Andreas J. Steck

Demyeliating neuropathy and monoclonal IgM antibody to myelin‐associated glycoprotein

We studied a patient with demyelinating neuropathy and monoclonal IgM kappa antibody to the major myelin-associated glycoprotein (MAG). Binding of this monoclonal antibody to the myelin antigen was demonstrated by imimunoelectroblot. Binding to MAG seemed to be specific, because it was completely inhibited by MAG isolated from human myelin. Immunostaining was observed with MAG from CNS and peripheral nervous system myelin.

Levodopa in Parkinsonism: Potentiation of Central Effects with a Peripheral Inhibitor

Abstract The clinical state achieved with levodopa was compared to that on levodopa plus alpha-methyldopa hydrazine, which blocks conversion of levodopa to dopamine within peripheral tissues only. Five children with dystonia remained unimproved by either regimen. In 26 adults with Parkinsonism less levodopa was needed for symptomatic control when levodopa was given with inhibitor than when used alone. The amount of inhibitor that had to be added to similar doses of levodopa was less in patients who had received levodopa chronically. Rapid induction of therapy, better diurnal symptomatic control and a new capability to administer pyridoxine to patients receiving levodopa constituted advantages of adding inhibitor to levodopa. The main disadvantage of these combinations was the rapid induction of involuntary movements.

Reactivity with the peripheral myelin glycoprotein Po in serum from patients with monoclonal IgM gammopathy and polyneuropathy

The major glycoprotein Po from human and bovine peripheral nerves carries the L2/HNK-1 and L3 carbohydrate epitopes and is recognized by serum from patients with IgM gammopathy and polyneuropathy. Only serum from patients with reactivity toward the myelin-associated glycoprotein (MAG) was reactive with Po, while serum that did not react with MAG also did not recognize Po. Furthermore, the neural adhesion molecules L1, N-CAM, and J1 were also recognized by the serum that reacted with MAG, while the L3 carbohydrate-carrying cell adhesion molecule AMOG was not recognized. These observations indicate a restricted specificity in carbohydrate reactivity of IgM paraproteins and implicate yet another and, for the first time, peripheral myelin-specific glycoprotein in the pathogenesis of demyelinating neuropathy.

Predictive value of anti-GM1 ganglioside antibodies in neuromuscular diseases: a study of 180 sera.

The incidence of anti-GM1 antibodies in the serum of 104 patients with neurological diseases, 35 patients with non-neurological diseases (NND) and 41 normal controls was determined by enzyme-linked immunosorbent assay (ELISA). Anti-GM1 antibodies were found in 90% of patients presenting with a motor neuropathy (all except one had multifocal conduction blocks). A large proportion (60%) of these patients displayed high antibody titer ranging from 101 to 788. A low incidence of anti-GM1 antibodies was found in the other groups of patients, i.e. 21% of amyotrophic lateral sclerosis (ALS), 26% of other neurological diseases (OND) and 23% of NND. High antibody titers ranging from 106 to 260 were found in two (5%) ALS patients, one (2%) OND patient (myasthenia gravis), and one (3%) NND patient (Waldenströms disease). This study shows that high titers of anti-GM1 antibodies are found in a large proportion of patients with motor neuropathy with multifocal conduction blocks. This argues for a possible autoimmune origin of this neuropathy. We suggest that anti-GM1 antibody determination should be included systematically in the evaluation of all patients with motor neuron diseases and predominantly motor neuropathies.

Immunostaining of motor nerve terminals by IgM M protein with activity against gangliosides GM1 and GDlb from a patient with motor neuron disease

We demonstrated the binding of an IgM monoclonal protein, obtained from a patient with motor neuron disease, with known antibody activity against gangliosides GM1, GDlb, and asialo GM1, to neuromuscular junctions in guinea pig gastrocnemius muscle, using an indirect immunofluorescence technique. Staining disappeared after delipidation of muscle sections. Denervated muscle sections showed no labeling at the neuromuscular junction after incubation with the patients serum. This indicates presynaptic binding of the IgM M protein and supports the concept that IgM monoclonal antibody to nerve terminal determinants may underlie a motor neuron disorder.

