Experimental allergic neuritis induced by sensitization with galactocerebroside.

Thirteen of 31 rabbits immunized repeatedly with bovine brain galactocerebroside developed experimental allergic neuritis, manifested by flaccid paresis and hypesthesia of four limbs, 2 to 11 months after the initial inoculation. Electrophysiological studies revealed multifocal conduction block of peripheral nerves. Perivenular demyelinative lesions associated with phagocytic mononuclear cells occurred in spinal ganglia, roots, and less frequently in distal nerves.

Expression of melanoma-associated antigens by normal and neurofibroma Schwann cells.

The cell surface antigen distribution on traumatic neuroma Schwann cells and neurofibroma Schwann-like cells was characterized using monoclonal antibodies that define melanoma-associated antigens. Immunofluorescence staining of cultured cells, immunoprecipitation of radioiodinated antigens from cells placed in short-term cultures, and immunoperoxidase staining of frozen tissue sections revealed most of the melanoma-associated antigens tested on traumatic neuroma and neurofibroma Schwann cells and on fetal and adult femoral nerve. The cross-reactivity of the antibodies with neural cells may reflect the common neural crest embryological origin of Schwann cells and melanocytes. Cell sorter analysis of neurofibroma cells using a monoclonal antibody directed against the melanoma nerve growth factor receptor resulted in cell cultures highly enriched for Schwann-like cells which may bear the genetic defect responsible for neurofibromatosis. The antigen detected by this monoclonal antibody is the neurofibroma nerve growth factor receptor and the antibody was a potent inhibitor of nerve growth factor binding to neurofibroma cells.

Long-term culture of oligodendrocytes isolated from rat corpus callosum by Percoll density gradient. Lysis by polyclonal antigalactocerebroside serum.

Oligodendrocytes isolated from the corpus callosum of four-week-old rats by trypsimization and Percoll density gradient centrifugation were cultured on poly-1-lysine coated coverslips. Some cells extended short processes within 24 hours (h), and at that time up to 95% of the cells showed surface binding of rabbit antiserum to galactocerebroside (anti-GalC) as demonstrated by indirect immunofluorescence. Oligodendrocytes survived up to two months in culture, extending processes with membranous elaborations. Exposure of living oligodendrocytes to varying dilutions of rabbit anti-GalC serum in the presence of complement produced cytotoxicity which was directly proportional to the concentration of antiserum and duration of exposure, as assessed by a nigrosin dye exclusion test. This system of isolating and culturing rat oligodendrocytes will permit further developmental and immunologic studies related to demyelinating diseases.

Transient global amnesia due to a dominant hemisphere tumor.

Transient global amnesia is generally regarded as a benign syndrome of probable vascular etiology. We describe a man who experienced a single episode of transient global amnesia and subsequently developed a progressive dominant hemispheric syndrome. Neuroradiologic investigations and the patient's subsequent death strongly suggest that his disease was due to a left temporal-parietal mass lesion. Although the syndrome is most often benign, such patients should be examined for mass lesions.

Multiple sclerosis: therapeutic update.

Therapy for multiple sclerosis (MS) is undergoing rapid changes. We discuss recent developments in the therapy of MS, failures as well as successes, and consider some newer approaches. Multiple sclerosis, a multifocal, initially remitting-relapsing, and in some cases primarily progressive, inflammatory central nervous system immune-mediated demyelinating disease, with some axonal involvement, is currently the most common disabling neurologic disease of young people in North America and Europe. Although much is known about the pathogenesis, there is no cure and the disease must be managed long-term. Recently, there have been a number of advances in the treatment of MS.

Antimyelin antibodies in neurologic diseases. Immunofluorescent demonstration.

Antimyelin binding activity was determined in patients with multiple sclerosis, amyotrophic lateral sclerosis, other neurologic diseases, and normals. There was an increase in the group mean titer of antimyelin antibodies in patients with multiple sclerosis (MS) in acute exacerbation, amyotrophic lateral sclerosis (ALS) and Guillain-Barré syndrome. A lesser degree of binding was found in normals of all ages. There was an increase in the incidence of antimyelin antibodies in the IgM class in patients with ALS and MS. The interaction between human immunoglobulins and myelin seems to be immunologically specific and has the nature of an antigen-antibody reaction.

Overview of the rationale for immunomodulating therapies in multiple sclerosis.

The presence of mononuclear inflammatory cells within the nervous system first led to the hypothesis that an immunopathologic mechanism is involved in the pathogenesis of multiple sclerosis (MS). While there is now quite convincing evidence that MS is an immunologically mediated disease, many questions relevant to the use of immunomodulating therapy remain to be answered. These pertain to both the etiology and the exact immunopathologic mechanism involved. In addition, the inability to identify a specific target antigen for MS has implications for therapy. Despite these considerations, however, a rationale exists for the further evaluation of immunosuppressive therapies in this disease. However, it is prudent to limit use of such therapy to agents that can be shown to clearly produce sufficient clinical benefit in controlled studies to offset potential long-term risks in this chronic disease.

