active zones 6neuromuscular junction/freeze-fracture electron microscopy/acetylcholine release/ca2" channels/autoantibodies)
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1 Proc. Natl. Acad. Scl. USA Vol. 80, pp , December 1983 Medical Sciences Passive transfer of Lambert-Eaton myasthenic syndrome with IgG from man to mouse depletes the presynaptic membrane active zones 6neuromuscular junction/freeze-fracture electron microscopy/acetylcholine release/ca2" channels/autoantibodies) HIDETOSHi FUKUNAGA*, ANDREW G. ENGEL*t, BETHAN LANGO, JOHN NEWSOM-DAVISt, AND ANGELA VINCENTt *Depament of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, MN 55905; and $Department of Neurological Science, Royal Free Hospital School of Medicine, London NW3 2PF, England Communicated by Ralph T. Holman, September 6, 1983 ABSTRACT In the Lambert-Eaton myasthenic syndrome (LEMS), there is a decreased release of acetylcholine quanta from the nerve terminal by nerve impulse. Recently, an autoimmune origin of LEMS was documented by passive transfer of its electrophysiologic features from man to mousewith IgG. Freeze-fracture electron microscopy of LEMS neuromuscular junctions has revealed a paucity of presynaptic membrane active zones. Thus, the active zones might be the targets of the pathogenic autoantibodies in LEMS. To test this assumption, freeze-fracture electron microscopic studies were done in mice injected with 10 mg of IgG daily from each of three LEMS patients and in control mice treated with normal human IgG or no IgG. IgG from patients 1 and 2 impaired neuromuscular transmission in mice, but IgG from patient 3 failed to do so. After days of treatment, diaphragm or anterior tibial muscles were removed and coded. Paired muscles from control mice and mice receiving LEMS IgG were studied "blindly." Satisfactory freeze-fracture replicas of 185 presynaptic membrane P-faces were analyzed by stereometric methods. In mice treated with LEMS IgG that was pathogenic by electrophysiologic criteria, there was a selective depletion of active zones and activezone particles but not of other membrane particles and there was a concomitant increase of large membrane particles aggregated into clusters. These findings provide additional evidence that the active zones facilitate quantal transmitter release by nerve impulse, lendiurther support to the assumption that the active-zone particles are Ca2+ channels, and establish mediation of the membrane lesions in LEMS by IgG. The clinical and electrophysiologic features of the Lambert-Eaton myasthenic syndrome (LEMS) have been well recognized for over two decades. The disease is frequently associated with carcinoma and especially with oat cell carcinoma of the lung. The defect of neuromuscular transmission is improved by repetitive nerve stimulation or by an increase of external Ca2+ concentration (1, 2). The failure of neuromuscular transmission is accounted for by a reduced release of acetylcholine quanta from the nerve terminal by the nerve action potential (2). Presynaptic acetylcholine stores (3) and the postsynaptic response to individual acetylcholine quanta are normal (2). In 1981, Lang et al. passively transferred the main electrophysiologic features of the disease from man to mouse with IgG and, thus, provided compelling evidence for an autoimmune pathogenesis of the disease (4). In 1982, in a quantitative freeze-fracture electron microscopic study of the LEMS neuromuscular junction, Fukunaga et al. (5) found paucity of the presynaptic membrane active zones. This provided a meaningful morphologic correlate The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C solely to indicate this fact of the electrophysiologic abnormality, for the active zones are topographically related to sites of synaptic vesicle exocytosis (6), and membrane particles in the active zone are thought to represent the voltage-sensitive calcium channels of the presynaptic membrane (7, 8). Thus, the reduced quantal release by nerve impulse in LEMS could be related to a reduced ingress of Ca2+ into the nerve terminal. Furthermore, the morphologic data suggested that the active-zone particles represented the target of the pathogenic autoantibodies in LEMS. The present paper