Serum IgG antibodies to P0 dimer and 35 kDa P0 related protein in neuropathy associated with monoclonal gammopathy.

BACKGROUND: Peripheral neuropathies (PN) associated with monoclonal gammopathy (MG) are widely considered as autoimmune disorders, but the putative role of incriminated antigens is still not understood. OBJECTIVE: Fifty five patients with PN associated with MG were studied to investigate whether new antigens could be found, and to evaluate their relation to clinical manifestations. METHODS: An immunological study was conducted on patient sera to identify autoreactivities against nerve proteins by western blotting. Antigen proteins were purified and analysed by proteomic tools. Correlation with ultrastrucural and clinical features was then studied. RESULTS: Of the 55 patients suffering from PN associated with MG, 17 exhibited IgG autoantibodies directed against peripheral nerve proteins of 35, 58, and 60 kDa. N-terminal microsequencing and mass spectrometry analyses of the 35 kDa protein revealed perfect peptidic matching with 47% of the amino acid sequence of P0, whereas the 58 and 60 kDa proteins were identified as the reduced and non-reduced forms of a P0 dimer. Deglycosylation did not affect IgG binding to the 35 kDa P0 related protein, suggesting a peptidic epitope. In contrast, deglycosylation abolished IgG recognition of the P0 dimer protein, so that a carbohydrate moiety may be implicated in the epitope formation. This confirmed the existence of two different types of IgG, one recognising the 58 and 60 kDa proteins and one directed against the 35 kDa protein. CONCLUSIONS: This is the first report of antibody activity directed against the dimeric association of P0. Although P0 oligomerisation and adhesion properties play a crucial part in the myelin sheath compaction, the pathogenic significance of these autoantibodies needs further investigations to be elucidated.

Anti-myelin-associated glycoprotein antibodies and endoneurial cryoglobulin deposits responsible for a severe neuropathy.

A 73-year-old man was investigated for a peripheral neuropathy which occurred in the course of a Waldenstrom's macroglobulinemia. Serum immuno-fixation electrophoresis demonstrated two IgM monoclonal gammopathies of the kappa and lambda chain isotypes, and one had the physical characteristics of cryoglobulin. Immunoblot studies on the patient's serum revealed antibodies which reacted with peripheral nervous system proteins of different molecular weights including the myelin-associated glycoprotein (MAG). An immunofluorescence study of a superficial peroneal nerve biopsy revealed not only a binding of IgM and kappa light chain on several myelin sheaths but also the presence of IgM and kappa light chain deposits in the endoneurium. On electron microscopic examination, numerous fibres presented a widely spaced myelin and the endoneurial deposits had the ultrastructure of cryoglobulin. This is the first case presenting features of widely spaced myelin related to serum anti-MAG activity associated with monoclonal cryoglobulin deposits in the endoneurium.

Histopathological variants of central neurocytoma: Report of 10 cases.

Central neurocytoma is a rare neuronal tumor affecting young adults and usually located in the lateral ventricles. Post-operative prognosis is generally good. Histologically, central neurocytoma is composed of isomorphous small round or ovoid cells alternating with irregularly shaped patches of fibrillary matrix similar to the neuropile. In a series of 10 cases, two central neurocytomas were histologically "atypical" at first examination. One was intra-ventricular, and the second had an intra-parenchymatous juxta-ventricular location. Both were highly cellular with mitotic activity, and tumor necrosis was seen in one. Neuronal differentiation was assessed by synaptophysin immunoreactivity in all 10 cases and by ultrastructural examination in four, including the two "atypical" forms. Neuronal differentiation was less marked in these "atypical" forms, one also presenting focal GFAP immunoreactivity. The proliferative potential was determined by MIB-1 labeling index and compared with clinical outcome. The eight classical central neurocytomas had a MIB-1 labeling index < 2.3%, whereas the two "atypical" forms had a MIB-1 labeling index > 5.2% and both recurred. We think that there is a spectrum of small-cell neuronal tumors. The two extremes could be the central neurocytoma and the primary cerebral neuroblastoma, while the intermediate forms might be qualified as "atypical neurocytoma". In our series, the histological and immunohistochemical criteria of biological aggressiveness appeared to be high mitotic activity, tumor necrosis, loss of neuronal differentiation and high MIB-1 labelling index.