Intravenous immunoglobulins in multiple sclerosis.

The spectrum of diseases being treated with intravenous immunoglobulins (IVIg) appears to be ever broadening, including use in neurologic diseases. After a period of anectodal reports and smaller uncontrolled series, recently there have been several randomized, prospective, double-blind, placebo-controlled studies employing IVIg in patients with relapsing remitting (RR) multiple sclerosis (MS). Reduction in relapse rate and some evidence of decreased MRI activity has been reported, but to date no effect on disability or MRI lesion burden has been noted. Because of differences in methodologic design and patient populations, as well as the relatively small number of patients in some of these studies, a rigorous direct comparison of efficacy with the type I interferons and glatiramer acetate is not possible. Given these data and the high cost of IVIg, routine use of this mode of therapy cannot be recommended, certainly not as a first-line treatment. Larger studies would clearly be helpful. At present there is no evidence to support the use of IVIg in secondary progressive (SP) or primary progressive (PP) MS.

Multiple sclerosis: evidence for immunopathogenesis.

I have attempted to review the evidence that one or more immunopathologic mechanisms are responsible for the clinical and pathologic findings in multiple sclerosis (MS). I believe that there is considerable evidence for an immunopathogenesis of MS, but it is not clear what type or types of reactions are involved or against which autoantigen, neoantigen, or microbial antigen the reaction is directed. In addition, there is growing evidence that there are abnormalities in immunologic control mechanisms in patients with MS, although whether these changes are a cause or a result of the disease is not clear.

The frequency of CD5+ B lymphocytes in the peripheral blood of patients with myasthenia gravis.

A subset of human B lymphocytes expresses Leu-1 (CD5), a pan-T cell marker, which is the equivalent of the murine Lyt-1 molecule. CD5+ B cells produce autoantibodies in vitro; therefore, they may play a role in the pathogenesis of autoimmune disorders. In myasthenia gravis (MG), autoantibodies are directed against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction. We examined the peripheral blood leukocytes of MG patients (n = 21) and controls (n = 15) for the presence of Leu-1+ B lymphocytes. A fraction of B-1 (CD20)+ cells expressed Leu-1 at a low density. There was a statistically significant difference in the frequency of Leu-1+ B cells between patients and controls. We observed 2 frequency ranges of Leu-1+ B cells (0 to 30% and above 30%), which were not related to the total percentage of B-1+ cells in the blood. Fifty-seven percent of MG patients had a high frequency of Leu-1+ B cells compared with 13% of controls.

Effect of clinical status and treatment on the frequency of CD5+ B cells in patients with myasthenia gravis.

CD5+ B cells comprise a subset of B lymphocytes that may play a pathogenetic role in the development of human autoimmune disease. We previously reported a high-frequency phenotype (greater than 30% CD5+ B cells) in the peripheral blood of 57% of myasthenia gravis (MG) patients and 13% of controls. We have now examined additional patients (n = 41) and controls (n = 27) and continue to find that 44% of MG patients have a high-frequency phenotype of CD5+ B cells compared with 7% of controls. Serial studies showed that the frequency of CD5+ B cells in peripheral blood remained fairly stable for controls and that it may decrease with immunosuppressive therapy of MG patients. In patients receiving anticholinesterase only or no therapy (n = 21), the age at onset of MG, presence or absence of detectable serum anti-acetylcholine receptor antibody, clinical extent of MG, and the duration of disease may affect the frequency of CD5+ B cells in the blood.

Guillain-Barré syndrome (GBS) with bilateral optic neuritis and central white matter disease.

A patient with acute Guillain-Barré syndrome (GBS), recovering following plasmapheresis, developed bilateral optic neuritis with extensive CNS white matter lesions on MRI. This illness was associated with Mycoplasma pneumoniae infection. The rare association of GBS with CNS disease raises a possibility of a shared pathogenic CNS and PNS epitope in these cases.

Immunologic characterization of cerebrospinal fluid lymphocytes: preliminary report.

Cellular immunocompetence of cerebrospinal fluid lymphocytes was investigated in several neurologic diseases. Microtechniques were developed to enable determination of E-rosetting capacity and phytohemagglutinin responsiveness of scant numbers of cells present in the cerebrospinal fluid specimens studied. Although most individuals had phytohemagglutinin-responsive cells in their CSF, reactivity was somewhat less than that found simultaneously in their blood. Three of eight patients had comparable percentages of E rosettes in their blood and CSF. Int the remainder, the values differed significantly. Although preliminary, these result illustrate a new approach to immunologic characterization of CSF lymphocytes in diseases.

Thymic and peripheral blood T- and B-cell levels in myasthenia gravis.