shows that in mice treated with LEMS IgG (which transfers the electrophysiologic features of the disease), the presynaptic membrane changes are the same as in human LEMS. Consequently, it follows that the depletion of active-zone particles in LEMS is mediated by IgG. MATERIALS AND METHODS Plasma was obtained from three LEMS patients by plasma exchange. Patients 1 and 2 had carcinoma, whereas patient 3 did not. In each patient the amplitude of the evoked compound muscle action potential was abnormally small, but it increased markedly after a brief period of voluntary contraction, as is typical of LEMS (Table 1). The IgG fractions were prepared from LEMS and pooled normal human plasmaby the Rivanol-ammonium sulphate method (9). LEMS or control IgG (10 mg) was injected daily intraperitoneally into male BKTO mice initially weighing 22 g. Cyclophosphamide (300 mg/kg of body weight) was given intraperitoneally on day 1 of the study to suppress the immune response to the injected IgG. Electrophysiologic studies were done on diaphragm muscles of mice treated with control or LEMS IgG for days to characterize the IgG fractions that were to be used for the freezefracture studies (10). IgG from patients 1 and 2 significantly reduced the quantum content of the end-plate potential in the recipient mice. By contrast, IgG from patient 3 failed to transfer the electrophysiologic features of LEMS (Table 2). The miniature end-plate potential amplitudes remained in the normal range in all animals; Preliminary reports of the electrophysiologic aspects of the transfer of LEMS to mouse have appeared (4, 11), and a detailed account will be published separately (12). Freeze-Fracture Studies. Freeze-fracture studies were done in 12 mice after days of treatment; 7 of these animals received LEMS IgG and 5 were controls. IgG was given to 1 mouse from patient 1, to 4 mice from patient 2, and to 2 mice Abbreviation: LEMS, Lambert-Eaton myasthenic syndrome. tto whom reprint requests should be addressed.
2 Medical Sciences: Fukunaga et A Proc. Nati. Acad. Sci. USA 80 (1983) 7637 Table 1. Clinical material Patient Sex/age Compound muscle action potential* Duration, Associated Initial Posttetanic Facilitation, yr disease mv mvt % 1 F/60 1 Small cell lung carcinoma 2 F/42 4 Undifferentiated ,275 lung carcinoma* 3 M/26 4 Celiac disease Normal >7.5 <100 * Measured in abductor digiti minimi muscle. tmeasured 3 sec after 15-sec maximal voluntary contraction. tcarcinoma became evident 1 yr after plasma sample was obtained. from patient 3. Three control mice received normal IgG, and 2 mice received no IgG. Diaphragms from 10 animals and anterior tibial muscles from 2 animals were removed and coded. Muscles from 5 mice treated with LEMS IgG and from 5 concurrently sacrificed control mice were paired, and the LEMS/ control pairs were studied blindly by freeze-fracture electron microscopy. The remaining LEMS/LEMS muscle pair was not blindly analyzed. The 2 mice in this pair received IgG from patients 2 and 3, respectively. However, the failure of IgG from patient 3 to impair neuromuscular transmission in the mouse was not known to the investigators involved in the freeze-fracture study. Animals were sacrificed by cervical dislocation. Immediately after this, muscles were fixed with 2% glutaraldehyde/0. 1 M sodium cacodylate, ph 7.3. For the diaphragm, fixative warmed to 300C was injected intrathoracically and intraperitoneally until these cavities were filled. Fixation of anterior tibial muscles was initiated by the intramuscular injection of the warm fixative through a 30-gauge needle. After 10 min, muscles were removed, pinned to a rubber mount, and fixed for an additional 2 hr on ice. After a rinse in cacodylate buffer, the specimens were reacted for cholinesterase to visualize end plates (13). End plate-enriched muscle segments were equilibrated with 25% glycerol in buffer and freeze-fractured in a Balzers 300 instrument at a stage temperature of -113 to - 115'C and at pressures ranging from 1.5 x 10-7 to 3.0 x 10-7 mbar (1 bar = 105 Pa). For each muscle pair, specimens from the two different animals were simultaneously fractured and replicated. The replicas were examined in a Philips 400 electron. microscope equipped