Abstract
To investigate the role of thymic myoid cells in the pathogenesis of myasthenia gravis (MG), mRNA of nonneoplastic thymuses from eight MG patients was analyzed by dot blot hybridization for the occurrence of acetylcholine receptor (AChR) subunit transcripts, using the five AChR-subunit cDNAs (alpha, beta, gamma, delta, and epsilon) as probes. Attention was particularly paid to the gamma- and epsilon-subunit transcripts that specify fetal- or adult-type AChR. In all eight thymuses, transcripts of the alpha-, beta-, gamma-, and delta-subunit genes were detected. Relative autoradiographic signal intensities correlated with the frequencies of thymic myoid cells as determined by immunostaining with anti-AChR monoclonal antibodies. In only one of these thymuses were transcripts of the epsilon-subunit gene detected in addition to those of the other subunit genes. Four MG-associated thymomas without myoid cells were devoid of any AChR-subunit mRNA. Our findings imply that fetal-type AChR is expressed in MG thymuses as a rule, whereas adult-type AChR is coexpressed with it only in a minority of cases. A similar pattern of cotranscription is known to occur at certain stages of muscle development, and can be found in human rhabdomyosarcomas with an intermediate stage of myogenesis. Because the serum autoantibodies of MG patients exhibit preferential reactivity with fetal AChRs, the presence of fetal AChRs in the thymus provides circumstantial evidence for an active involvement of thymic myoid cells in the autoimmune process.
Highlights
Myasthenia gravis (MG) is an autoimmune disease characterized by abnormally fatiguable neuromuscular transmission caused in 90% of patients by heterogeneous autoantibodies against the nicotinic acetylcholine receptors (AChR) of muscle endplates that are either reduced or functionally blocked (Compston et al, 1980; Drachman et al, 1980; Vincent et al, 1987)
There is strong evidence that tumor proteins with only a limited molecular similarity to the AChR may play a causative role in the pathogenesis of thymoma-associated myasthenia gravis (MG) (Kirchner et al, 1987, 1988; Marx et al, 1989, 1990; Geuder et al, 1989; Siara et al, 1991), the myoid cells of the thymic medulla have been suggested to be involved in autosensitization in nonthymoma-associated cases (Van de Velde et al, 1966; Kao and Drachman, 1977; Wekerle and Ketelsen, 1977)
A distinct correlation was encountered between the frequencies of thymic myoid cells as determined by immunohistochemistry (Fig. 1) and the relative intensities of autoradiographs of the respective dot blots probed with the AChR alpha-subunit cDNA (Fig. 2)
Summary
Myasthenia gravis (MG) is an autoimmune disease characterized by abnormally fatiguable neuromuscular transmission caused in 90% of patients by heterogeneous autoantibodies against the nicotinic acetylcholine receptors (AChR) of muscle endplates that are either reduced or functionally blocked (Compston et al, 1980; Drachman et al, 1980; Vincent et al, 1987). Beta, and delta subunits are indispensable parts of fully functional AChR, the additional presence of either the gamma or the epsilon subunit determines the fetal or adult receptor type, respectively (Mishina et al, 1986). Thymic myoid cells are the only differentiated muscle cells in adults presumed not to be physiologically innervated. Whether they express adult in addition to the demonstrated extrajunctional type AChR (Schleup et al, 1987) is not clear. To address this question, we have probed thymus mRNA with the AChR alpha-, beta-, gamma-, delta, and epsilon-subunit cDNAs. Given the known preferential reactivity of anti-AChR autoantibodies with extrajunctional. AChR (Weinstein and Hall, 1980; Vernet-der Garabedian et al, 1988), our finding of transcripts coding for the fetal AChR supports the view that thymic myoid cells participate actively in the pathogenesis of MG
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