We have compared the percentage of T and B lymphocytes in the thymus and peripheral blood populations of patients with myasthenia gravis. There were significantly fewer thymic T cells in myasthenic hyperplastic thymus (MG-H), but not in myasthenia gravis-thymoma (MG-T), compared with normal thymus biopsies obtained at cardiac surgery. Conversely, B cells were increased in MG-H versus MG-T and normals. Peripheral blood T and B cells were not different in any group of myasthenic patients compared to normal populations. In vitro autologous mixed lymphocyte reactions between thymus and peripheral blood lymphocytes occurred in MG-H, but did not correlate with the degree of thymic B-cell increases in these patients.

Spinal fluid basic protein immunoreactive material and spinal fluid lymphocyte reactivity to basic protein.

Levels of cerebrospinal fluid (CSF) basic protein (BP) immunoreactive material and CSF lymphocyte in vitro reactivity to BP were determined in patients with demyelinating and other inflammatory diseases of the nervous system. Elevated levels of BP and enhanced in vitro reactivity were observed, but there was no correlation between the magnitude of the in vitro response and the amount of BP-like material in CSF.

Serum-mediated oligodendrocyte cytotoxicity in multiple sclerosis patients and controls.

We examined serum-mediated cytotoxicity on cultured rat oligodendrocytes, using serum from patients with acute or chronic progressive multiple sclerosis and normal controls. We found heat-labile serum factors in serum from MS and also in controls. The cytotoxic effects of MS and normal sera were not restored by adding a source of complement. Despite apparent lack of disease specificity, such factors might damage oligodendrocytes if they gained access to these cells through a damaged blood-brain barrier in MS or other disorders.

In vitro synthesis of antibodies to acetylcholine receptor by peripheral blood mononuclear cells of patients with myasthenia gravis.

We studied the in vitro synthesis of antibodies to acetylcholine receptor (anti-AChR) by peripheral blood mononuclear cells (PBM) of patients with myasthenia gravis (MG) and normal subjects (NS). PBM from three of eight patients with generalized MG (MG-G) synthesized anti-AChR in vitro in the absence of pokeweed mitogen (PWM), and seven of eight did so in the presence of PWM. In individual subjects with MG-G, the levels of anti-AChR secreted in vitro by PBM correlated with serum anti-AChR antibody levels (r = 0.77) but not with the amount of IgG secreted in vitro (r = 0.44). No anti-AChR secretion was seen in culture of PBM from a patient with ocular MG, a patient with thymoma without MG, or six NS.

Epstein-Barr virus encephalomyelitis diagnosed by polymerase chain reaction: detection of the genome in the CSF.

A case of encephalomyelitis with polymerase chain reaction detection of Epstein-Barr virus (EBV) in the CSF, and concurrent serologic changes consistent with acute systemic EBV infection is presented and discussed. We document involvement of the brain, spinal cord, and nerve roots, summarize some unusual imaging findings, and note the evolution of CSF oligoclonal bands.

Inflammatory cytokines inhibit upregulation of glycolipid expression by Schwann cells in vitro.

OBJECTIVE: To determine whether products of inflammatory cells can inhibit differentiation and synthesis of myelin glycolipids by Schwann cells. BACKGROUND: Infiltration of the peripheral nervous system by inflammatory cells is a feature of acquired demyelinating neuropathies. It is not clear what role these cells have in causing demyelination or inhibiting myelin synthesis. METHODS: Nonmyelinating rat Schwann cells were incubated with 1) different concentrations of activated supernatants (AS) from mitogen-activated inflammatory cells; 2) 8-bromo cyclic adenosine monophosphate (8Br cAMP), known to induce Schwann cell differentiation and synthesis of glycolipids; 3) 8Br cAMP and varying concentrations of AS; 4) 8Br cAMP and cytosine arabinoside (Ara C), which inhibits Schwann cell proliferation; 5) 8Br cAMP, AS, and Ara C; or 6) additional medium. RESULTS: AS inhibits the capacity of cAMP to induce Schwann cell expression of myelin-associated glycolipids. Inhibition of glycolipid expression was independent of the capacity of these AS to induce Schwann cell proliferation. CONCLUSIONS: These data suggest that inflammatory mediators are capable of inhibition of Schwann cell differentiation and synthesis of myelin.

Antibody to myelin-associated glycoprotein produces central nervous system demyelination.

Antibodies to myelin-associated glycoprotein (MAG) have been implicated in certain human demyelinating diseases of the peripheral nervous system. In the present study, a monoclonal antibody to MAG with 20% guinea pig serum (GPS) was injected into mammalian optic nerves and produced in vivo demyelination associated with three ultrastructural patterns of myelin injury: (1) widened lamellae; (2) myelin vesiculation; and (3) cell-associated myelin damage. These patterns of myelin injury have been observed neuropathologically in MS and in a demyelinating peripheral neuropathy associated with plasma cell dyscrasias. Demyelination was not observed in nerves injected with anti-MAG and heated GPS or a monoclonal antibody to chick myoblasts and 20% GPS. These results establish the ability of anti-MAG to produce in vivo demyelination of mammalian CNS and indicate that a single antibody directed against a specific myelin component may initiate multiple types of myelin damage.