BackgroundSerum autoantibodies against the water channel aquaporin-4 (AQP4) are important diagnostic biomarkers and pathogenic factors for neuromyelitis optica (NMO). However, AQP4-IgG are absent in 5-40% of all NMO patients and the target of the autoimmune response in these patients is unknown. Since recent studies indicate that autoimmune responses to myelin oligodendrocyte glycoprotein (MOG) can induce an NMO-like disease in experimental animal models, we speculate that MOG might be an autoantigen in AQP4-IgG seronegative NMO. Although high-titer autoantibodies to human native MOG were mainly detected in a subgroup of pediatric acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) patients, their role in NMO and High-risk NMO (HR-NMO; recurrent optic neuritis-rON or longitudinally extensive transverse myelitis-LETM) remains unresolved.ResultsWe analyzed patients with definite NMO (n = 45), HR-NMO (n = 53), ADEM (n = 33), clinically isolated syndromes presenting with myelitis or optic neuritis (CIS, n = 32), MS (n = 71) and controls (n = 101; 24 other neurological diseases-OND, 27 systemic lupus erythematosus-SLE and 50 healthy subjects) for serum IgG to MOG and AQP4. Furthermore, we investigated whether these antibodies can mediate complement dependent cytotoxicity (CDC). AQP4-IgG was found in patients with NMO (n = 43, 96%), HR-NMO (n = 32, 60%) and in one CIS patient (3%), but was absent in ADEM, MS and controls. High-titer MOG-IgG was found in patients with ADEM (n = 14, 42%), NMO (n = 3, 7%), HR-NMO (n = 7, 13%, 5 rON and 2 LETM), CIS (n = 2, 6%), MS (n = 2, 3%) and controls (n = 3, 3%, two SLE and one OND). Two of the three MOG-IgG positive NMO patients and all seven MOG-IgG positive HR-NMO patients were negative for AQP4-IgG. Thus, MOG-IgG were found in both AQP4-IgG seronegative NMO patients and seven of 21 (33%) AQP4-IgG negative HR-NMO patients. Antibodies to MOG and AQP4 were predominantly of the IgG1 subtype, and were able to mediate CDC at high-titer levels.ConclusionsWe could show for the first time that a subset of AQP4-IgG seronegative patients with NMO and HR-NMO exhibit a MOG-IgG mediated immune response, whereas MOG is not a target antigen in cases with an AQP4-directed humoral immune response.

Multiple sclerosis is a chronic inflammatory disease characterized by perivenous inflammation and focal destruction of myelin. Many attempts have been undertaken previously to create animal models of chronic inflammatory demyelinating diseases through autoimmunity or virus infection. Recently, however, a new model of myelin oligodendrocyte glycoprotein (MOG) induced autoimmune encephalomyelitis became available, which, in a very standardized and predictable way, leads to chronic (relapsing or progressive) disease and widespread CNS demyelination. In the present study we actively induced MOG-experimental autoimmune encephalomyelitis (EAE) in different inbred rat strains using different immunization protocols. The pathology found in our models closely reflects the spectrum of multiple sclerosis (MS) pathology: Classical MS as well as variants such as optic neuritis, Devic's disease and Marburg's type of acute MS are mimicked in rats immunized with MOG antigen. Furthermore we demonstrate, that by using the proper strain/sensitization regime, subforms of MS such as for instance neuromyelitis optica can be reproducibly induced. Our study further supports the notion, that incidence and expression of the disease in this model, alike the situation in multiple sclerosis, is determined by genetic and environmental factors.

Axonal injury is considered the major cause of disability in patients with multiple sclerosis (MS), but the underlying effector mechanisms are poorly understood. Starting with a proteomics-based approach, we identified neurofascin-specific autoantibodies in patients with MS. These autoantibodies recognize the native form of the extracellular domains of both neurofascin 186 (NF186), a neuronal protein concentrated in myelinated fibers at nodes of Ranvier, and NF155, the oligodendrocyte-specific isoform of neurofascin. Our in vitro studies with hippocampal slice cultures indicate that neurofascin antibodies inhibit axonal conduction in a complement-dependent manner. To evaluate whether circulating antineurofascin antibodies mediate a pathogenic effect in vivo, we cotransferred these antibodies with myelin oligodendrocyte glycoprotein–specific encephalitogenic T cells to mimic the inflammatory pathology of MS and breach the blood–brain barrier. In this animal model, antibodies to neurofascin selectively targeted nodes of Ranvier, resulting in deposition of complement, axonal injury, and disease exacerbation. Collectively, these results identify a novel mechanism of immune-mediated axonal injury that can contribute to axonal pathology in MS.

