Myoid cells and myasthenia gravis: A phylogenetic overview

DEVELOPMENTAL AND COMLPARATIVE IMd~UNOLOGY, Vol. 4, pp. 385-394, 1980. 0145-305X/80/030385-IOS02.00/0 Printed in the USA. Copyright (c) 1980 Pergamon Press Ltd. All rights reserved.

MYOID

CELLS AND MYASTHENIA GRAVIS: A PHYLOGENETIC OVERVIEW

J.

JAMES

RIMMER

Department of Biological Sciences, University of Aston in Birmingham, Gosta Green, BIRMINGHAM B4 7ET. U.K.

The occurrence of myoid or muscle-like cells in thymic tissue appears to be widespread throughout the vertebrate sub-phylum. The ubiquity of such cells in the thymus raises interesting questions about the significance of muscle in this apparently unusual location. Although first described some 90 years ago the biological importance of myoid cells remains enigmatic. Recently however, myoid cells have been implicated in the aetiology of the neuromuscular disorder myasthenia gravis, a crippling disease syndrome manifested by weakness and fatiguability of voluntary muscles. The present article presents a brief phylogenetic overview of myoid cells and myasthenia gravis, and examines the proposed relationship between the two. As long ago as 1888,1ight microscope studies of amphibian thymus revealed the presence of large concentrically striated bodies which exhibited a pattern of cross-banding similar to that seen in the striations of skeletal muscle fibres (I). Their discoverer, Mayer, regarded these bodies as the degenerative products of muscle fibres of extrinsic origin and referred to them as "sarcolytes". Ensuing studies by many workers described similar structures in the thymic tissue of teleost fish (2,3); amphibians (4,5,6); reptiles (7,8,9,10,11); birds (8) and mammals (12,13,14,15) including man (16,17,18,19). It was Hammar in 1905 who first referred to these muscle-like bodies as "myoidzellen" or myoid cells (4). In mammals and man, myoid cells appear to be more prominent during embryonic and perinatal stages of development (12,18) although there is clear evidence that myoid cells are also present in human juvenile and adult thymic tissue (19). Many reports have shown that m y o i d cells appear most cons i s t e n t l y and in greatest numbers in the thymus of lower vertebrates; i n d e e d in b i r d s and r e p t i l e s they appear to increase in n u m b e r after hatching, e v e n t u a l l y d e c l i n i n g as the thymus re385

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gresses in later life (7,8,12). Although the number of specimens examined was small, Raviola and Raviola observed few myoid cells in pigeons less than one year old and in 4-day-old chicks, whereas in pigeons of 1 to 3 years of age numerous myoid cells were present (8). Van de Velde and Friedman reported large numbers of myoid cells in 2 year old tortoises and snakes, although older tortoises had few or none (12). Seasonal variations in myoid cells have also been reported. Dustin (7) suggested that in reptiles new myoid cells appear in the thymus each spring and degenerate during autumn. More recent studies on lizards and snakes (9,10,11) reveal a paucity of myoid cells during spring, whereas at other times of the year (winter in lizards, and both winter and summer in snakes) myoid cells appear to be plentiful. Other workers have noted numerous myoid cells in the thymus of turtles and snakes killed during autumn and winter (8). The thymus of hibernating adult frogs is also particularly rich in myoid cells (5); however,this may be a relative increase brought about by the egress of thymic lymphocytes during winter dormancy. The significance of such seasonal fluctuations is not known and more information is needed to piece together a clearer overall picture of any functional relationships which may exist between myoid cells and the seasons. With the advent of the electron microscope, earlier light microscopic studies were superseded by intensive and detailed ultrastructural investigations of myoid cell architecture. Such studies have been admirably reviewed elsewhere (5,8,20) and only the major findings will be summarized here. Myoid cells exhibit extreme variations in morphology and fine structure. They may exist as round, ovoid or pear-shaped structures with concentric~ly arranged muscle fibres, or sometimes as elongated strap-like or fusiform cells. Embryonal myoid cells display a fine-structure similar to that observed in differentiating skeletal or cardiac muscle with sparse and irregular myofibrils. Fully developed myoid cells exhibit a striation pattern typical of striated muscle often with well-defined Z-lines, A- and I- bands, H zone and Mline in longitudinal section. Transverse sections of such cells reveal a regular arrangement of thick and thin myofilaments. Aged or necrotic cells have also been reported with loss of crossstriations, myofibrillar disruption and sarcoplasmic vacuolation. This complete gamut of myoid cell types lends support to the suggestion that myoid cell neogenesis and destruction occurs throughout the life of the individual, although the relative rates of such processes may vary from one species to another. On the question of the embryonic origin of myoid cells it was originally supposed that they were accidental inclusions of embryogenesis (15) or were the progeny of adventitious cells which invaded the thymus via blood vessels (7). However, evidence suggestive of an intrinsic origin comes from ultrastructural observations of desmosomal attachments between immature myoid cells and neighbouring thymic reticular cells in amphibians,reptiles and man (5,8,20). In addition recent tissue culture experiments have demonstrated that myogenic stem cells may be generated in vitro from cultures of murine thymus reticulum (21).