Studies on the intrathecal humoral immune response in canine distemper encephalitis

Abstract Albumin and IgG were quantitated in paired cerebrospinal fluid (CSF) and serum samples from dogs with demyelinating canine distemper virus (CDV) infection by means of rocket immunoelectrophoresis. The IgG index as indicator for intrathecal immunoglobulin synthesis was normal in animals with non-inflammatory demyelinating lesions and elevated in dogs with inflammatory myelin lesions. Specific antibodies against CDV and myelin were quantitated in CSF and serum from 8 dogs with an elevated IgG index. Eight of these dogs had significant amounts of antimyelin antibody and 4 dogs had neutralizing anti-CDV antibody in the CSF. Whereas the pathogenetic significance of antimyelin antibodies remains uncertain, the intrathecal antiviral immune response provides a plausible explanation for immunopathologic destruction of myelin in distemper.

Activated T lymphocytes in patients with multiple sclerosis

We used four monoclonal antibodies designated MLR-1, -2, -3, and -4, specifically directed against determinants uniquely present on activated T lymphocytes to analyze peripheral blood lymphocytes (PBL) of patients with multiple sclerosis (MS). By indirect immunofluorescence techniques, we found that many PBL expressed one or more of these activation antigens. Thus, high percentages of MLR-2 positive cells were found in all 20 MS patients (66 ± 12% in 13 patients with the remitting form and 57 ± 14% in 7 patients with the progressive form). MLR-3 positive cells were found in three patients with the remitting form and five patients with progressive MS, MLR-4 in seven patients with remitting MS and in five with the progressive type. MLR-1 positive cells were prominent in only two cases (one remitting and one progressive). Discrepancies between expression of MLR antigens and molecules coded by the HLA-DR region (Ia antigens) were observed.

Confocal microscopic localization of anti-myelin-associated glycoprotein autoantibodies in a patient with peripheral neuropathy initially lacking a detectable IgM gammopathy

Abstract We report here on a patient with anti-myelin-associated glycoprotein (MAG) neuropathy in whom examination of a sural nerve biopsy by multichannel confocal microscopy showed a partly overlapping distribution of MAG and IgM deposits in myelinated fibers. Our data demonstrate that MAG in Schmidt-Lanterman incisures and paranodal loops, as well as some additional HNK-1-positive components of the basal lamina, are the major targets of the anti-MAG monoclonal IgM autoantibodies in this neuropathy in vivo. Perforation of the basal lamina can allow the penetration and binding of anti-MAG IgM inside myelinated fibers. Our results support and extend the notion that the production of monoclonal anti-MAG IgM may be antigenically driven by MAG molecules and that this process may occur in the immunologically privileged environment of the nerve prior to the appearance of a genuine gammopathy in serum.

Motor conduction block and high titres of anti-GM1 ganglioside antibodies: pathological evidence of a motor neuropathy in a patient with lower motor neuron syndrome.

A patient with a progressive lower motor neuron syndrome and neurophysiological evidence of motor axon loss, multifocal proximal motor nerve conduction block, and high titres of anti-ganglioside GM1 antibodies. Neuropathological findings included a predominantly proximal motor radiculoneuropathy with multifocal IgG and IgM deposits on nerve fibres associated with a loss of spinal motor neurons. These findings support an autoimmune origin of this lower motor neuron syndrome with retrograde degeneration of spinal motor neurons and severe neurogenic muscular atrophy.

Myelin-associated glycoprotein is produced before myelin basic protein in cultured oligodendrocytes

Mixed glial cell cultures from neonatal dog cerebellum were harvested daily between 3 and 21 days after seeding and studied with immunocytochemical techniques for the demonstration of myelin-associated glycoprotein (MAG) and myelin basic protein (MBP). Both MAG and MBP were detected in the cultures and by means of double labelling techniques shown to be produced by the same cells. MAG+ cells occurred earlier and were always more numerous than MBP+ cells. These results suggest that the oligodendrocyte in vitro expresses MAG before MBP. The findings are discussed in respect to oligodendroglial differentiation and myelination in vivo.