Original Article

Complement-Mediated Demyelination in Patients with IgM Monoclonal Gammopathy and Polyneuropathy

Salvatore Monaco, M.D., Bruno Bonetti, M.D., Sergio Ferrari, M.D., Giuseppe Moretto, M.D., Ettore Nardelli, M.D., Francesco Tedesco, M.D., Tom Eirik Mollnes, M.D., Eduardo Nobile-Orazio, M.D., Emanuela Manfredini, M.D., Luisa Bonazzi, Ph.D., and Nicola Rizzuto, M.D.

N Engl J Med 1990; 322:649-652March 8, 1990

Abstract

Abstract

We investigated the role of complement in the pathogenesis of the demyelinating polyneuropathy that occurs in some patients with IgM monoclonal gammopathy. Seven patients with chronic sensorimotor polyneuropathy and IgM monoclonal gammopathy were examined. In six patients, the monoclonal protein recognized an epitope shared by myelin-associated glycoprotein and two peripheral-nerve glycolipids, whereas in one patient, IgM bound to an unidentified myelin antigen.

Direct and indirect immunofluorescence and immunoperoxidase assays showed colocalization along the myelin sheaths of peripheral-nerve fibers of monoclonal protein with complement components C1q, C3d, and C5. In addition, terminal-complement complex that was not associated with S protein was detected in myelin sheaths. It appeared that alterations in myelin geometry caused by the separation of myelin lamellae corresponded to sites at which terminal-complement complex was deposited.

We conclude that demyelination in polyneuropathy associated with IgM monoclonal gammopathy may be mediated by complement. (N Engl J Med 1990; 322: 649–52.)

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Table 1Clinical and Electrophysiologic Features of the Seven Study Patients.*

Table 2Immunologic Findings in Seven Patients with Polyneuropathy and IgM Monoclonal Gammopathy.

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Article

MONOCLONAL antibodies directed against myelin antigens are frequently detected in patients with polyneuropathy associated with IgM monoclonal gammopathy.1 , 2 Some patients with demyelinating neuropathy and IgM monoclonal gammopathy have a monoclonal (M) protein that reacts with a carbohydrate epitope expressed by myelin-associated glycoprotein.2 3 4 5 6 7 8 9 The clinical picture of peripheral-nerve dysfunction encompasses a mixed sensorimotor polyneuropathy with distal weakness, tremor, ataxia, and loss of proprioception.10 11 12 The pathological changes in the peripheral nerves include ongoing segmental demyelination and remyelination, loss of large fibers, endoneurial edema, and microangiopathy; some fibers show separation or splitting of myelin lamellae.13 14 15 16

Demyelination is likely to be antibody-mediated, since direct immunohistochemical study of peripheral-nerve biopsy specimens shows deposition of M protein on myelin sheaths.17 , 18 However, the pathogenetic mechanisms whereby antimyelin M proteins induce nerve damage are still unclear. Recent observations have provided evidence that fragments of the classical pathway of complement are deposited at the same site as IgM.19 Moreover, nonlytic terminal-complement complex has been identified in the circulation of a patient with polyneuropathy and IgM monoclonal gammopathy.20 Laboratory studies demonstrate that passive transfer of the M protein to susceptible animals induces myelinolytic changes only in the presence of complement.21

Nevertheless, the extent of involvement of complement and the contribution of the terminal-complement complex to cytolytic nerve damage have not yet been established. To test the hypothesis that myelin damage may be mediated by terminal-complement complex, we used direct and indirect immunofluorescence and immunoperoxidase methods to examine peripheral-nerve biopsy specimens from patients with IgM monoclonal gammopathy and polyneuropathy for the presence of complement components and terminal-complement complex. Our study provides evidence of humoral, complement-mediated demyelination in this disorder.

Methods

Patients

Seven patients with polyneuropathy and IgM monoclonal gammopathy were studied. Their clinical and electrophysiologic features are summarized in Table 1Table 1Clinical and Electrophysiologic Features of the Seven Study Patients.*. Laboratory evaluation included serum protein electrophoresis, immunoelectrophoresis, and immunoglobulin quantitation; systemic or malignant disorders were excluded by a complete cell count, bone marrow studies, and a skeletal survey.

In addition, biopsies were performed in seven patients with hereditary sensorimotor neuropathy Type I, seven patients with diabetic polyneuropathy, and seven normal subjects. All patients gave their informed consent.