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Before examining the proposed relationship between myoid cells and myasthenia gravis, a brief outline of the disease will be given. For a more comprehensive account the reader is referred to two recent reviews by Drachman (22, 23). Myasthenia gravis (literally "severe muscle weakness") belongs to a group of illnesses in which autoimmune processes are thought to play a predominant pathogenetic role. It is hallmarked by muscular weakness of insidious onset, most commonly affecting muscles innervated by the cranial nerves (24). Thus, ocular muscles may be involved initially~but gradual spreading of the affliction can occur affecting muscles of the head and neck and ultimately affecting the whole body, making respiration difficult. The weakness and rapid tiring of muscles appears to involve a pharmacological blockade at the neuromuscular synapse. An autoimmune basis for myasthenia gravis was first proposed by Simpson (25) and Nastuk et al (26). Suggestive evidence for autoimmunity emerged from the frequent (though by no means absolute) association between myasthenia gravis and thymic hyperplasia or thymoma (27). Thymectomy during early stages of the disease has also been shown to have a beneficial effect (28). In addition myasthenia gravis sometimes occurs in association with other proposed autoimmune diseases (25). The finding that 12% of babies born to myasthenic mothers develop a transient form of the disease suggests that a humoral factor, capable of trans-placental passage, is a causative agent (29). This observation accords well with earlier reports that some myasthenic patients possess serum antibody capable of binding to striations of skeletal muscle (30). More recent studies employing sensitive radioimmunoassay techniques have detected antibodies to Acetylcholine receptor in 70 - 87% of myasthenic patients (31, 32). These findings suggest that the site of defect in myasthenia gravis is post-synaptic and involves blockade or destruction of Acetylcholine receptors located on the postsynaptic membrane. Although some authors have suggested that autoimmune antibodies are indicators rather than the cause of myasthenia gravis (33), experiments have shown that daily injection of serum fractions from myasthenic patients into mice may result in the transfer of certain neurophysiological changes similar to those observed in myasthenia gravis (34). The most effective serum fraction in such transfer experiments was found to be IgG. Complement (C3) also appears to be a critical co-mediator of pathogenicity. Further evidence for an autoimmune reactivity against the Acetylcholine receptor comes from the development of experimental animal models for the study of myasthenia. Thus, it is possible to prepare large amounts of purified Acetylcholine receptor from the electric organs of fish such as the electric ray (Torpedo) or the electric "eel" (Electrophorus). When rabbits are immunized with receptor from electric eel they develop muscular weakness and other neuropathological features which parallel those seen in human myasthenia gravis (35). Injection of other species, including monkeys, with receptor has given similar results (36, 37). A note of caution must be sounded here, however, since myoid antibodies have been detected in serum of nonmyasthenic individuals, particularly those with thymoma but not myasthenia (38)