with a eucentric goniometer stage. Stereo-pair micrographs were taken of all presynaptic membrane P-faces observed in the replicas at magnifications ranging from X4,600 to x36,000. The surface areas of adequately shadowed membranes were determined stereometrically by a previously reported method (14). Active zones and membrane particles per active zone were counted directly in each membrane sample. Table 2. Effect of LEMS IgG on quantum content of end-plate potential (m) in BKTO mice Days End plates per m, % Patient injected no. of mice studied* of controlt P 1 50, 52 13/2 40 < , 59 17/2 26 < , 75 12/2 93 NS NS, not significant. * One mouse in each case was injected concurrently with mice used in freeze-fracture study. t End-plate potentials were recorded during stimulation at 0.5 Hz. For mice treated with control human IgG, the mean + SEM for m was 136 ± 11 (37 end-plates with nine mice). Clusters composed of more than five 10- to 12-nm particles and the number of particles in these clusters also were counted. The density and diameters of particles not associated with active zones and clusters were determined by a sampling procedure as described (5). RESULTS General Observations. A total of 323 neuromuscular juncz tions were observed in the replicas, and these yielded 185 satisfactory presynaptic membrane P-faces. Even by simple inspection of membrane samples from a given muscle, it was possible to classify that muscle as "normal" or "abnormal.." This division was further supported by the quantitative analysis of the membrane samples (described below). Upon completion of the blind analysis, the treatment code was broken. It turned out that "abnormal muscles" were from mice treated with IgG from patients 1 or 2. The "normal muscles" were either from control mice or from mice treated with IgG from patient 3, which did not impair neuromuscular transmission in the mouse. Normal membrane samples always contained active zones. These typically consisted of double parallel rows of 10- to 12- nm particles with 3-15 particles per row. Most active zones curved slightly or were angulated. Some zones were aligned with their long axis parallel to each other (Fig. 1A), but others were randomly oriented (Fig. 1 B, C, and D). In some specimens the active zones were located in shallow grooves within the membrane (Fig. 1C). In some active zones, the four rows were of unequal length, or one or two rows were partly or completely missing (Fig. 1A). Clusters of large particles with more than five particles per cluster were infrequent (Fig. 1B). Of the presynaptic membrane P-faces, 77 fell into the abnormal group; 17 contained no active zones. Most of the remaining membrane samples showed a marked depletion of active zones (Fig. 2). All samples displayed clusters of large particles, with more than five particles per cluster (Fig. 2 B, C, and D), and these clusters were more abundant than in the normal group. Some clusters resembled disorganized active zones (Fig. 2C), and in some clusters a linear arrangement of particles suggested aggregation of active-zone particles (Fig. 2 B and C). The mean diameters of the particles in the active zones and clusters did not differ significantly from each other or from the corresponding values in the normal group. Quantitative Analysis of the Membrane Samples. Table 3 compares the number of active zones per unit of presynaptic membrane area for each of the six muscle pairs that were analyzed. The data clearly show that IgG from patients 1 and 2, which was pathogenic by electrophysiologic criteria, caused a severe depletion of the active zones. Table 4 shows the results of the stereometric analysis in the five control mice and the four mice treated with pathogenic
