BACKGROUND Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. Many findings suggest that the disease has an autoimmune pathogenesis; the target of the immune response is not yet known. METHODS We screened serum IgG from persons with multiple sclerosis to identify antibodies that are capable of binding to brain tissue and observed specific binding of IgG to glial cells in a subgroup of patients. Using a proteomic approach focusing on membrane proteins, we identified the ATP-sensitive inward rectifying potassium channel KIR4.1 as the target of the IgG antibodies. We used a multifaceted validation strategy to confirm KIR4.1 as a target of the autoantibody response in multiple sclerosis and to show its potential pathogenicity in vivo. RESULTS Serum levels of antibodies to KIR4.1 were higher in persons with multiple sclerosis than in persons with other neurologic diseases and healthy donors (P<0.001 for both comparisons). We replicated this finding in two independent groups of persons with multiple sclerosis or other neurologic diseases (P<0.001 for both comparisons). Analysis of the combined data sets indicated the presence of serum antibodies to KIR4.1 in 186 of 397 persons with multiple sclerosis (46.9%), in 3 of 329 persons with other neurologic diseases (0.9%), and in none of the 59 healthy donors. These antibodies bound to the first extracellular loop of KIR4.1. Injection of KIR4.1 serum IgG into the cisternae magnae of mice led to a profound loss of KIR4.1 expression, altered expression of glial fibrillary acidic protein in astrocytes, and activation of the complement cascade at sites of KIR4.1 expression in the cerebellum. CONCLUSIONS KIR4.1 is a target of the autoantibody response in a subgroup of persons with multiple sclerosis. (Funded by the German Ministry for Education and Research and Deutsche Forschungsgemeinschaft.)
Th1 lymphocytes preferentially infiltrate into the spinal cord during EAE via a VLA-4–mediated mechanism while Th17 lymphocyte infiltration is dependent on LFA-1 expression.
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...
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.
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.
Semiconductor quantum dots (QDs) and their assemblies have shown potential research interest due to their size dependent optical and electronic properties. Laser irradiation of larger sized semiconductor nanoparticles (NPs) suspended into liquid media is an easy, quick, versatile, environmental friendly, and rapidly growing method for the synthesis of QDs through melting/vaporization and fragmentation mechanisms. Most of the available reports in this field are related to the laser induced modification of shape, size, and morphology of noble metal nanoparticles, while only few exist for semiconductors. Synthesis of selenium QDs using laser induced melting/vaporization of water suspended selenium NPs of larger size and studies of their irradiation time or size dependent optical properties are subjects of current investigation. The fundamental wavelength of a pulsed nanosecond Nd:YAG laser is used for the irradiation of water suspended 69 nm average sized NPs for different times of irradiation. UV−visible absorption, XRD, TEM, and PL spectroscopic methods are utilized for the characterization of as synthesized QDs and raw NPs. Size and hence optical properties of produced selenium QDs are found to be highly dependent on the time of irradiation. The size of the produced selenium QDs follows a second order exponential decay function of irradiation time, while the rate of size reduction, da/dt, is directly dependent on the diameter, a, of the instantaneous QDs, very similar to the radioactive decay model. Laser irradiation causes transformation of β-Se NPs of 69 nm diameter to α-Se QDs of different sizes depending on the time of irradiation. We have achieved a minimum 2.74 ± 2.32 nm diameter of selenium QDs for 15 min laser irradiation and reported that almost 3.75 ± 0.15 nm size may be the quantum confinement limit for Se QDs. Surface defect density of the selenium QDs increases, while defect/electron trap level energy decreases, with the time of laser irradiation.
Background: Antibodies targeting membrane proteins play an important role in various autoimmune diseases of the nervous system. So far, assays allowing proper analysis of such autoantibodies are largely missing. A serum autoantibody to aquaporin 4 (AQP4) is associated with neuromyelitis optica (NMO). Although several assays are able to detect this autoantibody, they do not allow determination of the biological activity of anti-AQP4 antibodies.Objective: To develop a bioassay for quantification and characterization of human anti-AQP4 antibodies.Design, Setting, and Participants: We developed a novel bioassay for quantification and characterization of human anti-AQP4 antibodies based on high-level expression of native AQP4 (nAQP4) protein on the surface of human astroglioma cells. The test was validated in 2 independent cohorts of patients with NMO spectrum disease.Results: We detected anti-nAQP4-IgG with a sensitivity of 57.9% and specificity of 100% in patients with NMO spectrum diseases, suggesting that our bioassay is at least as sensitive and specific as the gold-standard NMO-IgG assay. The anti-AQP4 antibodies belonged predominantly to the IgG1 isotype and bound with high affinity to the extracellular domain of nAQP4. Our data suggest that the autoantibody exerts pathological properties because nAQP4-IgGpositive sera induced cell death of nAQP4-expressing cells by antibody-dependent cellular natural killer cell cytotoxic effect and complement activation. Furthermore, nAQP4-IgG titers strongly correlated with in vitro cytotoxic effect. Conclusions:In NMO, this assay may help to unravel the biological function of anti-nAQP4-IgG. Our findings demonstrate the potential of bioassays to characterize biologically relevant antibodies in human autoimmune diseases.
In the present paper, ZnO nanoparticles (NPs) with particle size of 20–50 nm have been synthesized by hydrothermal method. UV-visible absorption spectra of ZnO nanoparticles show absorption edge at 372 nm, which is blue-shifted as compared to bulk ZnO. Photoluminescence (PL) and photoconductive device characteristics, including field response, light intensity response, rise and decay time response, and spectral response have been studied systematically. The photoluminescence spectra of these ZnO nanoparticles exhibited different emission peaks at 396 nm, 416 nm, 445 nm, 481 nm, and 524 nm. The photoconductivity spectra of ZnO nanoparticles are studied in the UV-visible spectral region (366–691 nm). In spectral response curve of ZnO NPs, the wavelength dependence of the photocurrent is very close to the absorption and photoluminescence spectra. The photo generated current, Ipc = (Itotal - Idark) and dark current Idc varies according to the power law with the applied field IpcαVr and with the intensity of illumination IpcαIL r, due to the defect related mechanism including both recombination centers and traps. The ZnO NPs is found to have deep trap of 0.96 eV, very close to green band emission. The photo and dark conductivities of ZnO NPs have been measured using thick film of powder without any binder.
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