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There exists an alternative or additional contender for the role of humoral blocking factor in myasthenia gravis. Goldstein and co-workers (36) have proposed that the basic pathology of the disease is an inflammatory thymic lesion (thymitis) which results in excessive secretion of a polypeptide Thymopoietin (formerly Thymin). Thymopoietin itself is thought to induce the neuromuscular block (40,41). Corroborative evidence has been claimed on the basis of another experimental animal model involving the injection of thymic homogenates in Freund's adjuvant (42).Possible contradictory evidence against the operation of a thymic humoral factor in man is provided by the observation of transient neonatal myasthenia in babies born to thymectomised myasthenic mothers (43). Cell-mediated immune events have also been implicated in myasthenia gravis. Thus, positive stimulation indices have been obtained in mixed leucocyte cultures between peripheral blood lymphocytes and autologous thymocytes from some patients with myasthenia gravis (44). Thymocytes obtained from myasthenic patients develop cytotoxicity to foetal muscle cells following stimulation with phytohaemagglutinin, and produce leucocyte inhibitory factor following stimulation with thymic or muscle extracts (45). Histological studies of skeletal muscle from myasthenic patients only occasionally show evidence of lymphocytic infiltration, however, and the precise importance of cell-mediated events in myasthenia gravis remains obscure (46). As with other proposed autoimmune diseases it is difficult to demonstrate that immunological involvement is a primary cause rather than a secondary consequence of tissue-damage. Nevertheless, a corpus of information has accumulated which is at least suggestive of a primary involvement of the thymus in the aetiology of myasthenia gravis. Circumstantial evidence incriminating the myoid cell in myasthenia gravis emerged from the finding that serum from myasthenic patients contained antibody capable of binding to myoid cells in turtle thymus (47). Henry (48), and Bockman and Winborn (49) proposed that myoid cells play a central r~le in the sensitization and subsequent formation of anti-muscle antibodies. Certainly myoid cells occupy an apparently unique anatomical location which might render them particularly prone to immune recognition by surrounding thymocytes, with the subsequent generation of "helper" or cytotoxic T cells. Moreover, recent experiments have shown that during the differentiation of myogenic stem cells from murine thymic reticulum in culture, the developing muscle clones exhibit transient, high-density expression of acetylcholine receptors with localised "hot-spots" where acetylcholine receptor is even more concentrated (50). The authors suggest that if such cells were in some way arrested or "frozen" at this stage of differentiation(perhaps by viral infection), then they might supply the necessary and appropriate presentation of antigen for autoimmune sensitization. This assumes, of course, that differentiation events seen in rodent material in vitro are paralleled by those found in human tissue in vivo;however, supportive arguments have been made on the basis of reports of an increased number of myoid cells in myasthenic thymuses (20) and the demonstration of acetylcholine receptors on the surface of muscle cells cultured

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with

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(51).

