Objective-The serum of most neuromyelitis optica (NMO) patients contains autoantibodies (NMO-IgGs) directed against the aquaporin-4 (AQP4) water channel located on astrocyte foot processes in the perivessel and subpial areas of the brain. Our objectives were to determine the source of central nervous system (CNS) NMO-IgGs and their role in disease pathogenesis.Methods-Fluorescence activated cell sorting and single-cell reverse transcriptase PCR were used to identify overrepresented plasma cell immunoglobulin (Ig) sequences in the cerebrospinal fluid (CSF) of an NMO patient after a first clinical attack. Monoclonal recombinant antibodies (rAbs) were generated from the paired heavy and light chain sequences and tested for target specificity and Fc effector function. The effect of CSF rAbs on CNS immunopathology was investigated by delivering single rAbs to rats with experimental autoimmune encephalomyelitis (EAE).Results-Repertoire analysis revealed a dynamic, clonally expanded plasma cell population with features of an antigen-targeted response. Using multiple independent assays, 6 of 11 rAbs generated from CSF plasma cell clones specifically bound to AQP4. AQP4-specific rAbs recognized conformational epitopes and mediated both AQP4-directed antibody-dependent cellular cytotoxicity and complement-mediated lysis. When administered to rats with EAE, an AQP4-specific NMO CSF rAb induced NMO immunopathology: perivascular astrocyte depletion, myelinolysis and complement and Ig deposition.Interpretation-Molecular characterization of the CSF plasma cell repertoire in an early NMO patient demonstrates that AQP4-specfic Ig is synthesized intrathecally at disease onset and directly
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Although the cause of MS is still uncertain, many findings point toward an ongoing autoimmune response to myelin antigens. Because of its location on the outer surface of the myelin sheath and its pathogenicity in the experimental autoimmune encephalomyelitis model, myelin oligodendrocyte glycoprotein (MOG) is one of the potential disease-causing self antigens in MS. However, the role of MOG in the pathogenesis of MS has remained controversial. In this study we addressed the occurrence of autoantibodies to native MOG and its implication for demyelination and axonal loss in MS. We applied a high-sensitivity bioassay, which allowed detecting autoantibodies that bind to the extracellular part of native MOG. Antibodies, mostly IgG, were found in sera that bound with high affinity to strictly conformational epitopes of the extracellular domain of MOG. IgG but not IgM antibody titers to native MOG were significantly higher in MS patients compared with different control groups with the highest prevalence in primary progressive MS patients. Serum autoantibodies to native MOG induced death of MOGexpressing target cells in vitro. Serum from MS patients with high anti-MOG antibody titers stained white matter myelin in rat brain and enhanced demyelination and axonal damage when transferred to autoimmune encephalomyelitis animals. Overall these findings suggest a pathogenic antibody response to native MOG in a subgroup of MS patients.antibodies ͉ axonal damage ͉ demyelination ͉ lentiviral expression M ultiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by inflammation, demyelination, gliosis, and neurodegeneration (1). Inflammatory infiltrates composed of macrophages/microglia cells, T cells, and B cells are found in MS lesions (2). In a significant proportion of patients, demyelination appears to be antibody-mediated and complement-dependent, with loss of oligodendrocytes and axonal damage (3). Despite intensive studies, the etiology of disease still remains uncertain (4). It is believed that MS results from an autoimmune response to proteins expressed in oligodendrocytes or the myelin sheath (5). Myelin oligodendrocyte glycoprotein (MOG) is one candidate target self-antigen. MOG expression is confined to the CNS and sequestered at the outermost surface of the myelin sheath (6, 7). This allows easy access by antibodies from the extracellular space.MOG induces experimental autoimmune encephalomyelitis (EAE) in a variety of species (8-12). In contrast to other models, MOG protein elicited EAE is characterized by a pathogenic antibody response. Although anti-MOG antibodies cannot induce EAE on their own, they strongly enhance T cell and macrophage-initiated demyelination and may augment disease severity (12,13). Several studies suggest that the pathogenicity of antibodies resides in their ability to recognize native MOG protein with proper glycosylation and to fix complement, while the significance...
Multiple sclerosis (MS) is a chronic disease of the CNS that is characterized by inflammation, demyelination and axonal injury. Although the etiology of MS is still unknown, many findings point toward a central role for the immune system in the pathogenesis of the disease. This hypothesis is strongly supported by the beneficial effects of immunomodulatory and immunosuppressive therapy on disease activity. Over the past few years, substantial progress has been made in deciphering the immune response in MS. Although animal models have advanced our knowledge of basic mechanisms of immune responses in the CNS, recent studies have also highlighted the differences between MS and its animal equivalent, experimental autoimmune encephalomyelitis. New immunotherapeutic agents have been developed and evaluated in clinical trials. Here, we review current knowledge of the immunopathogenesis of MS and corresponding animal models of disease, and discuss new immunointerventional treatment strategies based on changing pathogenetic concepts.
MS is a chronic inflammatory and demyelinating disease of the CNS with as yet unknown etiology. A hallmark of this disease is the occurrence of oligoclonal IgG antibodies in the cerebrospinal fluid (CSF). To assess the specificity of these antibodies, we screened protein expression arrays containing 37,000 tagged proteins. The 2 most frequent MS-specific reactivities were further mapped to identify the underlying high-affinity epitopes. In both cases, we identified peptide sequences derived from EBV proteins expressed in latently infected cells. Immunoreactivities to these EBV proteins, BRRF2 and EBNA-1, were significantly higher in the serum and CSF of MS patients than in those of control donors. Oligoclonal CSF IgG from MS patients specifically bound both EBV proteins. Also, CD8 + T cell responses to latent EBV proteins were higher in MS patients than in controls. In summary, these findings demonstrate an increased immune response to EBV in MS patients, which suggests that the virus plays an important role in the pathogenesis of disease.
Capitalizing on experience based on a large body of well characterized patient data collected both cross-sectionally and longitudinally, pharmacotherapy has been improved and mortality and comorbidities due to ADEM have been reduced. Unfortunately, the pathogenic events that trigger the initial clinical attack, and possibly pave the way for ongoing relapsing disease, remain unknown. Clinically applicable diagnostic criteria are still lacking.
MS is a chronic inflammatory and demyelinating disease of the CNS with as yet unknown etiology. A hallmark of this disease is the occurrence of oligoclonal IgG antibodies in the cerebrospinal fluid (CSF). To assess the specificity of these antibodies, we screened protein expression arrays containing 37,000 tagged proteins. The 2 most frequent MS-specific reactivities were further mapped to identify the underlying high-affinity epitopes. In both cases, we identified peptide sequences derived from EBV proteins expressed in latently infected cells. Immunoreactivities to these EBV proteins, BRRF2 and EBNA-1, were significantly higher in the serum and CSF of MS patients than in those of control donors. Oligoclonal CSF IgG from MS patients specifically bound both EBV proteins. Also, CD8 + T cell responses to latent EBV proteins were higher in MS patients than in controls. In summary, these findings demonstrate an increased immune response to EBV in MS patients, which suggests that the virus plays an important role in the pathogenesis of disease.
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