West Nile Virus infection triggering autoimmune encephalitis: Pathophysiological and therapeutic implications.

BACKGROUND: A contributing factor in triggering autoimmune phenomena is pathogen infections. Here we describe a case that expands the spectrum of infection-associated autoimmune encephalitis and discuss plausible pathogenetic mechanisms. DESIGN: Case report and in silico analysis. RESULTS: A patient with West Nile Virus infection developed autoimmune encephalitis with positive anti-glycine receptor antibodies. Combination therapy with corticosteroids and intravenous immunoglobulin resulted in the resolution of encephalitis signs and symptoms. An in silico analysis unveiled certain sequence similarities between viral antigens and receptor sequence fragments suggesting a molecular mimicry autoimmunization process. CONCLUSIONS: Our case indicates that West Nile Virus infections can trigger autoimmune encephalitis. Our finding expands the spectrum of autoimmune conditions that can develop following an infection. Whether the autoimmunization process is due to molecular mimicry or due to the expansion of natural autoantibody clones merits further investigation.

Epileptic syndrome in systemic lupus erythematosus and neuronal autoantibody associations.

We investigated systemic lupus erythematosus (SLE) patients with epilepsy, a major and organic neurological symptom. Our aim was to test patients for the autoimmune epilepsy-associated antibodies anti-GAD, anti-NMDAR, anti-AMPAR1/2, anti-GABABR and anti-VGKC. We tested sera from ten SLE patients with current or previous episodes of epileptic seizures. In addition, sera were tested for staining on primary hippocampal neurons. The patients' clinical and neuroimaging profile, disease activity and accumulated damage scores and therapeutic regimens administered were recorded, and correlations were evaluated. Patients were negative for all anti-neuronal autoantibodies tested, and showed no staining on primary hippocampal cells, which suggests the absence of autoantibodies against neuronal cell surface antigens. Epileptic seizures were all tonic-clonic, and all patients had high disease activity (mean SLE Damage Acticity Index score 19.3 ± 7.3). Six patients had minor or no brain magnetic resonance imaging findings, and three had major findings. 9/10 patients received immunosuppression for 5 ± 4 months, while anti-convulsive treatment was administered to all patients (4.2 ± 3 years). Our results suggest that the majority of SLE-related epileptic seizures cannot be attributed to the action of a single antibody against neuronal antigens. Studies with larger neuropsychiatric SLE populations and stricter inclusion criteria are necessary to verify these findings.

GAD65 epitope mapping and search for novel autoantibodies in GAD-associated neurological disorders.

Antibodies against Glutamic-acid-decarboxylase (GAD65) are seen in various CNS excitability disorders including stiff-person syndrome, cerebellar ataxia, encephalitis and epilepsy. To explore pathogenicity, we examined whether distinct epitope specificities or other co-existing antibodies may account for each disorder. The epitope recognized by all 27 tested patients, irrespective of clinical phenotype, corresponded to the catalytic core of GAD. No autoantibodies against known GABAergic antigens were found. In a screen for novel specificities using live hippocampal neurons, three epilepsy patients, but no other, were positive. We conclude that no GAD-specific epitope defines any neurological syndrome but other antibody specificities may account for certain phenotypes.

Reactivity to AQP4 epitopes in relapsing-remitting multiple sclerosis.

Autoantibodies against the water channel AQP4, expressed predominately in central nervous system astrocytes, are markers and pathogenic factors in Devic's disease. In this study we examined whether Multiple Sclerosis (MS) patients recognize antigenic epitopes on AQP4 that may define distinct disease subsets. We screened sera from 45 patients with relapsing-remitting MS (RRMS) and 13 patients with primary progressive MS (PMS). 23 Neuromyelitis Optica (NMO) patients previously characterized were used as assay positive/negative controls. Sera from 23 patients with Systemic Lupus Erythematosus, 23 with primary Sjogren syndrome without neurological involvement and from 28 healthy individuals were also used as controls. NMO-positive sera exhibited reactivity against the intracellular epitope AQPaa252-275, confirming previous observations. All RRMS sera tested negative for anti-AQP4 antibodies using a cell-based assay, but surprisingly, 13% of them reacted with the epitope AQPaa252-275. PMS, healthy and disease controls showed no specific reactivity. Whether these antibodies define distinct MS subsets and have a pathogenic potential pointing to convergent pathogenetic mechanism with NMO, or are simply markers of astrocytic damage, remains to be determined.

Peripheral neuropathies in Sjögren's syndrome: a critical update on clinical features and pathogenetic mechanisms.

Sjögren's syndrome is a systemic autoimmune disease that, apart from exocrine glands, may affect every organ or system. Involvement of different sections of the peripheral nervous system results in a wide spectrum of neuropathic manifestations. Based on distinct clinical, electrophysiological and histological criteria, the types of neuropathies seen in Sjögren's syndrome include: a) pure sensory which presents with distal symmetric sensory loss due to axonal degeneration of sensory fibers; sensory ataxia due to loss of proprioceptive large fibers (ganglionopathy); or with painful dysethesias (small fiber sensory neuropathy) due to degeneration of cutaneous axons. The latter appears to be the most common neuropathy in Sjögren's syndrome and requires skin biopsy for diagnosis to document loss or reduction of nerve fiber density; b) sensorimotor polyneuropathy affecting sensory and motor axons, often associated with severe systemic or pro-lymhomatous manifestations, such as palpable purpura and cryoglobulinemia, and c) rare types that include autoimmune demyelinating neuropathy, mononeuropathy, mononeuropathy multiplex and autonomic neuropathy. In this review, the frequency, prevalence and diagnostic criteria for each neuropathy subset are discussed and possible pathogenetic mechanisms are outlined.