Biopsy

Biopsies of whole sural nerves were done at the ankle. A segment of the nerve was fixed for two hours at 4°C in 2.5 percent phosphate-buffered glutaraldehyde (pH 7.4), cut in small blocks, postfixed in 1 percent phosphate-buffered osmium tetroxide for two hours, and then dehydrated in graded acetone. The nerve specimens were then embedded in Spurr's medium, and 1-μm sections were stained with toluidine blue and examined under a light microscope. In addition, ultrathin sections were stained with aqueous uranyl acetate and lead citrate and examined under a Zeiss EM 109 electron microscope. The total number of fibers with abnormally spaced myelin lamellae in each nerve was counted after ultrastructural examination of all nerve fascicles. In each case, at least 100 teased fibers were obtained with the aid of a dissecting microscope from a segment of the nerve, fixed in 2.5 percent phosphate-buffered glutaraldehyde, postfixed for 24 hours in 1 percent osmium tetroxide, and immersed in unpolymerized Araldite.

Immunocytochemistry

A segment of the nerve adjacent to a segment processed for electron microscopy was frozen in liquid nitrogen for subsequent direct and indirect single or double immunofluorescence and immunoperoxidase studies. The following antibodies were used: rabbit antibodies against human IgM, IgG, IgA, and kappa and lambda light chains; the Clq, C3c, C3d, and C5 components of complement; antimouse IgG (Dako); mouse monoclonal antibody aEll, which recognizes C9 neoantigen expressed in the terminal-complement complex22; and anti–S protein (Cytotech). A cryostat was used to obtain sections 3 μm thick. The sections were then processed for immunofluorescence staining according to standard procedures,23 mounted in glycerin, and viewed with an Orthoplan fluorescence microscope. The number of fibers with deposits of terminal-complement complex was determined for the whole nerve on sections subjected to immunofluorescence. Peroxidase–antiperoxidase staining was performed as previously described.24

Immunologic Studies

Myelin and non-myelin fractions from the peripheral nervous system and central nervous system specimens from human brain were obtained at autopsy within three hours after death or from bovine cauda equina and processed as described elsewhere.1 , 8 Proteins (100 μg) were separated by slab gel electrophoresis as previously described.25 Western blotting was carried out according to the method of Towbin et al.26 After electrophoresis on 12 percent polyacrylamide gel, the proteins were transferred to nitrocellulose membranes at 60 V for two hours. The nitrocellulose filters were blocked with TRIS-buffered saline containing 5 percent bovine serum albumin, cut in strips, and incubated for two hours with serum from the patients at a 1:200 dilution. The samples were then washed for one hour, incubated, and exposed to a second antibody (Cappel) coupled to peroxidase specific for IgG, IgM, and kappa and lambda chains. The reaction was visualized with 3,3′-diaminobenzidine. Titration of antimyelin-associated glycoprotein antibodies was performed by immunoblotting at increasing twofold dilutions until the reaction was negative.

Immunostaining after High-Performance Thin-Layer Chromatography

Glycolipids from the peripheral nervous system were extracted with tetrahydrofuran from bovine cauda equina.27 Then 1-μg fractions of glycolipids were separated by high-performance thin-layer chromatography on aluminum-backed silica gel 60 plates (Merck), and the IgM reactivity of the patients' serum was detected by immunostaining1 at a serum dilution of 1:100 with use of the above-mentioned antibodies.

Results

Characterization of Antibodies

Immunoblotting of myelin fractions from the central and peripheral nervous systems showed that M protein from six patients with IgMκ monoclonal gammopathy reacted with myelin-associated glycoprotein and the myelin glycoproteins ranging from 23-to 26-kd from the peripheral nervous system.1 On immunostaining after high-performance thin-layer chromatography, the IgMκ recognized the peripheral-nerve acidic glycolipids sulfated glucuronic acid paragloboside and sulfated glucuronic acid lactosaminyl paragloboside. No reactivity was observed with the serum of the patient with IgMλ on either immunoblotting or immunostaining after chromatography (Table 2Table 2Immunologic Findings in Seven Patients with Polyneuropathy and IgM Monoclonal Gammopathy.).

Histopathological and Ultrastructural Findings

Examination of semithin sections revealed that myelinated fibers were homogeneously reduced in the fascicles of sural nerves; large fibers were somewhat more affected than smaller ones. In two cases intramyelin edema was observed on biopsy. Clusters of small regenerating myelinated axons, occasional fibers undergoing wallerian degeneration, and endoneurial capillaries with endothelial hyperplasia and thickened walls were seen in all cases, whereas no inflammatory infiltrates were observed. In the teased-fiber preparations, type C, D, and F abnormalities according to the scale of Dyck et al.28 were observed. Such abnormalities are consistent with a demyelinating process. Ultrastructural examination disclosed distinct changes, consisting of internodal separation or splitting of myelin lamellae in a small number of myelinated axons. These changes were confined to the outermost myelin lamellae, although in a few fibers the whole myelin sheath was affected.