Despite detailed studies of the structure and occurrence of myoid cells in different animal species, and the proposed relationship between myoid cells and myasthenia gravis, the phylogeny of myasthenia gravis has received little attention. Perhaps this is not surprising, since it would, in any case, be a difficult disease to detect in animals. Indeed, it should be stressed that even in man diagnosis can be troublesome without recourse to immunological tests: thus, emotional fatigue, thyrotoxic-disorders and diseases of the brain-stem can give rise to symptoms very similar to those seen in myasthenia gravis (52). Although a search of the literature reveals a dearth of information on myasthenia gravis in species other than man, the reader is referred to two reports of related interest. The first of these concerns a small South African rodent Mastomys natalensis which is remarkable for the apparently high incidence of thymic hyperplasia and thymoma in normal populations (53). Necropsies carried out on 113 Mastomys revealed 27 with thymoma and II with thymic hyperplasia. Although none of the animals studied displayed overt "clinical"symptoms of myasthenia gravis, 7 did show focal myositis of skeletal muscle. One animal with no thymic abnormalities also exhibited myositis of cervical and orbital muscles. The authors were unable to conclude, however, that the observed myositis bore any relationship to myasthenia gravis, and indeed cellular infiltration of muscle in human myasthenia gravis is rare (46). The report also surveys the incidence of thymoma in animal species other than man, and stresses the rarity of such thymic abnormalities. The authors concluded that no evidence exists for a combination of thymoma and myasthenia gravis in species other than man. The second report described a myasthenia-like syndrome in a young dog (54). Here, biopsies of muscle tissue were obtained and electron microscopic observations of motor end plates from the dog were compared with those obtained from a patient suffering from myasthenia gravis. Similar ultrastructural abnormalities were reported in both - these included evidence of membrane degeneration and also a widening of secondary synaptic clefts. The immunological status of the dog was not assessed however, and the precise cause of these abnormalities is not known. Despite this paucity of detail concerning the existence of myasthenia gravis in non-human species, it would clearly be of considerable interest to know when myasthenia gravis first appeared in the evolutionary history of the vertebrates; and to discover whether or not (as has been suggested) the disease is restricted to man (24). The events which trigger off myasthenia gravis are still not known, but evidence for the involvement of myoid cells in its pathogenesis remains purely'circumstantial. The increased numbers of myoid cells reported in myasthenic patients (20) may well be a consequence of immunological disturbance rather than the cause of it. Thus, it is possible that antibody directed against Acetylcholine receptors on muscle may also bind with and provoke division of myogenic clones within the thymus; indeed this proposal could be readily tested under controlled experimental conditions. It must also be remembered that lymphocyte populations within the thymus are also disturbed in myasthenic patients (44) and this in itself may reflect a more generalized disturbance of the immune system rather than a specific abnormality related to myoid cells.

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Moreover, this suggestion finds support in the observation that myasthenia gravis often occurs in association with other autoimmune diseases (25). Another argument which has been employed to militate against the involvement of myoid cells in myasthenia gravis, is their wide-spread distribution in vertebrate thymus (8). Their evolutionary persistence might be difficult to explain if they are indeed a primary cause of such a debilitating disease. On the other handmyasthenia gravis is extremely rare and may occur late in the reproductive period of affected individuals. From an evolutionary viewpoint it is possible that under these circumstances there would be little selective disadvantage in succumbing to the disease. The question of myoid cell function remains problematical. A number of proposals have been made regarding the putative role of myoid cells, but none of these has been confirmed or negated. Toro et al. (5) have suggested that they are involved in the propulsion of tissue fluids through the thymus, particularly during hibernation. Although some fairly straightforward observations could confirm or deny this proposal, no such evidence has been forthcoming. Others have suggested that the presence of myoid cells in the developing thymus is a prerequisite for the generation of tolerance to self (55);and whilst this proposal may be difficult to test experimentally, it seems strange a priori that only muscle tissue should have been 'selected' for this purpose when one considers the vast array of antigens which must exist in the organism as a whole. A further,highly speculative, proposal might also be considered. Biologists may have become so accustomed to thinking that each characteristic of an organism must possess aprecise and important function, honed to perfection by evolutionary selective pressure, that we are unready to concede that a trait or characteristic may be entirely neutral in its adaptive significance and may persist solely as a result of its association with a highly advantageous characteristic. Perhaps myoid cells survive only by virtue of their association with thymic tissue and serve no true physiological purpose whatsoever. Whatever the correct interpretation may be, the phylogenetic persistence of myoid cells in thymic tissue demands an explanation and the significance of myoid cells in health and disease represents a fertile area for continued future speculation and research.

ACKNOWLEDGEMENTS My thanks to Professor E.L. Cooper this review and to A.J.H. Gearing careful reading of the manuscript. O. Deeley who typed the manuscript.

who encouraged the writing of and Ms. S. McBride for their Thanks are also due to Mrs.

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