive weakness and decline of amplitude of endplate currents over a period of 14 years. We demonstrated a progressive widening and accumulation of debris in the synaptic cleft, resulting in loss of efficacy of released neurotransmitter and reduced safety factor. These studies demonstrate the role of previously unrecognized mechanisms of impairment of synaptic transmission caused by a novel mutation and show the importance of serial in vitro studies to elucidate novel disease mechanisms.