Immunofluorescence and Immunoperoxidase Findings

The results of the fluorescence study are summarized in Table 3Table 3Direct-Immunofluorescence Findings in Seven Patients with IgM Monoclonal Gammopathy, Seven Normal Subjects, Seven Patients with Hereditary Sensorimotor Neuropathy, and Seven Patients with Diabetic Polyneuropathy.*. IgM M protein and both early and late components of complement are present on the nerve fibers of patients with polyneuropathy and IgM monoclonal gammopathy. None of these components could be detected in biopsy specimens from seven patients with hereditary sensorimotor neuropathy Type I, seven patients with diabetic polyneuropathy, or seven normal subjects. Direct immunofluorescence revealed the deposition of the M protein along the myelin sheaths in 70 to 80 percent of the fibers of all nerves. Among the IgM-positive fibers, less than 0.1 percent were positive for Clq and C5 and none for C3c, whereas the majority showed deposition of C3d, as assessed by double immunofluorescence. Immunofluorescence also revealed C9 neoantigen along the myelin sheath in 0.1 to 0.2 percent of the IgM-positive fibers, whereas S protein was not found in any specimen. Complement components, but not M protein, appeared to have a segmental distribution, varying substantially in sections separated by 50 to 150 μm. The severity of the ultrastructural alterations of the myelin was related to the number of fibers in which terminal-complement complex was deposited (r = 0.993). This was particularly evident in the patient with IgMλ M protein, in whom myelin abnormalities and deposits of terminal-complement complex were observed in all the fibers of two of seven fascicles.

Discussion

The present study demonstrates the deposition of several components of complement and of the terminal-complement complex on the myelin sheaths of peripheral nerves in patients with polyneuropathy and IgM monoclonal gammopathy. The activation of the complement system was associated in six cases with IgMκ reactivity with myelin-associated glycoprotein, some myelin glycoproteins with an apparent molecular weight between 23 and 26, sulfated glucuronic acid paragloboside, and sulfated glucuronic acid lactosaminyl paragloboside, and in one case with IgMλ M protein directed against an unidentified myelin antigen. The presence of Clq on myelin sheaths indicates that the complement cascade is triggered by the classical pathway and proceeds as far as C3d, reaching completion with the assembly of the terminal-complement complex. The importance of C3d deposition on the fibers in the absence of terminal-complement complex is not known; however, the observation by light and electron microscopy of ongoing demyelination and remyelination strongly suggests an important role for complement in inducing demyelination. This conclusion is also supported by the finding that peripheral neuropathy occurs predominantly in patients with IgM monoclonal antibodies that fix complement.1 , 2 Further evidence is provided by the results of experimental work showing the importance of both antibodies directed against myelin and complement in the pathogenesis of demyelination.21

A goal of this study was to find correlations between morphologic and immunologic observations. Previous studies have stressed the distinctive increased separation or splitting that occurs in peripheral myelin lamellae in IgM monoclonal gammopathy associated with polyneuropathy.14 15 16 17 The prevailing theory attributes this abnormal spacing to the incorporation of IgM into normally myelinated fibers or to an impaired myelin wrapping in remyelinating internodes.14 , 29 Direct immunofluorescence showed, however, that M protein was deposited on the majority of myelinated fibers (70 to 80 percent), whereas abnormally spaced myelin was observed in a small percentage of fibers (0.1 to 0.2 percent). Moreover, evidence that these abnormalities occur in remyelinating internodes is lacking. The correlation observed between the numbers of fibers with abnormally spaced myelin and the extent of the deposition of terminal-complement complex suggests that the terminal complex contributes to myelin damage. Although definite proof is lacking, the abnormally spaced myelin seen in this disease may well be the consequence of the influx of intracellular water after damage by the terminal-complement complex, thus representing a form of intramyelin edema. In our opinion, this structural alteration could be regarded as an early phase of myelin damage. Our inability to detect S protein bound to terminal-complement complex indicates that the complex is functionally active30 and may be directly involved in causing the structural abnormalities of myelin. It is also possible that terminal-complement complex contributes to the microangiopathy and the endoneurial edema observed in this form of polyneuropathy, through the local release of inflammatory products.31 Our results do not allow any definitive conclusion about the mechanism of myelin damage induced by terminal-complement complex.

Supported by a grant (ctb 8701454.04) from the Consiglio Nazionale delle Ricerche.

Source Information

From the Istituto di Neurologia, Università di Verona, Verona, Italy (S.M., B.B., S.F., G.M., E.N., N.R.); the Istituto di Patologia Generale, Università di Trieste, Trieste, Italy (F.T.); the Institute of Immunology and Rheumatology, the National Hospital, Oslo, Norway (T.E.M.); the Istituto di Clinica Neurologica, Centro Dino Ferrari, Università di Milano, Milan, Italy (E.N.-O., E.M.); and the Istituto di Chimica e Microscopia Clinica, Università di Verona, Verona, Italy (L.B.). Address reprint requests to Dr. Rizzuto at the Clinica Neurologica, Università di Verona, Policlinico di Borgo Roma, 37134 Verona, Italy.

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