We describe a case of multiple sclerosis characterized by deposition of immunoglobulin and complement in the areas of active demyelination. This was particularly evident for the C9neo antigen, which is a marker for the activated lytic complement complex and was exclusively deposited in the areas of active myelin destruction. In addition, macrophages in the lesions contained degradation products that were immunoreactive for myelin antigens, immunoglobulins, and C9neo antigen. Destruction of myelin sheaths was associated with incomplete loss of oligodendrocytes in the active areas and reappearance of oligodendrocytes with remyelination in the inactive plaque center. Patient and Methods PatientThe patient was a 47-year-old woman with unremarkable family history. At 15 years of age she had an episode of diplopia and strabismus and bilateral extensor plantar reflexes were observed. A similar transient episode occurred in the subsequent year, and a diagnosis of MS was entertained. At age 28, her vision deteriorated and her gait was described as spastic and atactic. During pregnancy, at age 29, she developed spastic paraparesis and generalized sensory deficiency below T6-7, as well as urinary incontinency. Her optic discs were pale, and her cerebrospinal fluid (CSF) protein concentration was moderately elevated. After treatment with adrenocorticotropic hormone (ACTH) her condition improved and she had a stable remission of the disease for 18 years.At age 47, after an upper respiratory tract infection, her condition suddenly worsened, with abrupt onset of severe paralysis of the left upper extremity. In addition, the patient From the

Recent magnetic resonance (MR) studies of multiple sclerosis lesions indicate that axonal injury is a major correlate of permanent clinical deficit. In the present study we systematically quantified acute axonal injury, defined by immunoreactivity for beta-amyloid-precursor-protein in dystrophic neurites, in the central nervous system of 22 multiple sclerosis patients and 18 rats with myelin-oligodendrocyte glycoprotein (MOG)-induced chronic autoimmune encephalomyelitis (EAE). The highest incidence of acute axonal injury was found during active demyelination, which was associated with axonal damage in periplaque and in the normal appearing white matter of actively demyelinating cases. In addition, low but significant axonal injury was also observed in inactive demyelinated plaques. In contrast, no significant axonal damage was found in remyelinated shadow plaques. The patterns of axonal pathology in chronic active EAE were qualitatively and quantitatively similar to those found in multiple sclerosis. Our studies confirm previous observations of axonal destruction in multiple sclerosis lesions during active demyelination, but also indicate that ongoing axonal damage in inactive lesions may significantly contribute to the clinical progression of the disease. The results further emphasize that MOG-induced EAE may serve as a suitable model for testing axon-protective therapies in inflammatory demyelinating conditions.

Experimental autoimmune encephalomyelitis (EAE) induced in the rat by active immunization with myelin-oligodendrocyte-glycoprotein (MOG) is mediated by synergy between MOG-specific T cells and demyelinating MOGspecific antibody responses. The resulting disease is chronic and displays demyelinating central nervous system (CNS) pathology that closely resembles multiple sclerosis. We analyzed major histocompatibility complex (

Demyelination caused by inflammation of the CNS has been considered to be a major hallmark of multiple sclerosis (MS). Using experimental autoimmune encephalomyelitis, a model of MS, we demonstrate that an immune-mediated attack of the optic nerve is accompanied by an early degeneration of retinal ganglion cells (RGCs). The decrease of neuronal cell density was correlated with functional disabilities as assessed by visual evoked cortical potentials and electroretinogram. Visual acuity was significantly reduced. DNA degradation and activation of caspase-3 in RGCs indicate that cell death of RGCs is apoptotic. These findings show for the first time that an inflammatory attack against myelin components can lead to acute neuronal cell loss by apoptosis.

BackgroundNeuromyelitis optica (NMO), a severe demyelinating disease, represents itself with optic neuritis and longitudinally extensive transverse myelitis. Serum NMO-IgG autoantibodies (Abs), a specific finding in NMO patients, target the water channel protein aquaporin-4 (AQP4), which is expressed as a long (M-1) or a short (M-23) isoform.Methodology/Principal FindingsThe aim of this study was to analyze serum samples from patients with NMO and controls for the presence and epitope specificity of IgG and IgM anti-AQP4 Abs using an immunofluorescence assay with HEK293 cells expressing M-1 or M-23 human AQP4. We included 56 patients with definite NMO (n = 30) and high risk NMO (n = 26), 101 patients with multiple sclerosis, 27 patients with clinically isolated syndromes (CIS), 30 patients with systemic lupus erythematosus (SLE) or Sjögren's syndrome, 29 patients with other neurological diseases and 47 healthy controls. Serum anti-AQP4 M-23 IgG Abs were specifically detected in 29 NMO patients, 17 patients with high risk NMO and two patients with myelitis due to demyelination (CIS) and SLE. In contrast, IgM anti-AQP4 Abs were not only found in some NMO and high risk patients, but also in controls. The sensitivity of the M-23 AQP4 IgG assay was 97% for NMO and 65% for high risk NMO, with a specificity of 100% compared to the controls. Sensitivity with M-1 AQP4 transfected cells was lower for NMO (70%) and high risk NMO (39%). The conformational epitopes of M-23 AQP4 are the primary targets of NMO-IgG Abs, whereas M-1 AQP4 Abs are developed with increasing disease duration and number of relapses.ConclusionsOur results confirm M-23 AQP4-IgG Abs as reliable biomarkers in patients with NMO and high risk syndromes. M-1 and M-23 AQP4-IgG Abs are significantly associated with a higher number of relapses and longer disease duration.