3 7638 Medical Sciences: Fukunaga et al. Proc. Natl. Acad. Sci. USA 80 (1983) FIG. 1. Presynaptic membrane P-faces in anterior tibial (A) and diaphragm (B, C, and D) muscles of control mice, with numerous active zones identified by arrows in A, B, and D. In A, but not elsewhere, the active zones are aligned parallel to each other and perpendicular to the long axis of the nerve terminal. Some of the active zones consist of fewer than four rows or contain incomplete or interrupted rows (x). In B, a cluster of large membrane particles abuts on an active zone (arrowhead). [Bars = 1 Aum ina-c and 0. 1 Am in D; x 52,700 (A), x 69,000 (B), x 43,200 (C), and x 89,500 (D).] LEMS IgG. The average membrane sample was larger in the treated than in the control group, but this difference did not reach statistical significance. In comparison with the controls, mice treated with pathogenic LEMS IgG had only 25% of the active zones and active-zone particles and showed a 2.5-fold increase in large particles aggregated into clusters per AMm2. The combined sum of active-zone and cluster particles per unit area in the treated group was still only 59% of that in the control group. Thus, even if the cluster particles could function as active-zone particles, there would still be a depletion of activezone particles in the treated group. Depletion of active-zone particles could be associated with loss of other membrane particles. Therefore, we determined the density and frequency distribution according to size of those presynaptic membrane P-face particles not associated with active zones or clusters. Two membrane samples were selected at random from each of four control mice and from the four mice treated with pathogenic LEMS IgG. In the control mice, the particle density was 2, (mean ± SEM) per /IM2; in the treated mice, the corresponding value was 2,857 ± 61. Diameters of 200 particles were measured in each membrane sample, yielding 1,600 diameters for comparison from each group. The frequency distribution of the particles according to size were virtually identical for the two groups. DISCUSSION The present study clearly shows that the mouse passive transfer model of LEMS reproduces the presynaptic membrane lesions
4 MedicA Sciences: Fukunaga et al. Proc. Nati. Acad. Sci. USA 80 (1983) 7639 FIG. 2. Presynaptic membrane P-faces in diaphragm muscles of mice treated with pathogenic LEMS IgG for 52 days. (A) Branching nerve terminal (N). The fracture plane traverses the interior of the terminal and then skips to a large expanse of the presynaptic membrane P-face. Synaptic spacejunctional folds, and junctional region of muscle fiber (M) surround the nerve terminal. A representative region of the presynaptic membrane (asterisk) is shown at a higher magnification in C. (B, C, and D) Only a few active zones (arrows) and several clusters of large membrane particles with more than five particles per cluster (arrowheads) can be observed (compare with Fig. 1). In B and C, the arrangement of the particles in some clusters suggests aggregation of linearly arranged active-zone particles (x). [Bars = 1 pan in A-C and 0.1 pm inld, x14,000 (A), x57,400 (B), x75,600 (C), and x92,500 (D).]
5 7640 Medical Sciences: Fukunaga et al. Table 3. Paired comparison of numbers of active zones per unit of presynaptic membrane area in mouse muscles Treatment Mouse Days of Active zones per pm'* code pair treatment A B A = patient 1 it ± ± 0.62 B = control (12) (7) A = patient 2 2t ± ± 0.11 B = control (21) (16) 3t ± ± 0.17 (16) (20) 4t ± ± 0.13 (19) (16) A = patient 3 5t ± ± 0.19 B = control (12) (25) A = patient 3 6* ± ± 0.10 B = patient 2 (12) (9) Diaphragm muscles were studied except for mouse pair 3 in which anterior tibial muscles were studied. * Mean ± SEM; number of membrane samples is in parentheses. P < except for results when A = patient 3 and B = control, which were not significant. tblind comparison. t Comparison was not blind, but failure of IgG from patient 3 to alter neuromuscular transmission in mouse was not known during study. of the human disease. In both species there is a selective depletion of active zones and active zone particles but not of any other membrane particles, and there is a concomitant increase of large membrane particles aggregated into clusters. The induction of the membrane lesions in the mouse is linked to the ability of the LEMS IgG to impair quantal release from the mouse nerve terminal by nerve impulse. The clusters of large particles may arise by aggregation of active-zone particles. This is suggested by the resemblance of some clusters to disorganized active zones, the similar diameter of the cluster and active-zone particles, and the presence of linearly arrayed particles in some