Fine specificity of antibodies against AQP4: epitope mapping reveals intracellular epitopes.

The autoantibody to aquaporin-4 (AQP4) is a marker and a pathogenetic factor in Neuromyelitis Optica (NMO) (Devic's syndrome). Our aim was to identify B-cell antigenic linear epitopes of the AQP4 protein and investigate similarities with other molecules. To this end, we screened sera from 21 patients positive for anti-AQP4 antibodies (study group), from 23 SLE and 23 pSS patients without neurologic involvement (disease controls) and from 28 healthy individuals (normal controls). Eleven peptides, spanning the entire intracellular and extracellular domains of the AQP4 molecule, were synthesized, and all sera were screened for anti-peptide antibodies by ELISA. Specificity was evaluated by homologous inhibition assays. NMO positive sera exhibited reactivity against 3 different peptides spanning the sequences aa1-22 (AQPpep1) (42.9% of patients), aa88-113 (AQPpep4) (33%) and aa252-275 (AQPpep8) (23.8%). All epitopes were localized in the intracellular domains of AQP4. Homologous inhibition rates were ranging from 71.1% to 84.3%. A 73% sequence homology was observed between AQPpep8' aa257-271, a 15-mer peptide part of the AQPpep8 aa252-275, and the aa219-233 domain of the Tax1-HTLV-1 binding protein (TAX1BP1), a host protein associated with replication of the Human T-Lymphotropic Virus 1 (HTLV-1). Antibodies against the AQP4 and the TAX1BP1 15-mer peptides were detected in 26.3% (N = 5) and 31.6% (N = 6) of NMO positive sera (r(s) = 0.81, P < 0.0001). Healthy controls did not react with these peptides, while homologous and cross-inhibition assays confirmed binding specificity. This first epitope mapping for AQP4 reveals that a significant proportion of anti-AQP4 antibodies target linear epitopes localized in the intracellular domains of the channel. One of the epitopes displays high similarity with a portion of TAX1BP1 protein.

Innexins in the lobster stomatogastric nervous system: cloning, phylogenetic analysis, developmental changes and expression within adult identified dye and electrically coupled neurons.

Gap junctions play a key role in the operation of neuronal networks by enabling direct electrical and metabolic communication between neurons. Suitable models to investigate their role in network operation and plasticity are invertebrate motor networks, which are built of comparatively few identified neurons, and can be examined throughout development; an excellent example is the lobster stomatogastric nervous system. In invertebrates, gap junctions are formed by proteins that belong to the innexin family. Here, we report the first molecular characterization of two crustacean innexins: the lobster Homarus gammarus innexin 1 (Hg-inx1) and 2 (Hg-inx2). Phylogenetic analysis reveals that innexin gene duplication occurred within the arthropod clade before the separation of insect and crustacean lineages. Using in situ hybridization, we find that each innexin is expressed within the adult and developing lobster stomatogastric nervous system and undergoes a marked down-regulation throughout development within the stomatogastric ganglion (STG). The number of innexin expressing neurons is significantly higher in the embryo than in the adult. By combining in situ hybridization, dye and electrical coupling experiments on identified neurons, we demonstrate that adult neurons that express at least one innexin are dye and electrically coupled with at least one other STG neuron. Finally, two STG neurons display no detectable amount of either innexin mRNAs but may express weak electrical coupling with other STG neurons, suggesting the existence of other forms of innexins. Altogether, we provide evidence that innexins are expressed within small neuronal networks built of dye and electrically coupled neurons and may be developmentally regulated.

Null mutation in shaking-B eliminates electrical, but not chemical, synapses in the Drosophila giant fiber system: a structural study.

Mutations in the Drosophila shaking-B gene perturb synaptic transmission and dye coupling in the giant fiber escape system. The GAL4 upstream activation sequence system was used to express a neuronal-synaptobrevin-green fluorescent protein (nsyb-GFP) construct in the giant fibers (GFs); nsyb-GFP was localized where the GFs contact the peripherally synapsing interneurons (PSIs) and the tergotrochanteral motorneurons (TTMns). Antibody to Shaking-B protein stained plaquelike structures in the same regions of the GFs, although not all plaques colocalized with nsyb-GFP. Electron microscopy showed that the GF-TTMn and GF-PSI contacts contained many chemical synaptic release sites. These sites were interposed with extensive regions of close membrane apposition (3.25 nm +/- 0.12 separation), with faint cross striations and a single-layered array of 41-nm vesicles on the GF side of the apposition. These contacts appeared similar to rectifying electrical synapses in the crayfish and were eliminated in shaking-B2 mutants. At mutant GF-TTMn and GF-PSI contacts, chemical synapses and small regions of close membrane apposition, more similar to vertebrate gap junctions, were not affected. Gap junctions with more vertebratelike separation of membranes (1.41 nm +/- 0.08) were abundant between peripheral perineurial glial processes; these were unaffected in the mutants.