Antineuronal antibodies in Parkinson's disease.

Antineuronal antibodies (ANAs) have been implicated in the pathophysiology of postinfectious movement disorders, such as Sydenham's chorea. However, their relevance in other movement disorders--in the absence of infectious triggers--remains much disputed. We sought to assess the frequency of ANAs in idiopathic Parkinson's disease (IPD) and to explore whether a specific phenotype is associated with the presence of ANAs. For this purpose, we recruited 76 IPD patients, 9 patients with genetic parkinsonism, and 10 with one of the parkinson-plus syndromes. They were all subjected to a comprehensive clinical review. In addition, 50 patients with non-extrapyramidal neurological disease and 30 healthy blood donors served as control populations. Blood samples were tested for the presence of ANAs with Western blotting, using recombinant proteins of the three putative antigens (aldolase C, neuron-specific enolase, and pyruvate kinase M1). We found these antibodies in 11.8% of the 76 IPD patients, which differed significantly from healthy controls (0%, P = 0.043), but nonsignificantly from patients with genetic parkinsonism (11.1%), with a parkinson-plus syndrome (10%), or from neurological disease controls (4%). With respect to relevant disease characteristics, IPD patients with or without ANAs were indistinguishable, except for atypical disease features (mainly early falls or freezing and marked Pisa syndrome), which were more frequent in the ANA-positive IPD group. We conclude that ANAs do not play a role in the majority of patients with IPD, but might be relevant in the pathogenesis of IPD with atypical features.

Quantitative demonstration of intrathecal synthesis of high affinity immunoglobulin G in herpes simplex encephalitis using affinity-mediated immunoblotting.

Three paired serial samples of CSF and serum (from days 8, 13 and 22) were taken from a patient referred to the National Hospital for Neurology and Neurosurgery with what was duly confirmed as having herpes simplex encephalitis using PCR. The samples were investigated using affinity-mediated immunoblotting followed by incubation with sodium thiocyanate. Digitisation of the blots enabled further analysis. We showed that the clones of antigen-specific IgG, which were produced intrathecally, were of higher relative affinity than polyclonal antigen-specific IgG.

Neuronal surface glycolytic enzymes are autoantigen targets in post-streptococcal autoimmune CNS disease.

Infection with the Group A Streptococcus (GAS) can result in immune mediated brain disease characterised by a spectrum of movement and psychiatric disorders. We have previously described anti-neuronal antibodies in patients that bind to a restricted group of brain antigens with molecular weights 40 kDa, 45 kDa (doublet) and 60 kDa. The aim of this study was to define these antigens using 2-dimensional electrophoresis or ion exchange and hydrophobic interaction chromatography, followed by mass spectrometry. The findings were confirmed using commercial antibodies, commercial antigens and recombinant human antigens. The autoantigens were neuronal glycolytic enzymes--NGE (pyruvate kinase M1, aldolase C, neuronal-specific and non-neuronal enolase). These are multifunctional proteins that are all expressed intracellularly and on the neuronal cell surface. On the neuronal plasma membrane, NGE are involved in energy metabolism, cell signalling and synaptic neurotransmission. Anti-NGE antibodies were more common in the 20 unselected post-streptococcal CNS patients compared to 20 controls. In vitro experiments using cultured neurons showed that commercial anti-NGE antibodies induced apoptosis compared to blank incubation and control anti-HuD antibody. GAS also expresses glycolytic enzymes on cell surfaces that have 0-49% identity with human NGE, suggesting molecular mimicry and autoimmune cross-reactivity may be the pathogenic mechanism in post-streptococcal CNS disease.

Soluble adhesion molecules in acute disseminated encephalomyelitis.

Soluble adhesion molecules are overexpressed in neuroinflammatory disorders. Their synthesis parallels that of their membrane-bound counterparts, which modulate lymphocyte transmigration through the blood-brain barrier. Blood-brain barrier cellular migration may be essential in the evolution of postinfectious inflammatory central nervous system disease. The serum levels of soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, and soluble E-selectin were measured in 12 children with acute disseminated encephalomyelitis and in two control groups (35 healthy and 35 affected by noninflammatory neurologic diseases) of similar age. In patients with acute disseminated encephalomyelitis, soluble E-selectin serum levels were significantly higher (median 113 ng/mL, range 54-144) than in both control groups (median 44, range 31-63, and median 58, range 43-89, respectively; one-way analysis of variance, P < 0.0001); a statistical trend for higher levels of soluble intercellular adhesion molecule-1 was observed in acute disseminated encephalomyelitis subjects, whereas soluble vascular adhesion molecule-1 titers did not differ between the three groups. The specific role played by each of these molecules in lymphocyte extravasation and the differential cytokine modulation of their expression might explain the result. Further larger studies are required including serial measurements and cerebrospinal fluid analysis.

CSF and serum immune parameters in Sydenham's chorea: evidence of an autoimmune syndrome?

Previous investigations have suggested that Sydenham's chorea (SC) may be an autoantibody mediated disorder. We examined this autoimmune hypothesis by measuring Th1 (IFN-gamma, IL-12) and Th2 (IL-4, IL-10) cytokines, oligoclonal bands (OCB) and anti-basal ganglia antibodies (ABGA). CSF IL-4 was elevated in 31% of acute SC and 50% of persistent SC. CSF IL-10 was also elevated in 31% of acute SC but 0% of persistent SC. CSF IFN-gamma was undetectable in all patients. Serums IL-4, IL-10 and IL-12 were elevated in acute compared to persistent SC. OCB were found in 46% of acute SC, ABGA were in 93% of acute SC and 50% of persistent SC was of IgG(1) and IgG(3) subclass. These findings support an autoantibody pathogenesis.

Three cases of central nervous system complications associated with Mycoplasma pneumoniae.

We report three new cases of acute central nervous system disease occurring shortly after Mycoplasma pneumoniae infection. The clinical phenotypes were characterized by encephalopathy (n = 2), optic neuritis (n = 1), transverse myelitis (n = 1), and seizures (n = 1). Although there was strong supportive evidence of preceding M. pneumoniae infection, cerebrospinal fluid polymerase chain reaction for M. pneumoniae was negative in all three patients. We propose that these cases resulted from a para-infectious immune-mediated process rather than parenchymal invasion by the microorganism. The two patients treated with steroids improved rapidly, and all three patients have made a full recovery. We review the literature regarding M. pneumoniae central nervous system complications and discuss the proposed pathologic mechanisms; para-infectious immune-mediated disease and parenchymal invasion of the central nervous system. Systematic investigation to discriminate between these two processes will be essential to select appropriate antibiotic and immunomodulatory therapies.