of the clusters. Thus, it is possible that aggregation of active-zone particles is induced by a crosslinking antibody and that the paucity of active-zone particles is secondary to antigenic modulation by antibody. Table 4. Stereometric analysis of presynaptic membranes* Mice receiving Control pathogenic mice LEMS IgG Membranes analyzed Total membrane area, jim Area/membrane,,n2 7.2 ± ± 1.6 Active zones per,um ± ± 0.7t Active zone particles per Im ± ± 1.6t Clusters* 0.68 ± ± 0.07t Cluster particles per 1um ± ± 1.2t Particles in active zones and clusters per Am ± ± 1.9t * Each value is the mean ± SEM. tp < t Groups of predominantly large (10-12 nm) particles with more than five particles per cluster. Proc. Natl. Acad. Sci. USA 80 (1983) The freeze-fracture studies were done in mice treated for days. These periods were chosen because the time course of the reduction of quantal content was previously observed to be relatively slow, reaching a plateau value only after 35 days (12). The relatively slow time course of the passive transfer suggests either limited crossreactivity of pathogenic LEMS IgG with mouse epitopes or slow depletion of active zones or both. IgG from patient 3 failed to transfer either the physiologic or morphologic features of the disease to mouse. His disease was still autoimmune, for he responded well to plasmapheresis followed by immunosuppressive drug therapy. Thus, either a low circulating titer or a limited crossreactivity of his autoantibodies accounted for failure of the transfer. The findings in this study have several important implications. First, they further validate the freeze-fracture findings that revealed a depletion of the active zones in human LEMS (5). Second, they provide additional evidence for the role of the active zones in facilitating the release of transmitter quanta from the nerve terminal by nerve impulse. Third, they lend further support to the assumption that the active-zone particles are Ca2+ channels (7, 8), for a decreased Ca2+ ingress into the nerve terminal is an adequate explanation of reduced quantal release by nerve impulse (15). However, even if the active-zone particles facilitated quantal release in another manner, a clear structurefunction correlation is demonstrated in the present study. Finally, this investigation establishes that the presynaptic membrane lesions in LEMS are mediated by IgG. Therefore, the active-zone particles must be direct or indirect targets of the pathogenic LEMS autoantibodies. Further, these antibodies may become useful tools for probing the structure and function of the presynaptic membrane. Mr. C. Prior and Dr. D. Wray performed physiologic characterization of the IgG in case 3. This work was supported in part by U.S. Public Health Service Grant NS 06277, a Research Center grant from the Muscular Dystrophy Association, and by the British Medical Research Council. 1. Lambert, E. H., Rooke, E. D., Eaton, L. M. & Hodgson, C. H. (1961) in Myasthenia Gravis, ed. Viets, H. R. (Thomas, Springfield, IL), pp Lambert, E. H. & Elmqvist, D. (1971) Ann. N.Y. Acad. Sci. 183, Molenaar, P. C., Newsom-Davis, J., Polak, R. L. & Vincent, A. (1982) Neurology 32, Lang, B., Newsom-Davis, J., Wray, D. & Vincent, A. (1981) Lancet ii, Fukunaga, H., Engel, A. G., Osame, M. & Lambert, E. H. (1982) Muscle Nerve 5, Heuser, J. E., Reese, T. S., Dennis, M. J., Jan, Y., Jan, L. & Evans, L. (1979) J. Cell Biol. 81, Llinas, R., Steinberg, I. Z. & Walton, K. (1976) Proc. Natl. Acad. Sci. USA 73, Pumplin, D. W, Reese, T. S. & Llinas, R. (1981) Proc. Natl. Acad. Sci. USA 78, Horejsi, J. & Smetana, R. (1956) Acta Med. Scand. 155, Ginsborg, B. L. & Jenkinson, D. H. (1976) in Handbook of Experimental Pharmacology, ed. Zaimis, E. (Springer, Berlin), Vol. 42, pp Newsom-Davis, J., Murray, N., Wray, D., Lang, B., Prior, C., Gwilt, M. & Vincent, A. (1982) Muscle Nerve 5, S17-S Lang, B., Newsom-Davis, J. & Wray, D. (1983)J. Physiol. (London), in press. 13. Gautron, J. (1974) Microscopie 21, Engel, A. G., Fukunaga, H. & Osame, M. (1982) Muscle Nerve 5, Katz, B. & Miledi, R. (1968) J. Physiol. 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Medicine, University of Lund, Sweden
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